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Sample records for pharmacokinetics biodistribution safety

  1. A novel paclitaxel microemulsion containing a reduced amount of Cremophor EL: pharmacokinetics, biodistribution, and in vivo antitumor efficacy and safety.

    PubMed

    Wang, Ying; Wu, Ke-Chun; Zhao, Bing-Xiang; Zhao, Xin; Wang, Xin; Chen, Su; Nie, Shu-Fang; Pan, Wei-San; Zhang, Xuan; Zhang, Qiang

    2011-01-01

    The purpose of this study was to prepare a novel paclitaxel (PTX) microemulsion containing a reduced amount of Cremophor EL (CrEL) which had similar pharmacokinetics and antitumor efficacy as the commercially available PTX injection, but a significantly reduced allergic effect due to the CrEL. The pharmacokinetics, biodistribution, in vivo antitumor activity and safety of PTX microemulsion was evaluated. The results of pharmacokinetic and distribution properties of PTX in the microemulsion were similar to those of the PTX injection. The antitumor efficacy of the PTX microemulsion in OVCRA-3 and A 549 tumor-bearing animals was similar to that of PTX injection. The PTX microemulsion did not cause haemolysis, erythrocyte agglutination or simulative reaction. The incidence and degree of allergic reactions exhibited by the PTX microemulsion group, with or without premedication, were significantly lower than those in the PTX injection group (P < .01). In conclusion, the PTX microemulsion had similar pharmacokinetics and anti-tumor efficacy to the PTX injection, but a significantly reduced allergic effect due to CrEL, indicating that the PTX microemulsion overcomes the disadvantages of the conventional PTX injection and is one way of avoiding the limitations of current injection product while providing suitable therapeutic efficacy.

  2. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic

    PubMed Central

    Richter, Maximilian; Yumul, Roma; Saydaminova, Kamola; Wang, Hongjie; Gough, Michael; Baldessari, Audrey; Cattaneo, Roberto; Lee, Frank; Wang, Chung-Huei Katherine; Jang, Haishan; Astier, Anne; Gopal, Ajay; Carter, Darrick; Lieber, André

    2016-01-01

    Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the

  3. Safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized monoclonal antibody BIWA 4 (Bivatuzumab) in patients with early-stage breast cancer.

    PubMed

    Koppe, Manuel; Schaijk, Frank van; Roos, Jan; Leeuwen, Paul van; Heider, Karl-Heinz; Kuthan, Hartmut; Bleichrodt, Robert

    2004-12-01

    The aim of this prospective study was to evaluate the safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized anti-CD44v6 monoclonal antibody (MAb( BIWA 4 (Bivatuzumab( in 9 patients with early-stage breast cancer. Radioimmunoscintigraphy (RIS( was performed within 1, 24, and 72 hours after administration. BIWA 4 concentration in plasma (ELISA and radioactivity measurements( and the development of human antihuman antibody (HAHA( responses was determined. The biodistribution of (186)Re-BIWA 4 was determined by radioactivity measurements in tumor and normal tissue biopsies obtained during surgery 1 week after administration. Administration of (186)Re-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. The mean t(1/2) in plasma of BIWA 4 (ELISA( was 81 hours (range, 67-97(, whereas the mean radioactivity t(1/2) tended to be longer, at 105 hours (range, 90-114(. RIS unmistakably showed the tumor in 3 patients. Less clear identifications were established in 3 additional patients. In 2 patients, the tumor was wrongly identified in the contralateral breast. Median tumor CD44v6 expression, as determined by immunohistochemistry, was 70% (range, 10-90%). Mean tumor uptake was 2.96% ID/kg (range, 0.92-6.27(, with no apparent correlation with either tumor CD44v6 expression, tumor-cell cellularity, or tumor diameter. Tumor-to-nontumor ratios were unfavorable for blood, bone marrow, mammary gland tissue, and skin. The (186)Re-labeled humanized MAb BIWA 4 can safely be administered to patients with early-stage breast cancer. Tumorto- nontumor ratios were unfavorable, with no apparent correlation with CD44v6 expression, tumor-cell cellularity, or tumor diameter. BIWA 4, therefore, appears to have limitations as a vehicle for radioimmunotherapy in patients with breast cancer.

  4. Pharmacokinetics and Biodistribution of the Illegal Food Colorant Rhodamine B in Rats.

    PubMed

    Cheng, Yung-Yi; Tsai, Tung-Hu

    2017-02-08

    The International Agency for Research on Cancer (IARC) demonstrated rhodamine B as a potential carcinogen in 1978. Nevertheless, rhodamine B has been illegally used as a colorant in food in many countries. Few pharmacokinetic and toxicological investigations have been performed since the first pharmacokinetic study on rhodamine B in 1961. The aims of this study were to develop a simple and sensitive high-performance liquid chromatography method with fluorescence detection for the quantitative detection of rhodamine B in the plasma and organs of rats and to estimate its pharmacokinetics and biodistribution. The results demonstrated that the oral bioavailabilities of rhodamine B were 28.3 and 9.8% for the low-dose and high-dose exposures, respectively. Furthermore, rhodamine B was highly accumulated in the liver and, to a lesser extent, the kidney, but was undetectable in the brain. These results provide useful information for improving the pharmacokinetics and biodistribution of rhodamine B, supporting additional food safety evaluations.

  5. Safety, biodistribution, pharmacokinetics, and immunogenicity of 99mTc-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with squamous cell carcinoma of the head and neck.

    PubMed

    Colnot, David R; Roos, Jan C; de Bree, Remco; Wilhelm, Abraham J; Kummer, J Alain; Hanft, Gertraud; Heider, Karl-Heinz; Stehle, Gerd; Snow, Gordon B; van Dongen, Guus A M S

    2003-09-01

    Previous studies have shown the potential of murine and chimeric anti-CD44v6 monoclonal antibodies (MAbs) for radioimmunotherapy (RIT) of head and neck squamous cell carcinoma (HNSCC). A limitation of these MAbs, however, appeared to be their immunogenicity. Therefore, humanized monoclonal antibody BIWA 4 (bivatuzumab), with an intermediate affinity for CD44v6, was recently selected. As a prelude to RIT, we evaluated the safety, tumor-targeting potential, pharmacokinetics, and immunogenicity of technetium-99m-labeled BIWA 4 in patients undergoing operations for primary HNSCC in this study. Ten patients were treated at BIWA 4 dose levels of 25 mg (n=3), 50 mg (n=4), and 100 mg (n=3). Patients received 2 mg of 750 MBq 99mTc-BIWA 4, together with 23-, 48-, and 98-mg unlabeled BIWA 4, respectively. Radioimmunoscintigraphy (RIS) was performed within 1 h and after 21 h, and patients underwent surgery at 48 h after injection. Biodistribution of 99mTc-BIWA 4 was evaluated by radioactivity measurements in blood, bone marrow, and in biopsies of a surgical specimen obtained 48 h after injection. BIWA 4 concentration in blood was assessed by ELISA and high performance liquid chromatography and related to soluble CD44v6 levels in serum samples. The development of human anti-human antibody (HAHA) responses was determined. Administration of 99mTc-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. A mean t1/2 in plasma of 54.8 +/- 11.5 h, 76.1 +/- 21.8 h, and 68.5 +/- 21.2 h was found for the 25-, 50-, and 100-mg dose group, respectively. No complex formation of BIWA 4 with soluble CD44v6 in blood was observed. RIS showed targeting of primary tumors and lymph node metastases in 8 of 10 and 1 of 5 patients, respectively. The highest tumor uptake and tumor to nontumor ratios were observed for the 50-mg dose group. Tumor uptake was 12.9 +/- 5.9, 26.2 +/- 3.1, and 15.4 +/- 1.9% of the injected dose (ID)/kg for the 25-, 50-, and 100-mg dose group

  6. Image Guided Biodistribution and Pharmacokinetic Studies of Theranostics

    PubMed Central

    Ding, Hong; Wu, Fang

    2012-01-01

    Image guided technique is playing an increasingly important role in the investigation of the biodistribution and pharmacokinetics of drugs or drug delivery systems in various diseases, especially cancers. Besides anatomical imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), molecular imaging strategy including optical imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) will facilitate the localization and quantization of radioisotope or optical probe labeled nanoparticle delivery systems in the category of theranostics. The quantitative measurement of the bio-distribution and pharmacokinetics of theranostics in the fields of new drug/probe development, diagnosis and treatment process monitoring as well as tracking the brain-blood-barrier (BBB) breaking through by high sensitive imaging method, and the applications of the representative imaging modalities are summarized in this review. PMID:23227121

  7. Determining the pharmacokinetics and long-term biodistribution of SiO2 nanoparticles in vivo using accelerator mass spectrometry.

    PubMed

    Malfatti, Michael A; Palko, Heather A; Kuhn, Edward A; Turteltaub, Kenneth W

    2012-11-14

    Biodistribution is an important factor in better understanding silica dioxide nanoparticle (SiNP) safety. Currently, comprehensive studies on biodistribution are lacking, most likely due to the lack of suitable analytical methods. Accelerator mass spectrometry was used to investigate the relationship between administered dose, pharmacokinetics (PK), and long-term biodistribution of (14)C-SiNPs in vivo. PK analysis showed that SiNPs were rapidly cleared from the central compartment, were distributed to tissues of the reticuloendothelial system, and persisted in the tissue over the 8 week time course, raising questions about the potential for bioaccumulation and associated long-term effects.

  8. Pharmacokinetics and biodistribution of surface modification polymeric nanoparticles.

    PubMed

    Liu, Mingxing; Li, Huifang; Luo, Guoan; Liu, Qingfei; Wang, Yiming

    2008-04-01

    The objective of this study is to investigate the pharmacokinetics and biodistribution of free breviscapine (BVP) and coated BVP-loaded poly (D, L-lactic acid) nanoparticles (BVP-PLA-NPs) in rats after i.v. administration. Coated BVP-PLA-NPs were prepared by the spontaneous emulsification solvent diffusion method and characterized. The BVP content in the NPs, the biological samples and in vitro release was measured by the high-performance liquid chromatography (HPLC). The mean sizes of coated BVP-PLA-NPs were 177 and 319 nm with a narrow distribution and smooth sphere shapes, entrapment efficiency of 86.9% and 93.1%, respectively. Drug release profiles in phosphate buffer and plasma exhibited a biphasic release phenomenon. After i.v. administration of free BVP and NPs suspensions in rats, area under plasma concentration-time curve and elimination t(1/2) were increased 9.3-fold and 10.9-fold for 177 nm of NPs, and 4.4-fold and 17.1-fold for 319 nm of NPs compared with that of free BVP, respectively. NPs were mainly distributed in liver, spleen, heart and brain. In addition, NPs could penetrate blood brain barrier (BBB) and the particle size had some effect on pharmacokinetics and biodistribution. Coated BVP-PLA-NPs could effectively avoid the capture by the reticuloendothelial system and prolong the half-life of BVP. Moreover, these NPs could penetrate BBB and enhance the accumulation of BVP in brain.

  9. A Phase 1 Study of 131I-CLR1404 in Patients with Relapsed or Refractory Advanced Solid Tumors: Dosimetry, Biodistribution, Pharmacokinetics, and Safety

    PubMed Central

    Grudzinski, Joseph J.; Titz, Benjamin; Kozak, Kevin; Clarke, William; Allen, Ernest; Trembath, LisaAnn; Stabin, Michael; Marshall, John; Cho, Steve Y.; Wong, Terence Z.; Mortimer, Joanne; Weichert, Jamey P.

    2014-01-01

    Introduction 131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of 131I-CLR1404. Methods Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of 131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15–35 minutes, 4–6, 18–24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on 127I-CLR1404 mass measurements. To evaluate renal clearance of 131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software. Results Single administrations of 370 MBq of 131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma 127I-CLR1404 concentrations declined in a bi-exponential manner with a mean t½ value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ng•hr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow. Conclusions Preliminary data suggest that 131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent. Trial Registration ClinicalTrials.gov NCT00925275 PMID:25402488

  10. Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice

    SciTech Connect

    Agrawal, S. ); Temsamani, J.; Jin Yan Tang )

    1991-09-01

    The authors describe preliminary studies of the pharmacokinetics, biodistribution, and excretion of an oligodeoxynucleotide phosphorothioate ((S)oligonucleotide) in mice. After either intravenous or intraperitoneal administration of a single dose (S)oligonucleotide ({sup 35}S-labeled at each internucleotide linkage) was found in most of the tissues for up to 48 hr. About 30% of the dose was excreted in urine within 24 hr, irrespective of the mode of administration; the excreted (S)oligonucleotide was found to be extensively degraded. In plasma, stomach, heart, and intestine, the (S)oligonucleotide was degraded by only 15%, whereas in the kidney and liver degradation was about 50% in 48 hr. The surprising observation was made that chain length extension of administered (S)oligonucleotide occurred in kidney, liver, and intestine. These results provide an initial definition of parameters for the pharmaceutical development of antisense oligonucleotides.

  11. Nanodrugs: pharmacokinetics and safety

    PubMed Central

    Onoue, Satomi; Yamada, Shizuo; Chan, Hak-Kim

    2014-01-01

    To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. PMID:24591825

  12. Pharmacokinetics and biodistribution of zinc-enriched yeast in rats.

    PubMed

    Zhang, Shuangqing; Zhang, Yan; Peng, Ning; Zhang, Haibo; Yao, Juan; Li, Zhihong; Liu, Liegang

    2014-01-01

    Zinc-enriched yeast (ZnY) and zinc sulfate (ZnSO4) are considered zinc (Zn) supplements currently available. The purpose of the investigation was to compare and evaluate pharmacokinetics and biodistribution of ZnY and ZnSO4 in rats. ZnY or ZnSO4 were orally administered to rats at a single dose of 4 mg Zn/kg and Zn levels in plasma and various tissues were determined using inductively coupled plasma-optical emission spectrometry. Maximum plasma concentration values were 3.87 and 2.81 μg/mL for ZnY and ZnSO4, respectively. Both ZnY and ZnSO4 were slowly eliminated with a half-life of over 7 h and bone had the highest Zn level in all tissues. Compared to ZnSO4, the relative bioavailability of ZnY was 138.4%, indicating that ZnY had a significantly higher bioavailability than ZnSO4.

  13. Pharmacokinetics and Biodistribution of Zinc-Enriched Yeast in Rats

    PubMed Central

    Zhang, Shuangqing; Zhang, Yan; Peng, Ning; Zhang, Haibo; Yao, Juan; Li, Zhihong; Liu, Liegang

    2014-01-01

    Zinc-enriched yeast (ZnY) and zinc sulfate (ZnSO4) are considered zinc (Zn) supplements currently available. The purpose of the investigation was to compare and evaluate pharmacokinetics and biodistribution of ZnY and ZnSO4 in rats. ZnY or ZnSO4 were orally administered to rats at a single dose of 4 mg Zn/kg and Zn levels in plasma and various tissues were determined using inductively coupled plasma-optical emission spectrometry. Maximum plasma concentration values were 3.87 and 2.81 μg/mL for ZnY and ZnSO4, respectively. Both ZnY and ZnSO4 were slowly eliminated with a half-life of over 7 h and bone had the highest Zn level in all tissues. Compared to ZnSO4, the relative bioavailability of ZnY was 138.4%, indicating that ZnY had a significantly higher bioavailability than ZnSO4. PMID:25215316

  14. Factors Controlling the Pharmacokinetics, Biodistribution and Intratumoral Penetration of Nanoparticles

    PubMed Central

    Ernsting, Mark J.; Murakami, Mami; Roy, Aniruddha; Li, Shyh-Dar

    2014-01-01

    Nanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided. PMID:24075927

  15. Preclinical acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]fluorocholine in mice.

    PubMed

    Silveira, Marina B; Ferreira, Soraya M Z M D; Nascimento, Leonardo T C; Costa, Flávia M; Mendes, Bruno M; Ferreira, Andrea V; Malamut, Carlos; Silva, Juliana B; Mamede, Marcelo

    2016-10-01

    [(18)F]Fluorocholine ([(18)F]FCH) has been proven to be effective in prostate cancer. Since [(18)F]FCH is classified as a new radiopharmaceutical in Brazil, preclinical safety and efficacy data are required to support clinical trials and to obtain its approval. The aim of this work was to perform acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]FCH. The results could support its use in nuclear medicine as an important piece of work for regulatory in Brazil.

  16. Docetaxel-loaded PLGA and PLGA-PEG nanoparticles for intravenous application: pharmacokinetics and biodistribution profile

    PubMed Central

    Rafiei, Pedram; Haddadi, Azita

    2017-01-01

    Docetaxel is a highly potent anticancer agent being used in a wide spectrum of cancer types. There are important matters of concern regarding the drug’s pharmacokinetics related to the conventional formulation. Poly(lactide-co-glycolide) (PLGA) is a biocompatible/biodegradable polymer with variable physicochemical characteristics, and its application in human has been approved by the United States Food and Drug Administration. PLGA gives polymeric nanoparticles with unique drug delivery characteristics. The application of PLGA nanoparticles (NPs) as intravenous (IV) sustained-release delivery vehicles for docetaxel can favorably modify pharmacokinetics, biofate, and pharmacotherapy of the drug in cancer patients. Surface modification of PLGA NPs with poly(ethylene glycol) (PEG) can further enhance NPs’ long-circulating properties. Herein, an optimized fabrication approach has been used for the preparation of PLGA and PLGA–PEG NPs loaded with docetaxel for IV application. Both types of NP formulations demonstrated in vitro characteristics that were considered suitable for IV administration (with long-circulating sustained-release purposes). NP formulations were IV administered to an animal model, and docetaxel’s pharmacokinetic and biodistribution profiles were determined and compared between study groups. PLGA and PEGylated PLGA NPs were able to modify the pharmacokinetics and biodistribution of docetaxel. Accordingly, the mode of changes made to pharmacokinetics and biodistribution of docetaxel is attributed to the size and surface properties of NPs. NPs contributed to increased blood residence time of docetaxel fulfilling their role as long-circulating sustained-release drug delivery systems. Surface modification of NPs contributed to more pronounced docetaxel blood concentration, which confirms the role of PEG in conferring long-circulation properties to NPs. PMID:28184163

  17. [Pharmacokinetics and biodistribution of 3H-norcantharidin in mice].

    PubMed

    Wei, Chun-Min; Wang, Ben-Jie; Ma, Ya; Sun, Zi-Ping; Li, Xiao-Li; Guo, Rui-Chen

    2007-05-01

    A single dose of 3H-norcantharidin solution was intragastrically given, blood, tissues, urine and feces were collected as scheduled, and radioactivity in these samples was determined by tritium tracing method to investigate the pharmacokinetics, tissue distribution and excretion of norcantharidin in Kunming mice. The pharmacokinetic characteristics of norcantharidin were evaluated by DAS version 2.0. The blood concentration reached to maximum 0. 5 h after intragastric administration. The radioactivity in tissues was high in small intestine, gallbladder, stomach, adrenal gland, kidney, heart and uterus 15 minutes after administration, descending with time, and high in gallbladder, adrenal gland and uterus 3 hours post dosing. The 24 h accumulative excretion ratio of urine and feces were 65.40% and 1.33% respectively. 3H-norcantharidin was easily absorbed after orally given to mice, the radioactivity was high and existed for a long-time in gallbladder, adrenal gland and uterus, and low but also existed for a long-time in large intestine, thymus and fat tissue. 3H-norcantharidin was declined quickly in small intestine, stomach, kidney and heart, and occurred rarely in brain. Norcantharidin was excreted mainly by urinary route and seldom in feces, which may be the cause of the urinary stimulation side effects observed. Because the radioactivity measured were the sum of 3H labeled norcantharidin and its metabolites, further studies on the disposition of norcantharidin in mammal animals, on the separation or identification of metabolites and, if any, on their activities, are fairly needed.

  18. Pharmacokinetic parameters and biodistribution of soluble cytokine receptors.

    PubMed

    Jacobs, C A; Beckmann, M P; Mohler, K; Maliszewski, C R; Fanslow, W C; Lynch, D H

    1993-01-01

    The potential use of soluble cytokine receptors as therapeutics in disease states when excessive or prolonged cytokine expression leads to pathogenesis is just beginning (Van Brunt, 1989). The inhibitory effects of soluble receptors have been found to be highly potent and specific for their respective cytokines (Maliszewski and Fanslow, 1990; Maliszewski et al., 1990). Recent in vivo data have shown that exogenously administered soluble receptors can function as cytokine antagonists and suppress autoimmune inflammatory responses (Jacobs et al., 1991a), allograft rejection, and alloreactivity (Fanslow et al., 1990b). The proposed frequency of administration and dosage of a therapeutic agent is dependent on the half-life of the agent and the route of administration. The elimination or half-life of a drug usually depends on its physiochemical properties (molecular size, glycosylation, isoelectric point, and hydrophobic/hydrophilic properties) (DiPalma and DiGregorio, 1990; Katzung, 1984). The half-life will also depend on the mechanism of clearance for that specific receptor. Once pharmacokinetic data are available for soluble receptors, the therapeutic potential of these molecules can be better evaluated. Only limited pharmacokinetic data are currently available for soluble cytokine receptors (Jacobs et al., 1991b). For sIL-1R, the majority of an intravenously administered dose was cleared in the second elimination phase, with a reasonably long half-life (6.3 hr), such that the entire dose was not eliminated until 35 hr. If administration is by subcutaneous injection, the half-life was even more prolonged. One explanation for the prolonged half-life is the minimal distribution to liver and kidneys and thus low levels of clearance by these organs. In contrast, elimination of intravenously administered sIL-4R was relatively rapid, with a short half-life (2.3 hr). This appeared mainly due to liver distribution and clearance, which has been the highest observed for any

  19. Pharmacokinetic, pharmacodynamic and biodistribution following oral administration of nanocarriers containing peptide and protein drugs.

    PubMed

    Griffin, Brendan T; Guo, Jianfeng; Presas, Elena; Donovan, Maria D; Alonso, María J; O'Driscoll, Caitriona M

    2016-11-15

    The influence of nanoparticle (NP) formulations on the pharmacokinetic, pharmacodynamic and biodistribution profiles of peptide- and protein-like drugs following oral administration is critically reviewed. The possible mechanisms of absorption enhancement and the effects of the physicochemical properties of the NP are examined. The potential advantages and challenges of physiologically-based pharmacokinetic (PBPK) modelling to help predict efficacy in man are discussed. The importance of developing and expanding the regulatory framework to help translate the technology into the clinic and accelerate the availability of oral nanoparticulate formulations is emphasized. In conclusion, opportunities for future work to improve the state of the art of oral nanomedicines are identified. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Biodistribution and pharmacokinetics of uniform magnetite nanoparticles chemically modified with polyethylene glycol.

    PubMed

    Ruiz, A; Hernández, Y; Cabal, C; González, E; Veintemillas-Verdaguer, S; Martínez, E; Morales, M P

    2013-12-07

    The influence of polyethylene glycol (PEG) grafting on the pharmacokinetics, biodistribution and elimination of iron oxide nanoparticles is studied in this work. Magnetite nanoparticles (12 nm) were obtained via thermal decomposition of an iron coordination complex as a precursor. Particles were coated with meso-2,3-dimercaptosuccinic acid (DMSA) and conjugated to PEG-derived molecules by 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC) chemistry. Using a rat model, we explored the nanoparticle biodistribution pattern in blood and in different organs (liver, spleen and lungs) after intravenous administration of the product. The time of residence in blood was measured from the evolution of water proton relaxivities with time and Fe analysis in blood samples. The results showed that the residence time was doubled for PEG coated nanoparticles and consequently particle accumulation in liver and spleen was reduced. Post-mortem histological analyses showed no alterations in the liver and confirm heterogeneous distribution of NPs in the organ, in agreement with magnetic measurements and iron analysis. Finally, by successive magnetic resonance images we studied the evolution of contrast in the liver and measured the absorption, time of residence and excretion of nanoparticles in the liver during a one month period. On the basis of these results we propose different metabolic routes that determine the fate of magnetic nanoparticles.

  1. In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles

    PubMed Central

    Arami, Hamed; Khandhar, Amit; Liggitt, Denny; Krishnan, Kannan M.

    2015-01-01

    Iron oxide nanoparticles (IONPs) have been extensively used during the last two decades, either as effective bio-imaging contrast agents or as carriers of biomolecules such as drugs, nucleic acids and peptides for controlled delivery to specific organs and tissues. Most of these novel applications require elaborate tuning of the physiochemical and surface properties of the IONPs. As new IONPs designs are envisioned, synergistic consideration of the body's innate biological barriers against the administered nanoparticles and the short and long-term side effects of the IONPs become even more essential. There are several important criteria (e.g. size and size-distribution, charge, coating molecules, and plasma protein adsorption) that can be effectively tuned to control the in vivo pharmacokinetics and biodistribution of the IONPs. This paper reviews these crucial parameters, in light of biological barriers in the body, and the latest IONPs design strategies used to overcome them. A careful review of the long-term biodistribution and side effects of the IONPs in relation to nanoparticle design is also given. While the discussions presented in this review are specific to IONPs, some of the information can be readily applied to other nanoparticle systems, such as gold, silver, silica, calcium phosphates and various polymers. PMID:26390044

  2. Biodistribution and pharmacokinetics of uniform magnetite nanoparticles chemically modified with polyethylene glycol

    NASA Astrophysics Data System (ADS)

    Ruiz, A.; Hernández, Y.; Cabal, C.; González, E.; Veintemillas-Verdaguer, S.; Martínez, E.; Morales, M. P.

    2013-11-01

    The influence of polyethylene glycol (PEG) grafting on the pharmacokinetics, biodistribution and elimination of iron oxide nanoparticles is studied in this work. Magnetite nanoparticles (12 nm) were obtained via thermal decomposition of an iron coordination complex as a precursor. Particles were coated with meso-2,3-dimercaptosuccinic acid (DMSA) and conjugated to PEG-derived molecules by 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC) chemistry. Using a rat model, we explored the nanoparticle biodistribution pattern in blood and in different organs (liver, spleen and lungs) after intravenous administration of the product. The time of residence in blood was measured from the evolution of water proton relaxivities with time and Fe analysis in blood samples. The results showed that the residence time was doubled for PEG coated nanoparticles and consequently particle accumulation in liver and spleen was reduced. Post-mortem histological analyses showed no alterations in the liver and confirm heterogeneous distribution of NPs in the organ, in agreement with magnetic measurements and iron analysis. Finally, by successive magnetic resonance images we studied the evolution of contrast in the liver and measured the absorption, time of residence and excretion of nanoparticles in the liver during a one month period. On the basis of these results we propose different metabolic routes that determine the fate of magnetic nanoparticles.

  3. Pharmacokinetics, biodistribution and antitumour effects of Sclerotium rolfsii lectin in mice.

    PubMed

    Anupama, S; Laha, Preeti; Sharma, Mamta; Pathak, Kamal; Bane, Sanjay; Ingle, Arvind D; Gota, Vikram; Kalraiya, Rajiv D; Yu, Lu-Gang; Rhodes, Jonathan M; Swamy, Bale M; Inamdar, Shashikala R

    2017-04-03

    Sclerotium rolfsii lectin (SRL) is a lectin isolated from the fungus Sclerotium rolfsii and has exquisite binding specificity towards the oncofetal Thomsen-Friedenreich antigen (TF-Ag; Galβ1-3GalNAcα-O-Ser/Thr) and its derivatives. Previous studies have shown that SRL inhibits the proliferation of human colon, breast and ovarian cancer cells in vitro and suppresses tumour growth in mice when introduced intratumourally. The present study assessed the effect of SRL on tumour growth when introduced intraperitoneally in BALB/c nude mice and investigated the pharmacokinetics and biodistribution of SRL in Swiss albino mice. When 9 doses of SRL (30 mg/kg body weight/mice) was administered to BALB/c nude mice bearing human colon cancer HT-29 xenografts, a substantial reduction in tumour size was observed. A 35.8% reduction in tumour size was noted in the treated animals after 17 days. SRL treatment also inhibited angiogenesis, and the tumours from the treated animals were observed to carry fewer blood vessels and express less angiogenesis marker protein CD31, than that from the control animals. Pharmacokinetics and biodistribution analysis revealed that SRL was detected in the serum after 1 h and its level peaked after 24 h. SRL was not detected in any of the organs apart from the kidney where a trace amount was detected after 24 h of SRL injection. No significant changes were observed in any of the biochemical parameters tested including SGOT, SGPT, LDH, CREAT and BUN in the SRL-treated mice compared to these levels in the controls. This suggests that SRL has good potential to be developed as a therapeutic agent for cancer treatment and warrant further investigations in vivo and subsequent clinical trials.

  4. DETERMINING THE PHARMACOKINETICS AND LONG-TERM BIODISTRIBUTION OF SiO2 NANOPARTICLES IN VIVO USING ACCELERATOR MASS SPECTROMETRY

    PubMed Central

    Malfatti, Michael A.; Palko, Heather A.; Kuhn, Edward A.; Turteltaub, Kenneth W.

    2012-01-01

    Biodistribution is an important factor in better understanding silica dioxide nanoparticle (SiNP) safety. Currently, comprehensive studies on biodistribution are lacking, most likely due to the lack of suitable analytical methods. Accelerator mass spectrometry (AMS) was used to investigate the relationship between administered dose, PK, and long-term biodistribution of 14C-SiNPs in vivo. PK analysis showed that SiNPs were rapidly cleared from the central compartment, were distributed to tissues of the reticuloendothelial system, and persisted in the tissue over the 8-week time course, raising questions about the potential for bioaccumulation and associated long-term effects. PMID:23075393

  5. Alterations in favipiravir (T-705) pharmacokinetics and biodistribution in a hamster model of viral hemorrhagic fever

    PubMed Central

    Gowen, Brian B.; Sefing, Eric J.; Westover, Jonna B.; Smee, Donald F.; Hagloch, Joseph; Furuta, Yousuke; Hall, Jeffery O.

    2015-01-01

    Favipiravir (T-705) is a new anti-influenza drug approved for human use in Japan and progressing through Phase 3 clinical trials in the U.S. In addition to its potent inhibitory effects against influenza virus infection, the compound has been shown to be broadly active against RNA viruses from 9 different families, including the Arenaviridae. Several members of the Arenaviridae family of viruses are significant human pathogens that cause viral hemorrhagic fever, a severe systemic syndrome where vascular leak is a cardinal feature. Because arenaviral infections are unlikely to be diagnosed and treated until the illness has progressed to a more advanced state, it is important to understand the effects of the disease state on favipiravir pharmacokinetics (PK) and biodistribution to help guide therapeutic strategy. During acute arenavirus infection in hamsters, we found reduced plasma favipiravir concentrations and altered kinetics of absorption, elimination and time to maximum drug concentration. In addition, the amounts of the favipiravir M1 primary metabolite were higher in the infected animals, suggesting that favipiravir metabolism may favor the formation of this inactive metabolite during viral infection. We also discovered differences in favipiravir and M1 PK parameters associated with arenavirus infection in a number of hamster tissues. Finally, analysis at the individual animal level demonstrated a correlation between reduced plasma favipiravir concentration with increased disease burden as reflected by weight loss and viral load. Our study is the first to show the impact of active viral infection and disease on favipiravir PK and biodistribution, highlighting the need to consider alterations in these parameters when treating individuals with viral hemorrhagic fever of arenavirus or other etiology. PMID:26186980

  6. Alterations in favipiravir (T-705) pharmacokinetics and biodistribution in a hamster model of viral hemorrhagic fever.

    PubMed

    Gowen, Brian B; Sefing, Eric J; Westover, Jonna B; Smee, Donald F; Hagloch, Joseph; Furuta, Yousuke; Hall, Jeffery O

    2015-09-01

    Favipiravir (T-705) is a new anti-influenza drug approved for human use in Japan and progressing through Phase 3 clinical trials in the U.S. In addition to its potent inhibitory effects against influenza virus infection, the compound has been shown to be broadly active against RNA viruses from 9 different families, including the Arenaviridae. Several members of the Arenaviridae family of viruses are significant human pathogens that cause viral hemorrhagic fever, a severe systemic syndrome where vascular leak is a cardinal feature. Because arenaviral infections are unlikely to be diagnosed and treated until the illness has progressed to a more advanced state, it is important to understand the effects of the disease state on favipiravir pharmacokinetics (PK) and biodistribution to help guide therapeutic strategy. During acute arenavirus infection in hamsters, we found reduced plasma favipiravir concentrations and altered kinetics of absorption, elimination and time to maximum drug concentration. In addition, the amounts of the favipiravir M1 primary metabolite were higher in the infected animals, suggesting that favipiravir metabolism may favor the formation of this inactive metabolite during viral infection. We also discovered differences in favipiravir and M1 PK parameters associated with arenavirus infection in a number of hamster tissues. Finally, analysis at the individual animal level demonstrated a correlation between reduced plasma favipiravir concentration with increased disease burden as reflected by weight loss and viral load. Our study is the first to show the impact of active viral infection and disease on favipiravir PK and biodistribution, highlighting the need to consider alterations in these parameters when treating individuals with viral hemorrhagic fever of arenavirus or other etiology.

  7. Pharmacokinetics, biodistribution and metabolism of a novel selective androgen receptor modulator designed for prostate cancer imaging.

    PubMed

    Yang, Jun; Wu, Zengru; Wu, Di; Darby, Michael V; Hong, Seoung Soo; Miller, Duane D; Dalton, James T

    2010-01-01

    Knowledge of the presence and extent of disease plays a major role in clinical management of prostate cancer, as it provides meaningful information as to which therapy to choose and who might benefit from this therapy. The wide expression of androgen receptor (AR) in primary and metastatic prostate tumors offers a cellular target for receptor-mediated imaging of prostate cancer. In our previous study, a non-steroidal AR ligand, S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide] showed promising in vitro pharmacological properties as an AR-mediated imaging agent, with high AR binding affinity and AR specificity. The overall goal of this study was to characterize the in vivo metabolic and biodistribution profile of S-26 in rats. Non-compartmental pharmacokinetic analysis of S-26 in rat plasma showed that clearance (CL), volume of distribution (Vd(ss)), and half-life (T(1/2)) of S-26 were 0.30 + or - 0.07 l/h/kg, 1.44 + or - 0.33 l/kg, and 4 h, respectively, after intravenous (i.v.) administration. Dose proportionality (1, 10 and 30 mg/kg) studies suggested that the pharmacokinetics of S-26 are dose-independent. The plasma concentrations of all 3 doses were further simultaneously fitted with a two-compartmental model and the results were similar to those obtained from non-compartmental analysis. Biodistribution studies using (125)I-labeled S-26 indicated that it did not specifically target AR-rich tissue (e.g. prostate). A substantial amount of radioactivity recovered from thyroid gland indicated the release of free iodine. In metabolism studies, unchanged S-26 and its metabolites were detected in rat urine and fecal samples. Oxidation, de-iodination, hydrolysis, and sulfate conjugation were the major metabolic pathways of S-26 in rats, with de-iodination representing a unique metabolic pathway of S-26 among other selective androgen receptor modulators. In conclusion, the extensive plasma clearance and de-iodination of S-26 likely

  8. Pharmacokinetics and biodistribution of the cyclin-dependent kinase inhibitor -CR8- in mice

    PubMed Central

    2013-01-01

    Background CR8 is a second generation inhibitor of cyclin-dependent kinases derived from roscovitine. CR8 was shown to be 50–100 fold more potent than roscovitine in inducing apoptosis in different tumor cell lines. In the present investigation, we have established an analytical method for the quantification of CR8 in biological samples and evaluated its bioavailability, biodistribution and pharmacokinetics in mice. Methods A liquid chromatography method utilizing UV-detection was used for the determination of CR8. CR8 was administered either orally (100 mg/kg) or i.v. (50 mg/kg) and the animals were sacrificed at different time points. Blood samples and organs were collected, after which the pharmacokinetic parameters were calculated for plasma and organs. Results CR8 was eluted at 5 minutes in the high performance liquid chromatography system used. The LLOQ detection was 0.10 μg/ml and linearity was observed within the 0.10-10 μg/ml range (r2 > 0.998). The accuracy and precision were >86%, while the recovery from plasma was >95%. CR8 was stable for 2 months at room temperature in both solution and plasma. CR8 pharmacokinetics was fitted to a two-compartment open model after oral administration and to a one compartment model after i.v. injection. The elimination half-life was about 3 hours. Organ exposure to CR8 (expressed as % AUC organ vs. AUC plasma) was highest in liver (205%), adipose tissue (188%) and kidney (150%) and low in bone marrow (30%) and brain (15%) as compared to plasma. The oral bioavailability of CR8 was found to be essentially 100%. Conclusions We have developed a rapid and simple method for the analysis of CR8. CR8 pharmacokinetics pattern showed 100% bioavailability, long half-life and limited distribution to brain and bone marrow, which may allow systemic exposure higher than the IC50 reported for cell death in tumor cell lines. CR8 displays favorable pharmacological properties and is therefore a good candidate for future

  9. Efficacy, pharmacokinetics, and biodistribution of thermosensitive chitosan/β-glycerophosphate hydrogel loaded with docetaxel.

    PubMed

    Li, Cuiyun; Ren, Shuangxia; Dai, Yu; Tian, Fengjie; Wang, Xin; Zhou, Sufeng; Deng, Shuhua; Liu, Qi; Zhao, Jie; Chen, Xijing

    2014-04-01

    Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/β-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development.

  10. Gemcitabine-loaded PEGylated unilamellar liposomes vs GEMZAR: biodistribution, pharmacokinetic features and in vivo antitumor activity.

    PubMed

    Paolino, Donatella; Cosco, Donato; Racanicchi, Leda; Trapasso, Elena; Celia, Christian; Iannone, Michelangelo; Puxeddu, Efisio; Costante, Giuseppe; Filetti, Sebastiano; Russo, Diego; Fresta, Massimo

    2010-06-01

    The systemic efficacy of the chemotherapeutic agents presently used to treat solid tumors is limited by their low therapeutic index. Previously, our research group improved the in vitro antitumoral activity of gemcitabine, an anticancer agent rapidly deaminated to the inactive metabolite 2',2'-difluorodeoxyuridine, entrapping it into unilamellar pegylated liposomes made up of 1,2-dipalmitoyl-snglycero-3-phosphocholine monohydrate/cholesterol/N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (6:3:1 molar ratio). In this work, we investigated the in vivo efficiency of the gemcitabine liposomal formulation (5mg/kg) with respect to the antitumoral commercial product GEMZAR (50mg/kg) on an anaplastic thyroid carcinoma xenograft model obtaining similar effects in terms of inhibition of tumor mass proliferation after 4weeks of treatment. The investigation of the carrier biodistribution and the drug pharmacokinetic profile furnished the rationalization of the efficacy of the vesicular system containing the active compound 10-fold less concentrated; in fact, liposomes promoted the concentration of the drug inside the tumor and they increased its plasmatic half-life. In addition, no signs of blood toxicity were observed when vesicular devices of effective doses of the drug were used.

  11. Nano-encapsulation of plitidepsin: in vivo pharmacokinetics, biodistribution, and efficacy in a renal xenograft tumor model.

    PubMed

    Oliveira, Hugo; Thevenot, Julie; Garanger, Elisabeth; Ibarboure, Emmanuel; Calvo, Pilar; Aviles, Pablo; Guillen, Maria Jose; Lecommandoux, Sébastien

    2014-04-01

    Plitidepsin is an antineoplasic currently in clinical evaluation in a phase III trial in multiple myeloma (ADMYRE). Presently, the hydrophobic drug plitidepsin is formulated using Cremophor®, an adjuvant associated with unwanted hypersensitivity reactions. In search of alternatives, we developed and tested two nanoparticle-based formulations of plitidepsin, aiming to modify/improve drug biodistribution and efficacy. Using nanoprecipitation, plitidepsin was loaded in polymer nanoparticles made of amphiphilic block copolymers (i.e. PEG-b-PBLG or PTMC-b-PGA). The pharmacokinetics, biodistribution and therapeutic efficacy was assessed using a xenograft renal cancer mouse model (MRI-H-121 xenograft) upon administration of the different plitidepsin formulations at maximum tolerated multiple doses (0.20 and 0.25 mg/kg for Cremophor® and copolymer formulations, respectively). High plitidepsin loading efficiencies were obtained for both copolymer formulations. Considering pharmacokinetics, PEG-b-PBLG formulation showed lower plasma clearance, associated with higher AUC and Cmax than Cremophor® or PTMC-b-PGA formulations. Additionally, the PEG-b-PBLG formulation presented lower liver and kidney accumulation compared with the other two formulations, associated with an equivalent tumor distribution. Regarding the anticancer activity, all formulations elicited similar efficacy profiles, as compared to the Cremophor® formulation, successfully reducing tumor growth rate. Although the nanoparticle formulations present equivalent anticancer activity, compared to the Cremophor® formulation, they show improved biodistribution profiles, presenting novel tools for future plitidepsin-based therapies.

  12. Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer

    PubMed Central

    Xiao, Wenwu; Luo, Juntao; Jain, Teesta; Riggs, John W; Tseng, Harry P; Henderson, Paul T; Cherry, Simon R; Rowland, Douglas; Lam, Kit S

    2012-01-01

    Background A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel. Methods The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively. Results The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol. Conclusion Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications. PMID:22605931

  13. The clinical safety, biodistribution and internal radiation dosimetry of flutemetamol (¹⁸F) injection in healthy Japanese adult volunteers.

    PubMed

    Senda, Michio; Brooks, David J; Farrar, Gill; Somer, Edward J; Paterson, Carolyn L; Sasaki, Masahiro; McParland, Brian J

    2015-08-01

    The Phase I safety, biodistribution and internal radiation dosimetry study in adult healthy Japanese males of flutemetamol ((18)F) injection, an in vivo β-amyloid imaging agent, is reported and compared with previously obtained Caucasian data. Whole-body PET scans of 6 healthy volunteers (age 51.8-61.7 years) were acquired approximately 4 h post-injection (administered activity 102-160 MBq). Venous blood sampling determined (18)F activity concentrations in whole blood and plasma and high-performance liquid chromatography (HPLC) established the percentages of parent [(18)F]flutemetamol and its metabolites. Voided urine activity was recorded. The decay-corrected and normalised (18)F activity of 14 source organ regions as a function of time was entered into the OLINDA/EXM software to calculate the internal radiation dosimetry and effective dose of each subject following the MIRD schema. The pharmacokinetics, biodistribution and dosimetry profiles were compared to data obtained from a cohort of healthy Caucasian adult volunteers from a previous Phase I study of [(18)F]flutemetamol. Flutemetamol ((18)F) injection was well tolerated. The highest mean initial uptakes were measured in the liver (15.2%), lungs (10.2%) and brain (6.6%). The highest mean radiation absorbed doses were received by the gallbladder wall (366 μGy/MBq), upper large intestine (138 μGy/MBq) and small intestine (121 μGy/MBq). The mean effective dose was 34.9 μSv/MBq. HPLC analysis demonstrated that at 5-min post-injection about 75% of plasma (18)F radioactivity was in the form of parent [(18)F]flutemetamol, reducing to 8 and 2% at 25 and 90 min, respectively, giving rise to less lipophilic (18)F-labelled metabolites. Comparisons with the Caucasian cohort showed no differences that could be regarded as clinically significant. The clinical safety of [(18)F]flutemetamol demonstrated no differences of clinical significance in the pharmacokinetics, biodistribution and internal radiation dosimetry

  14. Biodistribution and Pharmacokinetic Studies of Bone-Targeting N-(2-Hydroxypropyl)methacrylamide Copolymer–Alendronate Conjugates

    PubMed Central

    Pan, Huaizhong; Sima, Monika; Kopečková, Pavla; Wu, Kuangshi; Gao, Songqi; Liu, Jihua; Wang, Dong; Miller, Scott C.; Kopeček, Jindřich

    2015-01-01

    The biodistribution and pharmacokinetics of bone-targeting N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer–alendronate conjugates were evaluated following intravenous administration of radioiodinated conjugates to young healthy BALB/c mice. The synthesis of a polymerizable and cathepsin K cleavable alendronate derivative, N-methacryloylglycylglycylprolylnorleucylalendronate, enabled the preparation of HPMA copolymer–alendronate conjugates with varying composition. Using the RAFT (reversible addition–fragmentation chain transfer) polymerization technique, four conjugates with different molecular weight and alendronate content and two control HPMA copolymers (without alendronate) with different molecular weight were prepared. The results of biodistribution studies in mice demonstrated a strong binding capacity of alendronate-targeted HPMA copolymer conjugates to bone. Conjugates with low (1.5 mol%) alendronate content exhibited a similar bone deposition capacity as conjugates containing 8.5 mol % of alendronate. The molecular weight was an important factor in the biodistribution of the HPMA copolymer conjugates. More conjugate structures need to be evaluated, but the data suggest that medium molecular weights (50–100 kDa) might be effective drug carriers for bone delivery. PMID:18505266

  15. Biodistribution and pharmacokinetic studies of bone-targeting N-(2-hydroxypropyl)methacrylamide copolymer-alendronate conjugates.

    PubMed

    Pan, Huaizhong; Sima, Monika; Kopecková, Pavla; Wu, Kuangshi; Gao, Songqi; Liu, Jihua; Wang, Dong; Miller, Scott C; Kopecek, Jindrich

    2008-01-01

    The biodistribution and pharmacokinetics of bone-targeting N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-alendronate conjugates were evaluated following intravenous administration of radioiodinated conjugates to young healthy BALB/c mice. The synthesis of a polymerizable and cathepsin K cleavable alendronate derivative, N-methacryloylglycylglycylprolylnorleucylalendronate, enabled the preparation of HPMA copolymer-alendronate conjugates with varying composition. Using the RAFT (reversible addition-fragmentation chain transfer) polymerization technique, four conjugates with different molecular weight and alendronate content and two control HPMA copolymers (without alendronate) with different molecular weight were prepared. The results of biodistribution studies in mice demonstrated a strong binding capacity of alendronate-targeted HPMA copolymer conjugates to bone. Conjugates with low (1.5 mol%) alendronate content exhibited a similar bone deposition capacity as conjugates containing 8.5 mol % of alendronate. The molecular weight was an important factor in the biodistribution of the HPMA copolymer conjugates. More conjugate structures need to be evaluated, but the data suggest that medium molecular weights (50-100 kDa) might be effective drug carriers for bone delivery.

  16. Pharmacokinetics, biodistribution, stability and toxicity of a cell-penetrating peptide-morpholino oligomer conjugate.

    PubMed

    Amantana, Adams; Moulton, Hong M; Cate, Melissa L; Reddy, Muralimohan T; Whitehead, Tom; Hassinger, Jed N; Youngblood, Derek S; Iversen, Patrick L

    2007-01-01

    Conjugation of arginine-rich cell-penetrating peptide (CPP) to phosphorodiamidate morpholino oligomers (PMO) has been shown to enhance cytosolic and nuclear delivery of PMO. However, the in vivo disposition of CPP-PMO is largely unknown. In this study, we investigated the pharmacokinetics, tissue distribution, stability, and safety profile of an anti-c-myc PMO conjugated to the CPP, (RXR)4 (X = 6-aminohexanoic acid) in rats. The PMO and CPP-PMO were administrated intravenously into rats. The concentrations of the PMO and the CPP-PMO in plasma and tissues were monitored by HPLC. The stability of the CPP portion of the CPP-PMO conjugate in rat plasma and tissue lysates was determined by mass spectrometry. The safety profile of the CPP-PMO was assessed by body weight changes, serum chemistry, and animal behavior. CPP conjugation improved the kinetic behavior of PMO with a 2-fold increase in the estimated elimination half-life, a 4-fold increase in volume of distribution, and increased area under the plasma concentration vs time curve. Consistent with the improved pharmacokinetic profile, conjugation to CPP increased the uptake of PMO in all tissues except brain, varied between organ type with greater uptake enhancement occurring in liver, spleen, and lungs. The CPP-PMO conjugate had greater tissue retention than the corresponding PMO. Mass spectrometry data indicated no observable degradation of the PMO portion, while there was identifiable degradation of the CPP portion. Time-dependent CPP degradation was observed in plasma and tissue lysates, with the degradation in plasma being more rapid. The pattern of degraded products differed between the plasma and lysates. Safety evaluation data showed that the CPP-PMO was well-tolerated at the dose of 15 mg/kg with no apparent signs of toxicity. In contrast, at the dose of 150 mg/kg, adverse events such as lethargy, weight loss, and elevated BUN (p < 0.01) and serum creatinine (p < 0.001) levels were recorded

  17. Pharmacokinetics, Metabolism and Partial Biodistribution of 'Pincer Therapeutic' Nitazoxanide in Mice Following Pulmonary Delivery of Inhalable Particl.

    PubMed

    Gupta, Anuradha; Tulsankar, Sachin L; Bhatta, Rabi S; Misra, Amit

    2017-03-06

    Nitazoxanide (NTZ) induces autophagy in mammalian cells and also has mycobactericidal activity, displaying a two-pronged therapeutic effect-- on the host as well as the pathogen. The pharmacokinetics and biodistribution of inhaled NTZ were investigated. Particles containing NTZ in a matrix of PLGA were prepared by spray drying. HPLC and LC-MS/MS methods were developed and validated. Particles were administered as inhalations to mice. Drug concentrations in plasma and tissues were estimated at different time points. Drug loading (~36%), entrapment efficiency (>90%) and the conversion of NTZ into metabolites in plasma and lung homogenates were assessed satisfactorily by HPLC. NTZ pharmacokinetics and biodistribution following intravenous administration or inhalation were established by LC-MS. NTZ converted in to TZX (99% in 30 min) and other metabolites. Pulmonary delivery of NTZ entrapped in particles increased the half-life of the drug by factors of 3, 12 and 200 in the plasma, lung tissue and alveolar macrophages respectively. Targeted delivery and prolonged lung retention along with dose sparing of the liver and kidneys was observed upon pulmonary delivery as compared to intravenous administration.

  18. Biodistribution, pharmacokinetics, and blood compatibility of native and PEGylated tobacco mosaic virus nano-rods and -spheres in mice

    PubMed Central

    Bruckman, Michael A.; Randolph, Lauren N.; VanMeter, Allen; Hern, Stephen; Shoffstall, Andrew J.; Taurog, Rebecca E.; Steinmetz, Nicole F.

    2014-01-01

    Understanding the pharmacokinetics, blood compatibility, biodistribution and clearance properties of nanoparticles is of great importance to their translation to clinical application. In this paper we report the biodistribution and pharmacokinetic properties of tobacco mosaic virus (TMV) in the forms of 300×18 nm rods and 54 nm-sized spheres. The availability of rods and spheres made of the same protein provides a unique scaffold to study the effect of nanoparticle shape on in vivo fate. For enhanced biocompatibility, we also considered a PEGylated formulation. Overall, the versions of nanoparticles exhibited comparable in vivo profiles; a few differences were noted: data indicate that rods circulate longer than spheres, illustrating the effect that shape plays on circulation. Also, PEGylation increased circulation times. We found that macrophages in the liver and spleen cleared the TMV rods and spheres from circulation. In the spleen, the viral nanoparticles trafficked through the marginal zone before eventually co-localizing in B-cell follicles. TMV rods and spheres were cleared from the liver and spleen within days with no apparent changes in histology, it was noted that spheres are more rapidly cleared from tissues compared to rods. Further, blood biocompatibility was supported, as none of the formulations induced clotting or hemolysis. This work lays the foundation for further application and tailoring of TMV for biomedical applications. PMID:24418549

  19. Preparation, characterization, in vivo pharmacokinetics, and biodistribution of polymeric micellar dimethoxycurcumin for tumor targeting

    PubMed Central

    Liu, Hui; Xu, Hui; Jiang, Yunxia; Hao, Shengyuan; Gong, Feirong; Mu, Hongjie; Liu, Ke

    2015-01-01

    Dimethoxycurcumin (DMC) is an analog of curcumin with superior efficacy in various disease models. Currently, drug delivery system research on DMC is very limited, and it has become a huge challenge to realize further developments and clinical applications. In the present study, a kind of amphiphilic block copolymer, N-t-butoxycarbonyl-phenylalanine terminated monomethoxyl poly (ethylene glycol)-b-poly (ε-caprolactone), or mPEG-PCL-Phe(Boc), was prepared from monomethoxyl poly (ethylene glycol)-b-poly (ε-caprolactone) (mPEG-PCL) with its hydroxyl terminal chemically converted into N-t-butoxycarbonyl-phenylalanine (Boc-Phe). This copolymer was determined to have a fairly low critical micelle concentration (2.56×10−3 mg/mL) and passive targeting potential to tumor tissue, and thus was applied to develop a polymeric micellar formulation of DMC for the first time. The DMC-loaded micelles prepared by thin-film hydration method had typical shell–core structure, with an average particle size of 17.9±0.4 nm and a polydispersity index of 0.045±0.011. The drug loading capacity and entrapment efficiency were 9.94%±0.15% and 97.22%±0.18%, respectively, indicating a high-affinity interaction between DMC and the copolymer. At a concentration of 2 mg/mL, the reconstituted micelle solution could be maintained for at least 10 days at room temperature, and displayed a low initial burst release followed by a sustained release in vitro. Pharmacokinetic study in rats revealed that in vivo drug exposure of DMC was significantly increased and prolonged by intravenously administering DMC-loaded micelles when compared with the same dose of free DMC dissolved in dimethyl sulfoxide. Furthermore, in vivo distribution results from tumor-bearing nude mice demonstrated that this micellar formulation significantly changed the biodistribution profile of DMC and increased drug accumulation in tumors. Therefore, the polymeric micellar formulation of DMC, based on the amphiphilic block

  20. Poly(n-butylcyanoacrylate) nanoparticles for oral delivery of quercetin: preparation, characterization, and pharmacokinetics and biodistribution studies in Wistar rats

    PubMed Central

    Bagad, Mayur; Khan, Zaved Ahmed

    2015-01-01

    Background Quercetin (QT) is a potential bioflavonol and antioxidant with poor bioavailability and very low distribution in the brain. A new oral delivery system comprising of poly(n-butylcyanoacrylate) nanoparticles (PBCA NPs) was introduced to improve the oral bioavailability of QT and to increase its distribution in the brain. Physicochemical characteristics, in vitro release, stability in simulated gastric fluid and intestinal fluids, and pharmacokinetics and biodistribution studies of QT-PBCA NPs coated with polysorbate-80 (P-80) were investigated. Objective This study aimed to investigate the physicochemical characteristics, in vitro release, stability in simulated gastric fluid and intestinal fluids, and pharmacokinetics and biodistribution studies of QT-PBCA NPs coated with polysorbate-80 (P-80). Results The results showed that QT-PBCA NPs and QT-PBCA NPs coated with P-80 (QT-PBCA+P-80) had mean particle sizes of 161.1±0.44 nm and 166.6±0.33 nm respectively, and appeared spherical in shape under transmission electron microscopy. The mean entrapment efficiency was 79.86%±0.45% for QT-PBCA NPs and 74.58%±1.44% for QT-PBCA+P-80. The in vitro release of QT-PBCA NPs and QT-PBCA+P-80 showed an initial burst release followed by a sustained release when compared to free QT. The relative bioavailability of QT-PBCA NPs and QT-PBCA+P-80 enhanced QT bioavailability by 2.38- and 4.93-fold respectively, when compared to free QT. The biodistribution study in rats showed that a higher concentration of QT was detected in the brain after the NPs were coated with P-80. Conclusion This study indicates that PBCA NPs coated with P-80 can be potential drug carriers for poorly water-soluble drugs. These NPs were observed to improve the drugs’ oral bioavailability and enhance their transport to the brain. PMID:26089668

  1. Biodistribution and pharmacokinetics of PEG-10kDa-cholecystokinin-10 in rats after different routes of administration.

    PubMed

    León-Tamariz, Fabián; Verbaeys, Isabelle; Van Boven, Maurits; De Cuyper, Marcel; Buyse, Johan; de Witte, Peter; Verbruggen, Alfons; Cokelaere, Marnix

    2010-04-01

    Cholecystokinin, produced in the proximal small intestine, is a short acting satiating peptide hormone. CCK-10, before and after mono-iodination, was previously coupled to 10kDa polyethylene glycol (PEG). The formed conjugates PEG10kDa-CCK-10 and PEG10kDa-[(127)I]-CCK-10 show after i.p. administration to rats a sustained food intake reduction during 8h in comparison to 2h for free CCK-10. The present study examined the blood pharmacokinetics of this pharmacological interesting molecule by means of PEG10kDa-[(123)I]-CCK-10 following intravenous, intraperitoneal, intramuscular and nasal administration and the biodistribution after i.p. administration. HPLC analysis with radiometric detection allowed the differentiation between inorganic iodide and the intact tracer in blood. Blood kinetics after i.v. injection was fitted to a bi-exponential with a distribution half-life of 15 min and with an elimination half-life of 8 hours for intact PEG10kDa-[(123)I]-CCK-10. The biodistribution studies showed a higher accumulation of the tracer for all administration routes in organs expressing CCK receptors localized in the gastrointestinal tract such as pancreas, duodenum and small intestine. No indication of blood brain barrier crossing for the conjugate could be observed independently of the administration route. Main clearance was via the urinary pathway.

  2. Correlation between radioactivity and chemotherapeutics of the (111)In-VNB-liposome in pharmacokinetics and biodistribution in rats.

    PubMed

    Lee, Wen-Chuan; Chang, Chih-Hsien; Huang, Chih-Min; Wu, Yu-Tse; Chen, Liang-Cheng; Ho, Chung-Li; Chang, Tsui-Jung; Lee, Te-Wei; Tsai, Tung-Hu

    2012-01-01

    The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [(111)In-VNB-liposome]) has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the (111)In-VNB-liposome. The VNB-liposome and (111)In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the (111)In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111. High uptake of the (111)In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation (r = 0.97) between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the (111)In-VNB-liposome. A significant positive correlation between the pharmacokinetics and biodistribution of (111)Indium radioactivity and vinorelbine in blood, spleen, and liver was found following administration of the (111)In-VNB-liposome. The liposome efficiently encapsulated both vinorelbine and Indium-111, and showed a similar concentration-radioactivity time profile, indicating the correlation between chemotherapy and radiotherapy could be identical in the liposomal formulation.

  3. Correlation between radioactivity and chemotherapeutics of the 111In-VNB-liposome in pharmacokinetics and biodistribution in rats

    PubMed Central

    Lee, Wen-Chuan; Chang, Chih-Hsien; Huang, Chih-Min; Wu, Yu-Tse; Chen, Liang-Cheng; Ho, Chung-Li; Chang, Tsui-Jung; Lee, Te-Wei; Tsai, Tung-Hu

    2012-01-01

    Background The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [111In-VNB-liposome]) has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the 111In-VNB-liposome. Methods The VNB-liposome and 111In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the 111In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111. Results High uptake of the 111In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation (r = 0.97) between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the 111In-VNB-liposome. Conclusion A significant positive correlation between the pharmacokinetics and biodistribution of 111Indium radioactivity and vinorelbine in blood, spleen, and liver was found following administration of the 111In-VNB-liposome. The liposome efficiently encapsulated both vinorelbine and Indium-111, and showed a similar concentration-radioactivity time profile, indicating the correlation between chemotherapy and radiotherapy could be identical in the liposomal formulation. PMID:22359447

  4. Biodistribution and PET Imaging of pharmacokinetics of manganese in mice using Manganese-52.

    PubMed

    Wooten, A Lake; Aweda, Tolulope A; Lewis, Benjamin C; Gross, Rebecca B; Lapi, Suzanne E

    2017-01-01

    Manganese is essential to life, and humans typically absorb sufficient quantities of this element from a normal healthy diet; however, chronic, elevated ingestion or inhalation of manganese can be neurotoxic, potentially leading to manganism. Although imaging of large amounts of accumulated Mn(II) is possible by MRI, quantitative measurement of the biodistribution of manganese, particularly at the trace level, can be challenging. In this study, we produced the positron-emitting radionuclide 52Mn (t1/2 = 5.6 d) by proton bombardment (Ep<15 MeV) of chromium metal, followed by solid-phase isolation by cation-exchange chromatography. An aqueous solution of [52Mn]MnCl2 was nebulized into a closed chamber with openings through which mice inhaled the aerosol, and a separate cohort of mice received intravenous (IV) injections of [52Mn]MnCl2. Ex vivo biodistribution was performed at 1 h and 1 d post-injection/inhalation (p.i.). In both trials, we observed uptake in lungs and thyroid at 1 d p.i. Manganese is known to cross the blood-brain barrier, as confirmed in our studies following IV injection (0.86%ID/g, 1 d p.i.) and following inhalation of aerosol, (0.31%ID/g, 1 d p.i.). Uptake in salivary gland and pancreas were observed at 1 d p.i. (0.5 and 0.8%ID/g), but to a much greater degree from IV injection (6.8 and 10%ID/g). In a separate study, mice received IV injection of an imaging dose of [52Mn]MnCl2, followed by in vivo imaging by positron emission tomography (PET) and ex vivo biodistribution. The results from this study supported many of the results from the biodistribution-only studies. In this work, we have confirmed results in the literature and contributed new results for the biodistribution of inhaled radiomanganese for several organs. Our results could serve as supporting information for environmental and occupational regulations, for designing PET studies utilizing 52Mn, and/or for predicting the biodistribution of manganese-based MR contrast agents.

  5. Biodistribution and PET Imaging of pharmacokinetics of manganese in mice using Manganese-52

    PubMed Central

    Aweda, Tolulope A.; Lewis, Benjamin C.; Gross, Rebecca B.; Lapi, Suzanne E.

    2017-01-01

    Manganese is essential to life, and humans typically absorb sufficient quantities of this element from a normal healthy diet; however, chronic, elevated ingestion or inhalation of manganese can be neurotoxic, potentially leading to manganism. Although imaging of large amounts of accumulated Mn(II) is possible by MRI, quantitative measurement of the biodistribution of manganese, particularly at the trace level, can be challenging. In this study, we produced the positron-emitting radionuclide 52Mn (t1/2 = 5.6 d) by proton bombardment (Ep<15 MeV) of chromium metal, followed by solid-phase isolation by cation-exchange chromatography. An aqueous solution of [52Mn]MnCl2 was nebulized into a closed chamber with openings through which mice inhaled the aerosol, and a separate cohort of mice received intravenous (IV) injections of [52Mn]MnCl2. Ex vivo biodistribution was performed at 1 h and 1 d post-injection/inhalation (p.i.). In both trials, we observed uptake in lungs and thyroid at 1 d p.i. Manganese is known to cross the blood-brain barrier, as confirmed in our studies following IV injection (0.86%ID/g, 1 d p.i.) and following inhalation of aerosol, (0.31%ID/g, 1 d p.i.). Uptake in salivary gland and pancreas were observed at 1 d p.i. (0.5 and 0.8%ID/g), but to a much greater degree from IV injection (6.8 and 10%ID/g). In a separate study, mice received IV injection of an imaging dose of [52Mn]MnCl2, followed by in vivo imaging by positron emission tomography (PET) and ex vivo biodistribution. The results from this study supported many of the results from the biodistribution-only studies. In this work, we have confirmed results in the literature and contributed new results for the biodistribution of inhaled radiomanganese for several organs. Our results could serve as supporting information for environmental and occupational regulations, for designing PET studies utilizing 52Mn, and/or for predicting the biodistribution of manganese-based MR contrast agents. PMID

  6. PEG Length and Chemical Linkage Controls Polyacridine Peptide DNA Polyplex Pharmacokinetics, Biodistribution, Metabolic Stability and In Vivo Gene Expression

    PubMed Central

    Khargharia, Sanjib; Kizzire, Koby; Ericson, Mark; Baumhover, Nicholas J.; Rice, Kevin G.

    2014-01-01

    The pharmacokinetics (PK), biodistribution and metabolism of non-viral gene delivery systems administered systemically are directly related to in vivo efficacy. The magnitude of luciferase expression in the liver of mice following a tail vein dose of a polyplex, composed of 1 μg of pGL3 in complex with a polyethylene glycol (PEG) polyacridine peptide, followed by a delayed hydrodynamic (HD) stimulation (1–9 h), depends on the HD stimulation delay time and the structure of the polyacridine peptide. As demonstrated in the present study, the PEG length and the type of chemical linkage joining PEG to the polyacridine peptide dramatically influence the in vivo gene transfer efficiency. To understand how PEG length, linkage and location influence gene transfer efficiency, detailed PK, biodistribution and HD-stimulated gene expression experiments were performed on polyplexes prepared with an optimized polyacridine peptide modified through a single terminal Cys or Pen (penicillamine) with a PEG chain of average length of 2, 5, 10, 20, or 30 kDa. The chemical linkage was examined by attaching PEG5kDa to the polyacridine peptide through a thiol-thiol (SS), thiol-maleimide (SM), thiol-vinylsulfone (SV), thiol-acetamide (SA), penicillamine-thiol-maleimide (PM) or penicillamine-thiol-thiol (PS). The influence of PEG location was analyzed by attaching PEG5kDa to the polyacridine peptide through a C-terminal, N-terminal, or a middle Cys residue. The results established rapid metabolism of polyplexes containing SV and SA chemical linkages leads to a decreased polyplex PK half-life and a complete loss of HD-stimulated gene expression at delay times of 5 hrs. Conversely, polyplexes containing PM, PS, and SM chemical linkages were metabolically stable, allowing robust HD-stimulated expression at delay times up to 5 hrs post polyplex administration. The location of PEG5kDa within the polyacridine peptide exerted only a minor influence on the gene transfer of polyplexes. However

  7. Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation.

    PubMed

    Garcia, Giani Martins; Oliveira, Líliam Teixeira; Pitta, Ivan da Rocha; de Lima, Maria do Carmo Alves; Vilela, José Mário Carneiro; Andrade, Margareth Spangler; Abdalla, Dulcinéia Saes Parra; Mosqueira, Vanessa Carla Furtado

    2015-07-10

    We report the in vitro release profile and comparative pharmacokinetics and biodistribution of a new peroxisome proliferator-activated receptor-γ agonist and cyclooxygenase inhibitor (Lyso-7) free or associated to poly(D,L-lactic acid) nanocapsules (NC) after intravenous administration in mice. Lyso-7 pertains to the class of insulin-sensitizing agents that shows potential beneficial effects in diabetes therapy. Monodispersed Lyso-7 NC with a mean diameter of 273 nm with high encapsulation efficiency (83%) were obtained. Lyso-7 dissolution rate was reduced (2.6-fold) upon loading in NC. The pharmacokinetic parameters were determined using a non-compartmental approach. In comparison with Lyso-7 in solution, the plasma-AUC increased 14-fold, the mean residence time 2.6-fold and the mean half-life (t1/2) 1.5-fold for Lyso-7-NC; the Lyso-7 plasma clearance, distribution volume and elimination rate were reduced 13, 10 and 1.4 fold, respectively, which indicates higher retention of encapsulated Lyso-7 in the blood compartment. Upon association with NC, organ exposure to Lyso-7 was higher in the heart (3.6-fold), lung (2.8-fold), spleen (2.3-fold), kidney (2-fold) and liver (1.8-fold) compared to Lyso-7 in solution. The analysis of whole data clearly indicates that body exposure to Lyso-7 was enhanced and the general toxicity reduced upon nanoencapsulation, allowing further evaluation of Lyso-7 in nonclinical and clinical studies.

  8. In vivo pharmacokinetics, biodistribution and antitumor effect of paclitaxel-loaded micelles based on α-tocopherol succinate-modified chitosan.

    PubMed

    Liang, Na; Sun, Shaoping; Hong, Juan; Tian, Jingzhuo; Fang, Liang; Cui, Fude

    2016-10-01

    In our previous study, α-tocopherol succinate modified chitosan (CS-TOS) was synthesized and encapsulated paclitaxel (PTX) to form micelles. Preliminary study revealed that the CS-TOS was a potential micellar carrier for PTX. In this study, some further researches were done using Taxol formulation as the control to evaluate the micelle system deeply. In vitro cell experiments demonstrated that the cytotoxic effect of PTX-loaded CS-TOS micelles against MCF-7 cells was comparable with that of Taxol formulation, and the PTX-loaded micelles had excellent cellular uptake ability, which was in a time-dependent manner. The in vivo pharmacokinetic study in rats showed that the micelles prolonged the half-life and increased AUC of PTX than Taxol formulation. From biodistribution study, it was clear that for micelles, the drug concentrations in the liver and spleen were significantly higher than those of Taxol formulation, but much lower in the heart and kidney. Furthermore, the PTX-loaded micelles showed superior antitumor effect, but yielded less toxicity as indicated by the results of antitumor efficacy study and survival study in U14 tumor-bearing mice. These results suggested that CS-TOS micelles could be a potentially useful drug delivery system to improve the performance and safety of PTX.

  9. Dependence of pharmacokinetics and biodistribution on polymer architecture: effect of cyclic versus linear polymers.

    PubMed

    Nasongkla, Norased; Chen, Bo; Macaraeg, Nichole; Fox, Megan E; Fréchet, Jean M J; Szoka, Francis C

    2009-03-25

    The ability of a polymer to reptate through a nanopore has an influence on its circulatory half-life and biodistribution, since many physiological barriers contain nanopores. A cyclic polymer lacks chain ends, and therefore, cyclic polymers with molecular weights greater than the renal threshold for elimination should circulate longer than their linear-polymer counterparts when injected into animals. As predicted, radiolabeled cyclic polymers with molecular weights greater than the renal threshold have longer blood circulation times in mice than do linear polymers of comparable molecular weight.

  10. Dependence of Pharmacokinetics and Biodistribution on Polymer Architecture: Effect of Cyclic Versus Linear Polymers

    PubMed Central

    Nasongkla, Norased; Chen, Bo; Macaraeg, Nichole; Fox, Megan E.; Fréchet, Jean M. J.; Szoka, Francis C.

    2009-01-01

    The ability of a polymer to reptate through a nanopore has an influence on its circulatory half-life and biodistribution since many physiological barriers contain nanopores. A cyclic polymer lacks chain ends, therefore, cyclic polymers with a MW above the renal threshold for elimination should circulate longer than their linear polymer counterparts when injected into animals. As predicted, radiolabeled cyclic polymers with MW above the renal threshold have a longer blood circulation time in mice compared to linear polymers of comparable MW. PMID:19256497

  11. Biodistribution, pharmacokinetic, and in-vivo fluorescence spectroscopic studies of photosensitizers

    NASA Astrophysics Data System (ADS)

    Moan, Johan; Peng, Qian; Iani, Vladimir; Ma, Li Wei; Horobin, Richard W.; Berg, Kristian; Kongshaug, Magne; Nesland, Jahn M.

    1996-01-01

    Some key data concerning the pharmacokinetics of PCT photosensitizers are reviewed. The following topics are discussed: The binding of photosensitizers to serum proteins, and the significance of LDL binding for tumor localization, the distribution of sensitizers among different tissue compartments and the significance of extracellular proteins and other stromal elements, such as macrophages, low tumor pH, leaky vasculature and poor lymphatic drainage for tumor selectivity of drugs, the retention and excretion of sensitizers, and intracellular pharmacokinetics. Furthermore, the usefulness of fluorescence measurements in the study of sensitizer pharmacokinetics is briefly discussed. A key observation is that 1O2 has a short radius of action. Since practically all PCT sensitizers act via the 1O2 pathway, only targets with significant sensitizer concentrations can be damaged. A given number of 1O2 entities generated in different organelles (mitochondria, lysosomes, plasma membrane, etc.) may lead to widely different effects with respect to cell inactivation. Similarly, sensitizers localizing in different compartments of tissues may have different photosensitizing efficiencies even under conditions of a similar 1O2 yield.

  12. Pharmacokinetics and bio-distribution of novel super paramagnetic iron oxide nanoparticles (SPIONs) in the anaesthetized pig.

    PubMed

    Edge, Deirdre; Shortt, Christine M; Gobbo, Oliviero L; Teughels, Stephanie; Prina-Mello, Adriele; Volkov, Yuri; MacEneaney, Peter; Radomski, Marek W; Markos, Farouk

    2016-03-01

    Manufactured nanomaterials have a variety of medical applications, including diagnosis and targeted treatment of cancer. A series of experiments were conducted to determine the pharmacokinetic, biodistribution and biocompatibility of two novel magnetic nanoparticles (MNPs) in the anaesthetized pig. Dimercaptosuccinic acid (DMSA) coated superparamagnetic iron oxide nanoparticles (MF66-labelled 12 nm, core nominal diameter and OD15 15 nm); at 0.5, or 2.0 mg/kg) were injected intravenously. Particles induced a dose-dependent decrease in blood pressure following administration which recovered to control levels several minutes after injection. Blood samples were collected for a 5-h period and stored for determination of particle concentration using particle electron paramagnetic resonance (pEPR). Organs were harvested post-mortem for magnetic resonance imaging (MRI at 1.5 T field strength) and histology. OD15 (2.0 mg/kg) MNP had a plasma half-life of approximately 15 min. Both doses of the MF66 (0.5 and 2.0 mg/kg) MNP were below detection limits. MNP accumulation was observed primarily in the liver and spleen with MRI scans which was confirmed by histology. MRI also showed that both MNPs were present in the lungs. The results show that further modifications may be required to improve the biocompatibility of these particles for use as diagnostic and therapeutic agents.

  13. Pharmacokinetics and in vivo biodistribution of optimized PLGA nanoparticulate drug delivery system for controlled release of emtricitabine.

    PubMed

    Singh, Gurinder; Pai, Roopa S

    2014-12-01

    The objective of this study was to develop systematically optimized (OPT) nanoparticles (NPs) providing a controlled release using PLGA of emtricitabine (FTC) employing Formulation by Design (FbD), and evaluate their in vitro and in vivo performance. FTC generates severe adverse effects with risks of toxicity. Thus, NPs were prepared to reduce these drawbacks in this study. The NPs were prepared by water-in-oil-in-water (w/o/w) emulsion method, followed by high-pressure homogenization. The FTC NPs were systematically OPT using 3(2) central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in vivo biodistribution of OPT-FTC NPs were investigated in male Wistar rats via the oral administration. Transmission electron microscopy studies on OPT-FTC NPs demonstrated uniform shape and size of particles. In vitro release was sustained up to 15 days in PBS pH 7.4. Augmentation in the values of Cmax (1.63 fold) and AUC0-∞ (5.39 fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT-FTC NPs compared to pure drug. OPT-FTC NPs showed 2.325 fold increase in the values of FTC concentrations in liver. The OPT-FTC NPs was found to be quite stable during 6 months of study period. Hence, the developed OPT-FTC NPs can be used as drug carrier for sustained/prolonged drug release and/or to reduce toxic effects.

  14. Biodistribution, pharmacokinetics and toxicology of Ag2S near-infrared quantum dots in mice.

    PubMed

    Zhang, Yan; Zhang, Yejun; Hong, Guosong; He, Wei; Zhou, Kun; Yang, Kai; Li, Feng; Chen, Guangcun; Liu, Zhuang; Dai, Hongjie; Wang, Qiangbin

    2013-05-01

    Ag2S quantum dots (QDs) have been demonstrated as a promising near-infrared II (NIR-II, 1.0-1.4 μm) emitting nanoprobe for in vivo imaging and detection. In this work, we carefully study the long-term in vivo biodistribution of Ag2S QDs functionalized with polyethylene glycol (PEG) and systematically examine the potential toxicity of Ag2S QDs over time. Our results show that PEGylated-Ag2S QDs are mainly accumulated in the reticuloendothelial system (RES) including liver and spleen after intravenous administration and can be gradually cleared, mostly by fecal excretion. PEGylated-Ag2S QDs do not cause appreciable toxicity at our tested doses (15 and 30 mg/kg) to the treated mice over a period of 2 months as evidenced by blood biochemistry, hematological analysis and histological examinations. Our work lays a solid foundation for further biomedical applications of Ag2S QDs as an important in vivo imaging agent in the NIR-II region.

  15. Biochemical modifications of avidin improve pharmacokinetics and biodistribution, and reduce immunogenicity.

    PubMed Central

    Chinol, M.; Casalini, P.; Maggiolo, M.; Canevari, S.; Omodeo, E. S.; Caliceti, P.; Veronese, F. M.; Cremonesi, M.; Chiolerio, F.; Nardone, E.; Siccardi, A. G.; Paganelli, G.

    1998-01-01

    Pretargeting techniques using the avidin-biotin system have shown encouraging results in both diagnostic and therapeutic clinical trials. It has been shown that in cancer therapy the ideal agent to be used for pretargeting should have a plasma half-life longer than avidin and lower immunogenicity than streptavidin in order for these procedures to be applied safely and repeatedly in patients. We prepared a recombinant form of avidin with no carbohydrates and avidins, biochemically modified either by decreasing the positive charges with succinic anhydride or by linking polyethylene glycol (PEG) at three different molar ratios and evaluated their in vivo behaviour after i.p. administration in mice. The succinylation and PEGylation of avidin increased the plasma half-life proportionally to the degree of protein modification. The procedures, however, affected the biotin binding to some extent. The biodistribution studies showed that, for all six time points (ranging from 20 min to 18 h post-injection), the liver and kidney to blood ratios were lower for PEGylated avidins than native, recombinant and succinyl avidin. Recombinant and low PEGylated avidin evoked an immune response in all mice after at least three injections. Native, recombinant and succinyl avidins showed higher serum titres than PEGylated avidins. In conclusion, the conjugation of avidin to PEG chains (n = 7) originates a compound with a suitable blood clearance, low immunogenicity and concurrent low cross-reactivity with avidin. PMID:9683292

  16. First-in-man Phase 1 Clinical Trial of Gene Therapy for Advanced Pancreatic Cancer: Safety, Biodistribution, and Preliminary Clinical Findings

    PubMed Central

    Buscail, Louis; Bournet, Barbara; Vernejoul, Fabienne; Cambois, Gilles; Lulka, Hubert; Hanoun, Naïma; Dufresne, Marlène; Meulle, Aline; Vignolle-Vidoni, Alix; Ligat, Laetitia; Saint-Laurent, Nathalie; Pont, Frédéric; Dejean, Sébastien; Gayral, Marion; Martins, Frédéric; Torrisani, Jérôme; Barbey, Odile; Gross, Fabian; Guimbaud, Rosine; Otal, Philippe; Lopez, Frédéric; Tiraby, Gérard; Cordelier, Pierre

    2015-01-01

    This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified. Treatment-related toxicities were mild, without serious adverse events. Pharmacokinetic analysis revealed a dose-dependent increase in CYL-02 DNA exposure in blood and tumors, while therapeutic RNAs were detected in tumors. No objective response was observed, but nine patients showed stable disease up to 6 months following treatment and two of these patients experienced long-term survival. Panels of plasmatic microRNAs and proteins were identified as predictive of gene therapy efficacy. We demonstrate that CYL-02 nonviral gene therapy has a favorable safety profile and is well tolerated in patients. We characterize CYL-02 biodistribution and demonstrate therapeutic gene expression in tumors. Treated patients experienced stability of disease and predictive biomarkers of response to treatment were identified. These promising results warrant further evaluation in phase 2 clinical trial. PMID:25586689

  17. Fate of nanostructured lipid carriers (NLCs) following the oral route: design, pharmacokinetics and biodistribution.

    PubMed

    Beloqui, Ana; Solinís, María Ángeles; Delgado, Araceli; Evora, Carmen; Isla, Arantxazu; Rodríguez-Gascón, Alicia

    2014-01-01

    The aim of this study was to develop a nanostructured lipid carriers (NLC) formulation containing spironolactone (SPN-NLCs), and to investigate its potential for the oral delivery of poorly water-soluble compounds. SPN-NLCs were orally administered to rabbits and the pharmacokinetics of spironolactone and its metabolites was evaluated. As reference formulation, we administered syrup. Spironolactone was only detected in a few plasma samples; hence, metabolite levels were employed for the pharmacokinetic analysis. The absolute bioavailability of 7α-TMS was significantly higher with the syrup than those obtained with the SPN-NLCs (0.7 versus 0.4, p < 0.05). However, no significant differences were observed in the bioavailability of canrenone, revealing a different canrenone/7α-TMS ratio depending on the administered formulation. Orally administered (99m)Tc-radiolabeled SPN-NLCs were mainly detected in the small intestine. These results suggest the retention of the nanocarriers in the underlying epithelium and further uptake by the epithelial cells.

  18. Mass spectrometry imaging of cassette-dosed drugs for higher throughput pharmacokinetic and biodistribution analysis.

    PubMed

    Swales, John G; Tucker, James W; Strittmatter, Nicole; Nilsson, Anna; Cobice, Diego; Clench, Malcolm R; Mackay, C Logan; Andren, Per E; Takáts, Zoltán; Webborn, Peter J H; Goodwin, Richard J A

    2014-08-19

    Cassette dosing of compounds for preclinical drug plasma pharmacokinetic analysis has been shown to be a powerful strategy within the pharmaceutical industry for increasing throughput while decreasing the number of animals used. Presented here for the first time is data on the application of a cassette dosing strategy for label-free tissue distribution studies. The aim of the study was to image the spatial distribution of eight nonproprietary drugs (haloperidol, bufuralol, midazolam, clozapine, terfenadine, erlotinib, olanzapine, and moxifloxacin) in multiple tissues after oral and intravenous cassette dosing (four compounds per dose route). An array of mass spectrometry imaging technologies, including matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI), liquid extraction surface analysis tandem mass spectrometry (LESA-MS/MS), and desorption electrospray ionization mass spectrometry (DESI-MS) was used. Tissue analysis following intravenous and oral administration of discretely and cassette-dosed compounds demonstrated similar relative abundances across a range of tissues indicating that a cassette dosing approach was applicable. MALDI MSI was unsuccessful in detecting all of the target compounds; therefore, DESI MSI, a complementary mass spectrometry imaging technique, was used to detect additional target compounds. In addition, by adapting technology used for tissue profiling (LESA-MS/MS) low spatial resolution mass spectrometry imaging (∼1 mm) was possible for all targets across all tissues. This study exemplifies the power of multiplatform MSI analysis within a pharmaceutical research and development (R&D) environment. Furthermore, we have illustrated that the cassette dosing approach can be readily applied to provide combined, label-free pharmacokinetic and drug distribution data at an early stage of the drug discovery/development process while minimizing animal usage.

  19. Biodistribution and pharmacokinetics of Mad2 siRNA-loaded EGFR-targeted chitosan nanoparticles in cisplatin sensitive and resistant lung cancer models

    PubMed Central

    Nascimento, Ana Vanessa; Gattacceca, Florence; Singh, Amit; Bousbaa, Hassan; Ferreira, Domingos; Sarmento, Bruno; Amiji, Mansoor M

    2016-01-01

    Background: The present study focuses on biodistribution profile and pharmacokinetic parameters of EGFR-targeted chitosan nanoparticles (TG CS nanoparticles) for siRNA/cisplatin combination therapy of lung cancer. Material & methods: Mad2 siRNA was encapsulated in EGFR targeted and nontargeted (NTG) CS nanoparticles by electrostatic interaction. The biodistribution of the nanoparticles was assessed qualitatively and quantitatively in cisplatin (DDP) sensitive and resistant lung cancer xenograft model. Results: TG nanoparticles showed a consistent and preferential tumor targeting ability with rapid clearance from the plasma to infiltrate and sustain within the tumor up to 96 h. They exhibit a sixfold higher tumor targeting efficiency compared with the NTG nanoparticles. Conclusion: TG nanoparticles present as an attractive drug delivery platform for RNAi therapeutics against NSCLC. PMID:26980454

  20. In vivo pharmacokinetics and biodistribution of resveratrol-loaded solid lipid nanoparticles for brain delivery.

    PubMed

    Jose, S; Anju, S S; Cinu, T A; Aleykutty, N A; Thomas, S; Souto, E B

    2014-10-20

    Resveratrol is a potent anticancer. However, because of its low half-life (<0.25 h) the molecule is difficult to achieve the therapeutic concentration at the site of action. The aim of this work was to check the brain targeting ability of glyceryl behenate-based solid lipid nanoparticles (SLN) for resveratrol. SLN were prepared by solvent evaporation technique employing high speed homogenization followed by ultrasonication. SLN were designed at varying drug-lipid ratios (1:5, 1:9, 1:10, 1:11, 1:12 and 1:15) using Tween 80 or a combination of Tween 80 and polyvinyl alcohol (PVA) as surfactants. The mean particle size and zeta potential of the optimized formulation (drug-lipid ratio of 1:10) were 248.30 ± 3.80nm and -25.49 ± 0.49mV, respectively. The particle size and the encapsulation efficiency (EE) increased when varying the drug-lipid ratio from 1:5 to 1:15. Scanning electron microscopic (SEM) analysis showed that SLN were spherical in shape and had a smooth surface. The X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses revealed that the matrix of drug-loaded SLN was in disordered crystalline phase. The in vitro release study in phosphate buffer pH 7.4 followed a sustained release pattern. The drug release data was found to fit best into Higuchi kinetic model suggesting the diffusion controlled mechanism of drug release. The cytotoxicity assay (MAT) showed that SLN were equally effective (P<0.5) as free resveratrol, as an anti-tumor agent. The in vivo biodistribution study using Wistar rats demonstrated that SLN could significantly (P<0.001) increase the brain concentration of resveratrol (17.28 ± 0.6344 μg/g) as compared to free resveratrol (3.45 ± 0.3961 μg/g). The results showed that our resveratrol-loaded SLN serve as promising therapeutic systems to treat neoplastic diseases located in the brain tissue. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Biodistribution and pharmacokinetics of In-111-labeled Stealth{reg_sign} liposomes in patients with solid tumours

    SciTech Connect

    Harrington, K.J.; Peters, A.M.; Mohammadtaghi, S.

    1996-05-01

    The use of liposomal doxorubicin yields response rates of up to 70-80% in patients with AIDS-related Kaposi`s sarcoma with favourable alteration of the toxicity profile of the drug. Liposomal delivery of therapy in patients with solid cancers is currently under investigation. Our aim is to determine the biodistribution and pharmacokinetics of In-111-labeled Stealth{reg_sign} liposomes (SEQUUS{trademark}) liposomes (SEQUUS{trademark} Pharmaceuticals Inc., Menlo Park, USA) in patients with advanced solid malignant tumours. Ten patients (4 male, 6 female) with a median age of 59 (range 43 - 75) received 100 MBq of In-111-labeled Stealth{reg_sign} liposomes. Four had breast cancer, 3 head and neck tumours, 2 lung and 1 cervical cancer. Blood samples and whole body gamma camera images were obtained at 0.5, 4, 24, 48, 72, 96 and 240 hours after injection and sequential 24 hour urine collections were performed for the first 96 h. SPECT imaging was performed when indicated. High definition images of tumours were obtained in 9 patients (3/4 breast, 3/3 head and neck, 2/2 lung and 1/1 cervix cancers). One patient (breast cancer) had negative images. The median cumulative urinary excretion of In-111 over the first 96 h was 17.8 (range 3.5-21.3) % of the injected dose. The uptake of liposomes in various tissues was estimated from regions of interest on the whole body images. Prominent uptake was seen in the liver (10-15% of injected dose), lungs (4-9%) and spleen (2-8%). Tumour uptake in the first 96 h varied form 0.5-4% of the injected dose. This is approximately 10 fold higher than might be expected from experience with other targeting methods (eg monoclonal antibodies). These data confirm that Stealth liposomes have a prolonged circulation half-life and localise to solid tumour tissue.

  2. Improved pharmacokinetics, biodistribution and necrosis in vivo using a new near infra-red photosensitizer: tetrahydroporphyrin tetratosylat.

    PubMed

    Schastak, Stanislaw; Jean, Benedikt; Handzel, Romy; Kostenich, Genady; Hermann, Ralf; Sack, Ulrich; Orenstein, Arie; Wang, Yu-Sheng; Wiedemann, Peter

    2005-03-01

    The search for better photosensitizers for photodynamic therapy of malignancies has led to the investigation of a new water-soluble, positively charged, and chemical stable tetrahydroporphyrin tetratosylat (THPTS) with a strong absorption at 760.5 nm, belonging to the bacteriochlorophyll family. THPTS undergoes a rapid uptake by human choroidal melanoma (CM) cells with a weak dark toxicity after a 24-h incubation (LD10 = 150 microM, LD50 = 6.0 mM). In response to laser light at 760+/-3 nm and doses of 10, 15 and 30 J/cm2, around 71%, 76%, and 92% of the CM cells were killed, respectively. Studies of pharmacokinetics and biodistribution in vivo (living mice) and ex vivo (excised organs) were made in a Balb/c mice bearing subcutaneously inoculated C26 colon carcinoma using fiber-optic spectrofluorimetry (FOS). Tumours were irradiated 3 h after intraperitoneal (i.p.) injection of 5.0 mg/kg THPTS with an incoherent light source at 750+/-20 nm and an intensity of 100 mW/cm2 and fluences of 60, 90 and 120 J/cm2. THPTS demonstrated preferential accumulation in C26 colon carcinoma in comparison with most normal tissues except kidneys. For the tissues of liver, colon, muscle, and spleen the tumour/normal tissue ratio (TNTR) ranged from 8.0 to 50. After irradiation with 120 J/cm2 the depth of tumour necrosis reached 15 mm. Histological examination of the tumour samples 24 h after THPTS-PDT, revealed severe stasis in the blood vessels and coagulative necrosis. These results suggest that THPTS-PDT may be of particular importance in the treatment of accessible malignancies.

  3. Effects of anti-VEGF on pharmacokinetics, biodistribution, and tumor penetration of trastuzumab in a preclinical breast cancer model.

    PubMed

    Pastuskovas, Cinthia V; Mundo, Eduardo E; Williams, Simon P; Nayak, Tapan K; Ho, Jason; Ulufatu, Sheila; Clark, Suzanna; Ross, Sarajane; Cheng, Eric; Parsons-Reponte, Kathryn; Cain, Gary; Van Hoy, Marjie; Majidy, Nicholas; Bheddah, Sheila; dela Cruz Chuh, Josefa; Kozak, Katherine R; Lewin-Koh, Nicholas; Nauka, Peter; Bumbaca, Daniela; Sliwkowski, Mark; Tibbitts, Jay; Theil, Frank-Peter; Fielder, Paul J; Khawli, Leslie A; Boswell, C Andrew

    2012-03-01

    Both human epidermal growth factor receptor 2 (HER-2/neu) and VEGF overexpression correlate with aggressive phenotypes and decreased survival among breast cancer patients. Concordantly, the combination of trastuzumab (anti-HER2) with bevacizumab (anti-VEGF) has shown promising results in preclinical xenograft studies and in clinical trials. However, despite the known antiangiogenic mechanism of anti-VEGF antibodies, relatively little is known about their effects on the pharmacokinetics and tissue distribution of other antibodies. This study aimed to measure the disposition properties, with a particular emphasis on tumor uptake, of trastuzumab in the presence or absence of anti-VEGF. Radiolabeled trastuzumab was administered alone or in combination with an anti-VEGF antibody to mice bearing HER2-expressing KPL-4 breast cancer xenografts. Biodistribution, autoradiography, and single-photon emission computed tomography-X-ray computed tomography imaging all showed that anti-VEGF administration reduced accumulation of trastuzumab in tumors despite comparable blood exposures and similar distributions in most other tissues. A similar trend was also observed for an isotype-matched IgG with no affinity for HER2, showing reduced vascular permeability to macromolecules. Reduced tumor blood flow (P < 0.05) was observed following anti-VEGF treatment, with no significant differences in the other physiologic parameters measured despite immunohistochemical evidence of reduced vascular density. In conclusion, anti-VEGF preadministration decreased tumor uptake of trastuzumab, and this phenomenon was mechanistically attributed to reduced vascular permeability and blood perfusion. These findings may ultimately help inform dosing strategies to achieve improved clinical outcomes.

  4. Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice.

    PubMed

    Nimesh, Hemlata; Tiwari, Vinod; Yang, Chunhua; Gundala, Sushma R; Chuttani, Krishna; Hazari, Puja P; Mishra, Anil K; Sharma, Abhisheak; Lal, Jawahar; Katyal, Anju; Aneja, Ritu; Tandon, Vibha

    2015-10-01

    Radiotherapy, a therapeutic modality of cancer treatment, nonselectively damages normal tissues as well as tumor tissues. The search is ongoing for therapeutic agents that selectively reduce radiation-induced normal tissue injury without reducing tumoricidal effect, thereby increasing the therapeutic ratio of radiation therapy. Our laboratory established 5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxyphenyl)-5'benzimidazolyl] benzimidazole (DMA) as noncytotoxic radioprotector in mammalian cells. DMA showed an excellent radioprotection in mice at single nontoxic oral dose by a dose-reduction factor of 1.28. An oxygen radical absorbing capacity assay confirmed its free-radical quenching ability. Single bolus dose and 28-days of repeated administration of DMA in mice for toxicity studies determined an LD50 of >2000 mg/kg body weight (bw) and 225 mg/kg bw, respectively, suggesting DMA is safe. Histopathology, biochemical parameters, and relative organ weight analysis revealed insignificant changes in the DMA-treated animals. The pharmacokinetic study of DMA at oral and intravenous doses showed its C(max) = 1 hour, bioavailability of 8.84%, elimination half-life of 4 hours, and an enterohepatic recirculation. Biodistribution study in mice with Ehrlich ascites tumors showed that (99m)Tc-DMA achieved its highest concentration in 1 hour and was retained up to 4 hours in the lungs, liver, kidneys, and spleen, and in a low concentration in the tumor, a solicited property of any radioprotector to protect normal cells over cancerous cells. We observed that the single-dose treatment of tumor-bearing mice with DMA 2 hours before 8 Gy total body irradiation showed an impressive rescue of radiation-induced morbidity in terms of weight loss and mortality without a change in tumor response.

  5. Improved systemic pharmacokinetics, biodistribution, and antitumor activity of CpG oligodeoxynucleotides complexed to endogenous antibodies in vivo

    PubMed Central

    Palma, Enzo; Cho, Moo J.

    2007-01-01

    CpG oligodeoxynucleotides (CpG-ODNs) fail to elicit antitumor immunity after intravenous administration presumably due to their rapid renal clearance and low tumor accumulation. To address this issue, we tested the hypothesis that endogenous IgG can be used as systemic drug carriers to improve the pharmacokinetics, tumor accumulation, and antitumor activity of intravenously administered CpG-ODNs. To this end, tritium-labeled CpG-ODNs conjugated with one or two dinitrophenyl (DNP) haptens (DNP- and DNP2-[3H]-CpG-ODN) were intravenously dosed into DNP-immunized Balb/c mice bearing subcutaneous CT26 colorectal tumors. Serum and tissue samples for pharmacokinetic and biodistribution profiling were collected at predetermined timepoints and analyzed by liquid scintillation. In antitumor efficacy studies, DNP-immunized, CT26 tumor-bearing mice were intravenously dosed with PBS, CpG-ODN, or DNP-CpG-ODN every five days. Tumor volumes and macroscopic and histological examination of resected solid tumors were used to quantitatively and qualitatively assess tumor growth inhibition. Relative to [3H]-CpG-ODN, dinitrophenylated [3H]-CpG-ODNs displayed substantial increases in systemic exposure (900–1650 fold) and half-life (100–300 fold), marked decreases in systemic clearance (750–1500 fold) and volume of tissue distribution (13–37 fold), as well as substantial and sustained tumor accumulation (~30% vs. <2% injected dose/g). Antitumor efficacy studies demonstrated that DNP-CpG-ODN inhibited tumor growth by up to 60% relative to PBS control whereas CpG-ODN treatment had no apparent effect. Macroscopic and histological examination of harvested tumors at various timepoints revealed the presence of regions of necrotic tissue only in tumors from mice treated with DNP-CpG-ODN. Collectively, these results show the potential of endogenous IgG to mediate the systemic delivery of CpG-ODN to solid tumors and to enhance their antitumor activity following intravenous administration

  6. Long chain lipid based tamoxifen NLC. Part II: pharmacokinetic, biodistribution and in vitro anticancer efficacy studies.

    PubMed

    Shete, Harshad; Chatterjee, Sushmita; De, Abhijit; Patravale, Vandana

    2013-09-15

    Long chain lipid (LCL) based tamoxifen loaded nanostructured lipid carriers (Tmx-NLCs) meant to target intestinal lymphatic systems (ILSs) was developed and characterized previously. The aim of the present work was to evaluate in vitro efficacy of developed Tmx-NLC against breast cancer cell lines and to confirm the hypothesis of targeting ILS after single dose oral administration. In vitro anticancer activity of Tmx-NLC was assessed in human estrogen receptor expressing breast cancer cell lines viz. MCF-7 and ZR-75-1. The study revealed relatively improved activity for Tmx-NLC compared to free Tmx against MCF-7 cells. However, the activity was compromised against ZR-75-1 cells which could be attributed to its up regulation of MUC1 gene. Confocal and flow cytometric analysis revealed remarkable intracellular uptake of Tmx-NLC and its localization in nuclear and perinuclear region of cells. Tmx-NLC exhibited distinctly different pharmacokinetic profile compared to Tamoxifen suspension (Tmx-susp) and exhibited an increment in the bioavailability by 2.71-fold and prolonged the T1/2 by 7.10-fold. Moreover, detectable drug concentration in mesenteric lymph nodes justifies our hypothesis of targeting ILS and explains the major uptake of Tmx to occur via lymphatic system.

  7. Biodistribution and pharmacokinetics of the (99m)Tc labeled human elastase inhibitor, elafin, in rats.

    PubMed

    Kaschwich, Mark; Lützen, Ulf; Zhao, Yi; Tjiong, Angelina; Marx, Marlies; Haenisch, Sierk; Wiedow, Oliver; Preuss, Stefanie; Culman, Juraj; Zuhayra, Maaz

    2016-04-01

    Elafin is a potent reversible inhibitor of the pro-inflammatory proteases leukocyte elastase and protease 3. It is currently in clinical development for the use in postoperative inflammatory diseases. We investigated the pharmacokinetics of (99m)Tc-labeled elafin ((99m)Tc-Elafin) in blood and individual organs in rat after bolus intravenous injection using the single photon emission tomography (SPECT). (99m)Tc-Elafin predominantly accumulated in the kidney reaching a maximum of 8.5% ± 0.1% of the injected dose per gram (ID/g) at 5 min post injection (p.i) and decreased only slowly during 24 h. In contrast, the initially high radio activity recorded in the other organs rapidly decreased parallel to the radioactivity detected in blood. The blood kinetics fits to a two compartment kinetics model. The radio activity in the dissected kidney was 4.98 ± 1.24%ID/g 24 h p.i, while in other organs, including the brain, no accumulation of (99m)Tc-Elafin was detected. At this time point 30% of the detected radioactivity in the kidney was identified to be not metabolized (99m)Tc-Elafin. In conclusion, the blood and organ-specific kinetic data provide a basis for planning of adequate dosing regimens and the high accumulation of intact elafin in the kidney favors clinical developments targeting inflammatory kidney diseases, such as chronic allograft nephropathy after kidney transplantation.

  8. Noninvasive visualization of pharmacokinetics, biodistribution and tumor targeting of poly[N-(2-hydroxypropyl)methacrylamide] in mice using contrast enhanced MRI.

    PubMed

    Wang, Yanli; Ye, Furong; Jeong, Eun-Kee; Sun, Yongen; Parker, Dennis L; Lu, Zheng-Rong

    2007-06-01

    To study a non-invasive method of using contrast enhanced magnetic resonance imaging (MRI) to visualize the real-time pharmacokinetics, biodistribution and tumor accumulation of paramagnetically labeled poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) copolymer conjugates with different molecular weights and spacers in tumor-bearing mice. Paramagnetically labeled HPMA copolymer conjugates were synthesized by free radical copolymerization of HPMA with monomers containing a chelating ligand, followed by complexation with Gd(OAc)(3). A stable paramagnetic chelate, Gd-DO3A, was conjugated to the copolymers via a degradable spacer GlyPheLeuGly and a non-degradable spacer GlyGly, respectively. The conjugates with molecular weights of 28, 60 and 121 kDa and narrow molecular weight distributions were prepared by fractionation with size exclusion chromatography. The conjugates were injected into athymic nude mice bearing MDA-MB-231 human breast carcinoma xenografts via a tail vein. MR images were acquired before and at various time points after the injection with a 3D FLASH sequence and a 2D spin-echo sequence at 3T. Pharmacokinetics, biodistribution and tumor accumulation of the conjugates were visualized based on the contrast enhancement in the blood, major organs and tumor tissue at various time points. The size effect of the conjugates was analyzed among the conjugates. Contrast enhanced MRI resulted in a real-time, three-dimensional visualization of blood circulation, pharmacokinetics, biodistribution and tumor accumulation of the conjugates, and the size effect on these pharmaceutical properties. HPMA copolymer conjugates with high molecular weight had a prolonged blood circulation time and high passive tumor targeting efficiency. Non-biodegradable HPMA copolymers with molecular weights higher than the threshold of renal filtration demonstrated higher efficiency for tumor drug delivery than biodegradable poly(L-glutamic acid). Contrast enhanced MRI is an effective

  9. Pharmacokinetics and safety of intravitreal caspofungin.

    PubMed

    Shen, Ying-Cheng; Liang, Chiao-Ying; Wang, Chun-Yuan; Lin, Keng-Hung; Hsu, Min-Yen; Yuen, Hon-Leung; Wei, Li-Chen

    2014-12-01

    Caspofungin exhibits potent antifungal activities against Candida and Aspergillus species. The elimination rate and retinal toxicity of caspofungin were determined in this study to assess its pharmacokinetics and safety in the treatment of fungal endophthalmitis. Intravitreal injections of 50 μg/0.1 ml of caspofungin were administered to rabbits. Levels of caspofungin in the vitreous and aqueous humors were determined using high-performance liquid chromatography (HPLC) at selected time intervals (10 min and 1, 2, 4, 8, 16, 24, and 48 h), and the half-lives were calculated. Eyes were intravitreally injected with caspofungin to obtain concentrations of 10 μg/ml, 50 μg/ml, 100 μg/ml, and 200 μg/ml. Electroretinograms were recorded 4 weeks after injections, and the injected eyes were examined histologically. The concentrations of intravitreal caspofungin at various time points exhibited an exponential decay with a half-life of 6.28 h. The mean vitreous concentration was 6.06 ± 1.76 μg/ml 1 h after intravitreal injection, and this declined to 0.47 ± 0.15 μg/ml at 24 h. The mean aqueous concentration showed undetectable levels at all time points. There were no statistical differences in scotopic a-wave and b-wave responses between control eyes and caspofungin-injected eyes. No focal necrosis or other abnormality in retinal histology was observed. Intravitreal caspofungin injection may be considered to be an alternative treatment for fungal endophthalmitis based on its antifungal activity, lower retinal toxicity, and lower elimination rate in the vitreous. More clinical data are needed to determine its potential role as primary therapy for fungal endophthalmitis.

  10. Biodistribution and safety of a live attenuated tetravalent dengue vaccine in the cynomolgus monkey.

    PubMed

    Ravel, Guillaume; Mantel, Nathalie; Silvano, Jeremy; Rogue, Alexandra; Guy, Bruno; Jackson, Nicholas; Burdin, Nicolas

    2017-10-13

    The first licensed dengue vaccine is a recombinant, live, attenuated, tetravalent dengue virus vaccine (CYD-TDV; Sanofi Pasteur). This study assessed the biodistribution, shedding, and toxicity of CYD-TDV in a non-human primate model as part of the nonclinical safety assessment program for the vaccine. Cynomolgus monkeys were given one subcutaneous injection of either one human dose (5log10 CCID50/serotype) of CYD-TDV or saline control. Study endpoints included clinical observations, body temperature, body weight, food consumption, clinical pathology, immunogenicity, and post-mortem examinations including histopathology. Viral load, distribution, persistence, and shedding in tissues and body fluids were evaluated by quantitative reverse transcriptase polymerase chain reaction. The subcutaneous administration of CYD-TDV was well tolerated. There were no toxicological findings other than expected minor local reactions at the injection site. A transient low level of CYD-TDV viral RNA was detected in blood and the viral genome was identified primarily at the injection site and in the draining lymph nodes following immunization. These results, together with other data from repeat-dose toxicity and neurovirulence studies, confirm the absence of toxicological concern with CYD-TDV and corroborate clinical study observations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. In vivo pharmacokinetics, biodistribution and the anti-tumor effect of cyclic RGD-modified doxorubicin-loaded polymers in tumor-bearing mice.

    PubMed

    Wang, Chen; Li, Yuan; Chen, Binbin; Zou, Meijuan

    2016-10-01

    In our previous study, we successfully produced and characterized a multifunctional drug delivery system with doxorubicin (RC/GO/DOX), which was based on graphene oxide (GO) and cyclic RGD-modified chitosan (RC). Its characteristics include: pH-responsiveness, active targeting of hepatocarcinoma cells, and efficient loading with controlled drug release. Here, we report the pharmacokinetics, biodistribution, and anti-tumor efficacy of RC/GO/DOX polymers in tumor-bearing nude mice. The objective of this study is to assess its targeting potential for tumors. Pharmacokinetic and biodistribution profiles demonstrated that tumor accumulation of RC/GO/DOX polymers was almost three times higher than the others, highlighting the efficacy of the active targeting strategy. Furthermore, the tumor inhibition rate of RC/GO/DOX polymers was 56.64%, 2.09 and 2.93 times higher than that of CS/GO/DOX polymers (without modification) and the DOX solution, respectively. Anti-tumor efficacy results indicated that the tumor growth was better controlled by RC/GO/DOX polymers than the others. Hematoxylin and eosin (H&E) staining showed remarkable changes in tumor histology. Compared with the saline group, the tumor section from the RC/GO/DOX group revealed a marked increase in the quantity of apoptotic and necrotic cells, and a reduction in the quantity of the blood vessels. Together, these studies show that this new system could be regarded as a suitable form of DOX-based treatment of the hepatocellular carcinoma.

  12. Biodistribution and pharmacokinetics in rats and antitumor effect in various types of tumor-bearing mice of novel self-assembled gelatin-oleic acid nanoparticles containing paclitaxel.

    PubMed

    Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Lee, Beom-Jin

    2014-01-01

    The aim of this study was to investigate the pharmacokinetics and biodistribution in Sprague-Dawley rats, anti-tumor activity and acute toxicity in different tumor-bearing mice of novel biocompatible nanoparticles. Paclitaxel (PTX) was selected as a model drug and loaded on different tumor types and at various doses. The nanoparticles were prepared using a newly synthesized gelatin-oleic acid conjugate via self-assembly in an aqueous solution. The nanoparticles were further functionalized using folic acid (FA) as a targeting ligand for cancer. The in vivo effects of the nanoparticles were compared with the commercially available Taxol (a solution form of PTX) as a reference dosage form. The in vivo studies confirmed that nanoparticles showed improved therapeutic effects on tumors and significantly reduced the toxic effects associated with Taxol, even at the 50% lethal dose (LD50). The in vivo pharmacokinetic parameters and biodistribution of the nanoparticles containing PTX also indicated slower clearance, longer blood circulation and higher tumor selectivity. Furthermore, the functionalized nanoparticles with FA were more effective than the non-functionalized nanoparticles. Thus, the suitable properties of gelatin-oleic nanoparticles (GON) as a drug carrier and the effective targeting ligand could synergistically maximize the in vivo anti-tumor efficacy resulting in delayed tumor volume growth and hence, providing versatile strategies in cancer therapy and drug delivery.

  13. Biodistribution, pharmacokinetics, and nuclear imaging studies of 111In-labeled rGel/BLyS fusion toxin in SCID mice bearing B cell lymphoma.

    PubMed

    Wen, Xiaoxia; Lyu, Mi-Ae; Zhang, Rui; Lu, Wei; Huang, Qian; Liang, Dong; Rosenblum, Michael G; Li, Chun

    2011-08-01

    We examined the biodistribution and pharmacokinetics of (111)In-labeled rGel/BLyS, a gelonin toxin (rGel)-B lymphocyte stimulator (BLyS) fusion protein. rGel/BLyS was labeled with In-111 through DTPA with a labeling efficiency >95%. Biodistribution/imaging studies were obtained in severe-combined immunodeficiency mice bearing diffuse large B cell lymphoma OCI-Ly10. Pharmacokinetic studies were performed in BALB/c mice. In vitro, DTPA-conjugated rGel/BLyS displayed selective cytotoxicity against OCI-Ly10 cells and mantle cell lymphoma JeKo cells. In vivo, rGel/BLyS exhibited a tri-exponential disposition with a rapid initial mean distribution followed by an extensive mean distribution and a long terminal elimination phase. At 48 h after injection, uptake of the radiotracer in tumors was 1.25 %ID/g, with a tumor-to-blood ratio of 13. Tumors were clearly visualized at 24-72 h post-injection. Micro-SPECT-CT images and ex vivo analyses confirmed the accumulation of rGel/BLyS in OCI-Ly10 tumors. (111)In-DTPA-rGel/BLyS are distributed to B cell tumors and induce apoptosis in tumors. Preclinical antitumor studies using rGel/BLyS should use a twice-per-week treatment schedule.

  14. Pharmacokinetic, biodistribution and therapeutic efficacy of 5-fluorouracil-loaded pH-sensitive PEGylated liposomal nanoparticles in HCT-116 tumor bearing mouse

    PubMed Central

    Udofot, Ofonime; Affram, Kevin; Smith, Taylor; Tshabe, Bulumko; Krishnan, Sunil; Sachdeva, Mandip; Agyare, Edward

    2016-01-01

    The objective of the study was to investigate the pharmacokinetics and efficacy of 5-FU entrapped pH-sensitive liposomal nanoparticles with surface-modified anti-epidermal growth factor receptor (EGFR) antibody (pHLNps-5-FU) delivery system. Cytotoxicity of 5-FU and pHLNps-5-FU was determined in vitro against HCT-116 cells. The biodistribution and pharmacokinetic parameters of the administered 5-FU and pHLNps-5-FU as well as efficacy of 5-FU and pHLNps-5-FU were determined in HCT-116 subcutaneous mouse model. Mean size of pHLNp-5-FU was 164.3 ± 8.4 nm with entrapment efficiency (E.E) of 54.17%. While cytotoxicity of 5-FU and pHLNps-5-FU showed a strong dose-dependent, pHLNps-5-FU proved to be more effective (2–3 fold high) than that of 5-FU against HCT-116 cells. Pharmacokinetic study showed a prolonged plasma circulation of pHLNps-5-FU and a more significant body exposure while accumulation of pHLNps-5-FU in tumor was significantly higher than that of free 5-FU. Further, the efficacy of pHLNps-5-FU, was greater than free 5-FU at equivalent 5-FU dose. The study suggests that pHLNps may be an effective drug delivery system to enhance the anticancer activity of 5-FU against colorectal tumor growth. PMID:27200415

  15. Pharmacokinetics and biodistribution of squalene-containing emulsion adjuvant following intramuscular injection of H5N1 influenza vaccine in mice.

    PubMed

    Tegenge, Million A; Von Tungeln, Linda S; Mitkus, Robert J; Anderson, Steven A; Vanlandingham, Michelle M; Forshee, Richard A; Beland, Frederick A

    2016-11-01

    Squalene is a component of oil-in-water emulsion adjuvants developed for potential use in some influenza vaccines. The biodistribution of the squalene-containing emulsion adjuvant (AddaVax™) alone and as part of complete H5N1 vaccine was quantified in mechanistically and toxicologically relevant target tissues up to 336 h (14 days) following injection into quadriceps muscle. At 1 h, about 55% of the intramuscularly injected dose of squalene was detected in the local quadriceps muscles and this decreased to 26% at 48 h. Twenty-four hours after the injection, approximately 5%, 1%, and 0.6% of the injected dose was detected in inguinal fat, draining lymph nodes, and sciatic nerve, respectively. The peak concentration for kidney, brain, spinal cord, bone marrow, and spleen was each less than 1% of the injected dose, and H5N1 antigen did not significantly alter the biodistribution of squalene to these tissues. The area-under-blood-concentration curve (AUC) and peak blood concentration (Cmax) of squalene were slightly higher (20-25%) in the presence of H5N1 antigen. A population pharmacokinetic model-based statistical analysis identified body weight and H5N1 antigen as covariates influencing the clearance of squalene. The results contribute to the body of knowledge informing benefit-risk analyses of squalene-containing emulsion vaccine adjuvants. Published by Elsevier Inc.

  16. Biodistribution and pharmacokinetics of variously molecular sized 117mSn(II)-polyethyleneiminomethyl phosphonate complexes in the normal primate model as potential selective therapeutic bone agents.

    PubMed

    Zeevaart, Jan R; Louw, Werner K A; Kolar, Zvonimir I; Kilian, Elmaré; van Rensburg, Frederika E Jansen; Dormehl, Irene C

    2004-01-01

    In the search for a cure for metastatic bone cancer, 117mSn with its conversion electrons and low energy photons both of discrete energies shows little bone marrow toxicity, providing the opportunity to increase the administered dose. Selective accumulation in lesions would capitalise on this advantage. The 10-30 kDa fraction of the water-soluble polymer polyethyleneimine, functionalised with methyl phosphonate groups (PEI-MP) and labelled with 99mTc, has shown selective uptake into bone tumours. Furthermore using speciation calculations it was predicted that the Sn(II)-PEI-MP complex would remain intact in the blood plasma. Because of this positive indication animal experiments were carried out to test this prediction. This paper relates the labelling, biodistribution and pharmacokinetics of various fractions of 117mSn-(II) PEI-MP in the normal primate model, and points to promising therapeutic possibilities.

  17. A Phase 1, Open-Label Study of the Biodistribution, Pharmacokinetics, and Dosimetry of 223Ra-Dichloride in Patients with Hormone-Refractory Prostate Cancer and Skeletal Metastases.

    PubMed

    Chittenden, Sarah J; Hindorf, Cecilia; Parker, Christopher C; Lewington, Valerie J; Pratt, Brenda E; Johnson, Bernadette; Flux, Glenn D

    2015-09-01

    The aim of this single-site, open-label clinical trial was to determine the biodistribution, pharmacokinetics, absorbed doses, and safety from 2 sequential weight-based administrations of (223)Ra-dichloride in patients with bone metastases due to castration-refractory prostate cancer. Six patients received 2 intravenous injections of (223)Ra-dichloride, 6 wk apart, at 100 kBq/kg of whole-body weight. The pharmacokinetics and biodistribution as a function of time were determined, and dosimetry was performed for a range of organs including bone surfaces, red marrow, kidneys, gut, and whole body using scintigraphic imaging; external counting; and blood, fecal, and urine collection. Safety was assessed from adverse events. The injected activity cleared rapidly from blood, with 1.1% remaining at 24 h. The main route of excretion was via the gut, although no significant toxicity was reported. Most of the administered activity was taken up rapidly into bone (61% at 4 h). The range of absorbed doses delivered to the bone surfaces from α emissions was 2,331-13,118 mGy/MBq. The ranges of absorbed doses delivered to the red marrow were 177-994 and 1-5 mGy/MBq from activity on the bone surfaces and from activity in the blood, respectively. No activity-limiting toxicity was observed at these levels of administration. The absorbed doses from the second treatment were correlated significantly with the first for a combination of the whole body, bone surfaces, kidneys, and liver. A wide range of interpatient absorbed doses was delivered to normal organs. Intrapatient absorbed doses were significantly correlated between the 2 administrations for any given patient. The lack of gastrointestinal toxicity is likely due to the low absorbed doses delivered to the gut wall from the gut contents. The lack of adverse myelotoxicity implies that the absorbed dose delivered from the circulating activity may be a more relevant guide to the potential for marrow toxicity than that due to activity

  18. Biodistribution and Pharmacokinetic Analysis of Combination Lonidamine and Paclitaxel Delivery in an Orthotopic Animal Model of Multi-drug Resistant Breast Cancer Using EGFR-Targeted Polymeric Nanoparticles

    PubMed Central

    Milane, Lara; Duan, Zhen-feng; Amiji, Mansoor

    2011-01-01

    The aim of this study was to assess the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)-targeted polymer blend nanoparticles loaded with the anticancer drugs lonidamine and paclitaxel. Plasma, tumor, and tissue distribution profiles were quantified in an orthotopic animal model of multi-drug resistant (MDR) breast cancer and were compared to treatment with non-targeted nanoparticles and to treatment with drug solution. Poly(D,L-lactide-co-glycolide)/poly(ethylene glycol)/EGFR targeting peptide (PLGA/PEG/EFGR peptide) construct was synthesized for incorporation in poly(ε-caprolactone) (PCL) particles to achieve active EGFR targeting. An isocratic HPLC method was developed to quantify lonidamine and paclitaxel in mice plasma, tumors, and vital organs. The targeted nanoparticles demonstrated superior pharmacokinetic profile relative to drug solution and non-targeted nanoparticles, particularly for lonidamine delivery. The first target site of accumulation is the liver, followed by the kidneys, and then the tumor mass; maximal tumor accumulation occurs at 3 hours post-administration. Lonidamine/paclitaxel combination therapy administered via EGFR-targeted polymer blend nanocarriers may become a viable platform for the future treatment of MDR cancer. PMID:21220050

  19. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease.

    PubMed

    Binley, Katie; Widdowson, Peter; Loader, Julie; Kelleher, Michelle; Iqball, Sharifah; Ferrige, Georgina; de Belin, Jackie; Carlucci, Marie; Angell-Manning, Diana; Hurst, Felicity; Ellis, Scott; Miskin, James; Fernandes, Alcides; Wong, Paul; Allikmets, Rando; Bergstrom, Christopher; Aaberg, Thomas; Yan, Jiong; Kong, Jian; Gouras, Peter; Prefontaine, Annick; Vezina, Mark; Bussieres, Martin; Naylor, Stuart; Mitrophanous, Kyriacos A

    2013-06-12

    StarGen is an equine infectious anemia virus (EIAV)-based lentiviral vector that expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein that is mutated in Stargardt disease (STGD1), a juvenile macular dystrophy. EIAV vectors are able to efficiently transduce rod and cone photoreceptors in addition to retinal pigment epithelium in the adult macaque and rabbit retina following subretinal delivery. The safety and biodistribution of StarGen following subretinal delivery in macaques and rabbits was assessed. Regular ophthalmic examinations, IOP measurements, ERG responses, and histopathology were carried out in both species to compare control and vector-treated eyes. Tissue and fluid samples were obtained to evaluate the persistence, biodistribution, and shedding of the vector following subretinal delivery. Ophthalmic examinations revealed a slightly higher level of inflammation in StarGen compared with control treated eyes in both species. However, inflammation was transient and no overt toxicity was observed in StarGen treated eyes and there were no abnormal clinical findings. There was no StarGen-associated rise in IOP or abnormal ERG response in either rabbits or macaques. Histopathologic examination of the eyes did not reveal any detrimental changes resulting from subretinal administration of StarGen. Although antibodies to StarGen vector components were detected in rabbit but not macaque serum, this immunologic response did not result in any long-term toxicity. Biodistribution analysis demonstrated that the StarGen vector was restricted to the ocular compartment. In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration.

  20. Transduction of Photoreceptors With Equine Infectious Anemia Virus Lentiviral Vectors: Safety and Biodistribution of StarGen for Stargardt Disease

    PubMed Central

    Binley, Katie; Widdowson, Peter; Loader, Julie; Kelleher, Michelle; Iqball, Sharifah; Ferrige, Georgina; de Belin, Jackie; Carlucci, Marie; Angell-Manning, Diana; Hurst, Felicity; Ellis, Scott; Miskin, James; Fernandes, Alcides; Wong, Paul; Allikmets, Rando; Bergstrom, Christopher; Aaberg, Thomas; Yan, Jiong; Kong, Jian; Gouras, Peter; Prefontaine, Annick; Vezina, Mark; Bussieres, Martin; Naylor, Stuart; Mitrophanous, Kyriacos A.

    2013-01-01

    Purpose. StarGen is an equine infectious anemia virus (EIAV)-based lentiviral vector that expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein that is mutated in Stargardt disease (STGD1), a juvenile macular dystrophy. EIAV vectors are able to efficiently transduce rod and cone photoreceptors in addition to retinal pigment epithelium in the adult macaque and rabbit retina following subretinal delivery. The safety and biodistribution of StarGen following subretinal delivery in macaques and rabbits was assessed. Methods. Regular ophthalmic examinations, IOP measurements, ERG responses, and histopathology were carried out in both species to compare control and vector-treated eyes. Tissue and fluid samples were obtained to evaluate the persistence, biodistribution, and shedding of the vector following subretinal delivery. Results. Ophthalmic examinations revealed a slightly higher level of inflammation in StarGen compared with control treated eyes in both species. However, inflammation was transient and no overt toxicity was observed in StarGen treated eyes and there were no abnormal clinical findings. There was no StarGen-associated rise in IOP or abnormal ERG response in either rabbits or macaques. Histopathologic examination of the eyes did not reveal any detrimental changes resulting from subretinal administration of StarGen. Although antibodies to StarGen vector components were detected in rabbit but not macaque serum, this immunologic response did not result in any long-term toxicity. Biodistribution analysis demonstrated that the StarGen vector was restricted to the ocular compartment. Conclusions. In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration. PMID:23620430

  1. Folic acid functionalized long-circulating co-encapsulated docetaxel and curcumin solid lipid nanoparticles: In vitro evaluation, pharmacokinetic and biodistribution in rats.

    PubMed

    Pawar, Harish; Surapaneni, Sunil Kumar; Tikoo, Kulbhushan; Singh, Charan; Burman, Rohani; Gill, Manjinder Singh; Suresh, Sarasija

    2016-05-01

    The purpose of this study was to develop folic acid functionalized long-circulating co-encapsulated docetaxel (DTX) and curcumin (CRM) solid lipid nanoparticles (F-DC-SLN) to improve the pharmacokinetic and efficacy of DTX therapy. F-DC-SLN was prepared by hot melt-emulsification method and optimized by face centered-central composite design (FC-CCD). The SLN was characterized in terms of size and size distribution, drug entrapment efficiency and release profile. The cytotoxicity and cell uptake of the SLN formulations were evaluated in MCF-7 and MDA-MB-231 cell lines. The in vivo pharmacokinetic and biodistribution were studied in Wistar rats. F-DC-SLN exhibited 247.5 ± 3.40 nm particle size with 73.88 ± 1.08% entrapment efficiency and zeta potential of 14.53 ± 3.6 mV. Transmission electron microscopy (TEM) revealed spherical morphology of the SLN. Fluorescence microscopy confirmed the targeting efficacy of F-DC-SLN in MCF-7 cells. F-DC-SLN exhibited a significant increase in area under the curve (594.21 ± 64.34 versus 39.05 ± 7.41 μg/mL h) and mean residence time (31.14 ± 19.94 versus 7.24 ± 4.51 h) in comparison to Taxotere®. In addition, decreased DTX accumulation from F-DC-SLN in the heart and kidney in comparison to Taxotere may avoid to toxicity these vital organs. In conclusion, the F-DC-SLN improved the efficacy and pharmacokinetic profile of DTX exhibiting enhanced potential in optimizing breast cancer therapy.

  2. Biodistribution, pharmacokinetic, and imaging studies with sup 186 Re-labeled NR-LU-10 whole antibody in LS174T colonic tumor-bearing mice

    SciTech Connect

    Goldrosen, M.H.; Biddle, W.C.; Pancook, J.; Bakshi, S.; Vanderheyden, J.L.; Fritzberg, A.R.; Morgan, A.C. Jr.; Foon, K.A. )

    1990-12-15

    Biodistribution, pharmacokinetic, and radioimaging studies were performed with 186Re-labeled NR-LU-10 whole antibody in athymic nude mice bearing the LS174T tumor growing either s.c. or in an experimental hepatic metastasis model. NR-LU-10 is an IgG2b murine monoclonal antibody (MAb) that reacts with virtually all human tumors of epithelial origin. NR-BC-1, a IgG2b murine MAb that reacts with normal human B-cell and B malignancies, was used as an isotype-matched control. These MAbs were radiolabeled with 186Re by a preformed chelate approach by using the triamide thiolate ligand system. 186Re-labeled NR-LU-10 (50 microCi) was injected into nude mice bearing LS174T tumors growing s.c. Biodistribution studies revealed that the LS174T tumor retained the highest concentration of 186Re-labeled NR-LU-10 at day 6. The tumor:blood ratio ranged from 0.1:1 to 10.8:1 by day 6, the last day of analysis. In contrast the tumor:blood ratio of 186Re-labeled NR-BC-1, the isotype-matched MAb control, was 1:1 on day 6. Pharmacokinetic analysis indicated that the t1/2 beta of NR-LU-10 for blood and other tissues ranged from 21 to 25 h, while the t1/2 beta for the LS174T tumor averaged 52 h. The area under the curve for tumor compared to blood was 2.8- to 5.7-fold higher than the area under the curve for all other tissues and organs. The mean residence time for NR-LU-10 in blood and all other organs ranged from 23 to 26 h, while the mean residence time for NR-LU-10 in the LS174T tumor was 72 h. Scintigraphic images revealed selective uptake of the 186Re-labeled NR-LU-10, but not of the 186Re-labeled NR-BC-1, at the LS174T tumor site. Studies in an experimental model of hepatic metastasis revealed a similar selective pattern of 186Re-labeled NR-LU-10 accumulation. Scintigraphic images of the LS174T tumor growing within the athymic nude mouse liver were obtained.

  3. Biodistribution and safety assessment of AAV2-GAD following intrasubthalamic injection in the rat

    PubMed Central

    Fitzsimons, Helen L.; Riban, Veronique; Bland, Ross J.; Wendelken, Jennifer L.; Sapan, Christine V.; During, Matthew J.

    2010-01-01

    Background The steps necessary to translate promising new biological therapies to the clinic are poorly documented. For gene therapy there are unique aspects that need to be addressed in biodistribution studies. Notably, spread of the vector beyond the intended target cells or tissue may result in persistent unwanted biological activity or unpredictable biological events, thus it is critical to evaluate risks associated with viral vector-mediated gene transfer prior to embarking on human clinical trials. Methods Here we present a rodent study comprising of a comprehensive assessment of vector biodistribution through the brain, blood and major organs of rats injected into the subthalamic nucleus with recombinant adeno-associated virus (AAV) expressing glutamic acid decarboxylase (GAD). In addition, behavioral and histological analyses were also performed. Results AAV genomes were not detected in blood or CSF, and did not disseminate to organs outside of the brain in the majority of animals. In the brain, an average 97.3% of AAV2-GAD genomes were restricted to the area of the ipsilateral STN. There were no discernable effects of AAV2-GAD on general health and behavioral assessment of the animals did not reveal any alteration in general behavior, exploration, locomotion or motor symmetry. Conclusions This study met FDA requirements, in addition to efficacy and toxicity studies in rodents and non-human primates, to support and supplement a Phase II clinical trial for gene transfer of AAV2-GAD to the human STN for the potential therapy of Parkinson’s disease. PMID:20352617

  4. [Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis].

    PubMed

    Goullé, Jean-Perre; Guerbet, Michel

    2014-03-01

    Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself.

  5. The Pharmacokinetics and Biodistribution of a 64 kDa PolyPEG Star Polymer After Subcutaneous and Pulmonary Administration to Rats.

    PubMed

    Khor, Song Yang; Hu, Jinming; McLeod, Victoria M; Quinn, John F; Porter, Christopher J H; Whittaker, Michael R; Kaminskas, Lisa M; Davis, Thomas P

    2016-01-01

    PolyPEG star polymers have potential utility as cost-effective polymeric drug delivery vehicles, and as such, it is important to develop an understanding of their biopharmaceutical behavior. Moreover, although a number of studies have evaluated the utility of PolyPEG stars in vitro, investigation of these novel materials in vivo has been limited. Herein, we evaluated the pharmacokinetics of a 64 kDa tritiated PEG-based star polymer after subcutaneous and pulmonary administration in rats. After subcutaneous administration, the star polymer showed near complete bioavailability (∼80%) and a similar organ biodistribution profile to the polymer after intravenous administration. After intratracheal instillation to the lungs, the star polymer showed limited bioavailability (∼3%), and most of the administered radiolabel was recovered in lung tissue and feces after 6 d. The data reported here suggest that star polymers display similar pharmaceutical behavior to PEGylated dendrimers after subcutaneous and inhaled delivery and may therefore be used as similar, but more cost-effective drug delivery vehicles. Copyright © 2016. Published by Elsevier Inc.

  6. Biodistribution and pharmacokinetic analysis of Paclitaxel and ceramide administered in multifunctional polymer-blend nanoparticles in drug resistant breast cancer model.

    PubMed

    van Vlerken, Lilian E; Duan, Zhenfeng; Little, Steven R; Seiden, Michael V; Amiji, Mansoor M

    2008-01-01

    In this study, we have investigated the biodistribution and pharmacokinetic analysis of paclitaxel (PTX) and the apoptotic signaling molecule, C6-ceramide (CER), when administered in a multifunctional polymer-blend nanoparticle formulation to female nude mice bearing an orthotopic drug sensitive MCF7 and multidrug resistant MCF7 TR (MDR-1 positive) human breast adenocarcinoma. A polymer-blend nanoparticle system was engineered to incorporate temporally controlled sequential release of the combination drug payload. Hereby, PTX was encapsulated in the pH-responsive rapid releasing polymer, poly(beta-amino ester) (PbAE), while CER was present in the slow releasing polymer, poly(D,L-lactide-co-glycolide) (PLGA) within these blend nanoparticles. When particle formulations were administered intravenously to MCF7 and MCF7 TR tumor bearing mice, higher concentrations of PTX were found in the blood due to longer retention time and an enhanced tumor accumulation relative to administration of free drug. In addition, the PLGA/PbAE blend nanoparticles were effective in enhancing the residence time of both drugs at the tumor site by reducing systemic clearance. Overall, these results are highly encouraging for development of multifunctional polymer-blend nanoparticle formulations that can be used for temporal-controlled administration of two drugs from a single formulation.

  7. Comparative biodistribution and safety profiling of olmesartan medoxomil oil-in-water oral nanoemulsion.

    PubMed

    Gorain, Bapi; Choudhury, Hira; Tekade, Rakesh Kumar; Karan, Saumen; Jaisankar, P; Pal, Tapan Kumar

    2016-12-01

    Poor aqueous solubility and unfavourable de-esterification of olmesartan medoxomil (a selective angiotensin II receptor blocker), results in low oral bioavailability of less than 26%. Improvement of oral bioavailability with prolonged pharmacodynamics activity of olmesartan in Wistar rats had been approached by nanoemulsification strategy in our previous article [Colloid Surface B, 115, 2014: 286]. In continuation to that work, we herewith report the biodistribution behaviour and 28-day repeated dose sub-chronic toxicity of olmesartan medoxomil nanoemulsion in Wistar rats following oral administration. The levels of olmesartan in collected biological samples were estimated using our validated LC-MS/MS technique. Our biodistribution study showed significantly higher brain concentrations of olmesartan (0.290 ± 0.089 μg/mL, 0.333 ± 0.071 μg/mL and 0.217 ± 0.062 μg/mL at 0.5, 2.0 and 8.0 h post dosing, respectively) when administered orally as nanoemulsion formulation as compared to the aqueous suspension. In addition, the olmesartan nanoemulsion was found to be safe and non-toxic, as it neither produced any lethality nor remarkable haematological, biochemical and structural adverse effects as observed during the 28-days sub-chronic toxicity studies in experimental Wistar rats. It is herewith envisaged that the developed nanoemulsion formulation approach for the delivery of olmesartan medoxomil via oral route can further be explored in memory dysfunction and brain ischemia, for better brain penetration and improved clinical application in stroke patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Pharmacokinetics and preliminary safety evaluation of azithromycin in adult horses.

    PubMed

    Leclere, M; Magdesian, K G; Cole, C A; Szabo, N J; Ruby, R E; Rhodes, D M; Edman, J; Vale, A; Wilson, W D; Tell, L A

    2012-12-01

    Azithromycin is widely used in foals but has not been studied in adult horses. The goals of this study were to determine the pharmacokinetic profile and to make a preliminary assessment of the safety of azithromycin in adult horses. Azithromycin was administered intravenously (5 mg/kg) and intragastrically (10 mg/kg) to six healthy mares in a crossover design. Serial plasma samples, blood neutrophils, and pulmonary macrophages were collected for the measurement of azithromycin concentrations. Azithromycin was also administered orally (10 mg/kg) once a day for 5 days to five healthy mares for preliminary evaluation of safety in adult horses. The bioavailability of azithromycin following intragastric administration was 45 ± 12%. Concentrations within peripheral neutrophils and bronchoalveolar macrophages were several fold higher than that of plasma. Mild decreases in appetite (n = 3) and alterations in fecal consistency (n = 3) were noted following repeated oral administration. The pharmacokinetic profiles of azithromycin in adult horses, especially the slow elimination rate and intraneutrophil and intrapulmonary macrophage accumulation, demonstrate that it is conducive to use in this age group. Because of the gastrointestinal alterations noted, further studies are warranted before azithromycin can be recommended for use in adult horses.

  9. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension.

    PubMed

    Savale, Laurent; Magnier, Romain; Le Pavec, Jérôme; Jaïs, Xavier; Montani, David; O'Callaghan, Dermot S; Humbert, Marc; Dingemanse, Jasper; Simonneau, Gérald; Sitbon, Olivier

    2013-01-01

    Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomised controlled trials with pulmonary arterial hypertension (PAH)-specific therapies. This study investigated the short- and long-term efficacy/safety of bosentan in these patients, as well as its pharmacokinetics. All 34 consecutive patients with PoPH treated with first-line bosentan (December 2002 to July 2009) were retrospectively evaluated. Assessments included the New York Heart Association functional class (NYHA FC), blood tests, haemodynamics, 6-min walk distance (6MWD) and event-free status. The pharmacokinetics of bosentan in five patients with Child-Pugh (C-P) class B cirrhosis were compared with idiopathic PAH patients. Significant improvements from baseline were observed in NYHA FC, 6 MWD and haemodynamics, and were largely maintained during follow-up. Patients with C-P class B cirrhosis (n=9) had significantly larger haemodynamic improvement after mean ± SD 5 ± 2 months. Mean follow-up time was 43 ± 19 months; four patients died and seven patients had significant elevation of liver enzymes (annual rate 5.5%). Plasma concentrations of bosentan were higher in patients with C-P class B cirrhosis than those observed in idiopathic PAH. These data confirm the benefit of bosentan treatment for patients with PoPH. Haemodynamic improvements were particularly pronounced in patients with more severe cirrhosis. The safety profile of bosentan was consistent with previous studies.

  10. Biodistribution and Pharmacokinetics of EGFR-Targeted Thiolated Gelatin Nanoparticles Following Systemic Administration in Pancreatic Tumor-Bearing Mice

    PubMed Central

    Xu, Jing; Gattacceca, Florence; Amiji, Mansoor

    2013-01-01

    The objective of this study was to evaluate qualitative and quantitative biodistribution of epidermal growth factor receptor (EGFR)-targeted thiolated type B gelatin nanoparticles in vivo in a subcutaneous human pancreatic adenocarcinoma (Panc-1) bearing female SCID Beige mice. EGFR-targeted nanoparticles showed preferential and sustained accumulation in the tumor mass, especially at early time points. Higher blood concentrations and higher tumor accumulations were observed with PEG-modified and EGFR-targeted nanoparticles during the study (AUClast: 17.38 and 19.56 %ID/mL*h in blood, 187 and 322 %ID/g*h in tumor for PEG-modified and EGFR-targeted nanoparticles, respectively), as compared to control, unmodified particles (AUClast: 10.71 %ID/mL*h in blood and 138 %ID/g*h in tumor). EGFR-targeted nanoparticles displayed almost twice tumor targeting efficiency than either PEG-modified or the unmodified nanoparticles, highlighting the efficacy of the active targeting strategy. In conclusion, this study shows that EGFR-targeted and PEG-modified nanoparticles were suitable vehicles for specific systemic delivery in subcutaneous Panc-1 tumor xenograft models. PMID:23544877

  11. Pharmacokinetics, biodistribution and metabolism of squalenoyl adenosine nanoparticles in mice using dual radio-labeling and radio-HPLC analysis.

    PubMed

    Gaudin, Alice; Lepetre-Mouelhi, Sinda; Mougin, Julie; Parrod, Martine; Pieters, Grégory; Garcia-Argote, Sébastien; Loreau, Olivier; Goncalves, Jordan; Chacun, Hélène; Courbebaisse, Yann; Clayette, Pascal; Desmaële, Didier; Rousseau, Bernard; Andrieux, Karine; Couvreur, Patrick

    2015-08-28

    Adenosine is a pleiotropic endogenous nucleoside with potential neuroprotective pharmacological activity. However, clinical use of adenosine is hampered by its extremely fast metabolization. To overcome this limitation, we recently developed a new squalenoyl nanomedicine of adenosine [Squalenoyl-Adenosine (SQAd)] by covalent linkage of this nucleoside to the squalene, a natural lipid. The resulting nanoassemblies (NAs) displayed a dramatic pharmacological activity both in cerebral ischemia and spinal cord injury pre-clinical models. The aim of the present study was to investigate the plasma profile and tissue distribution of SQAd NAs using both Squalenoyl-[(3)H]-Adenosine NAs and [(14)C]-Squalenoyl-Adenosine NAs as respective tracers of adenosine and squalene moieties of the SQAd bioconjugate. This study was completed by radio-HPLC analysis allowing to determine the metabolization profile of SQAd. We report here that SQAd NAs allowed a sustained circulation of adenosine under its prodrug form (SQAd) for at least 1h after intravenous administration, when free adenosine was metabolized within seconds after injection. Moreover, the squalenoylation of adenosine and its formulation as NAs also significantly modified biodistribution, as SQAd NAs were mainly captured by the liver and spleen, allowing a significant release of adenosine in the liver parenchyma. Altogether, these results suggest that SQAd NAs provided a reservoir of adenosine into the bloodstream which may explain the previously observed neuroprotective efficacy of SQAd NAs against cerebral ischemia and spinal cord injury. Copyright © 2015. Published by Elsevier B.V.

  12. Evaluation of a Flexible NOTA-RGD Kit Solution Using Gallium-68 from Different (68)Ge/(68)Ga-Generators: Pharmacokinetics and Biodistribution in Nonhuman Primates and Demonstration of Solitary Pulmonary Nodule Imaging in Humans.

    PubMed

    Ebenhan, Thomas; Schoeman, Isabel; Rossouw, Daniel D; Grobler, Anne; Marjanovic-Painter, Biljana; Wagener, Judith; Kruger, Hendrik G; Sathekge, Mike M; Zeevaart, Jan Rijn

    2017-06-01

    Radiopharmaceuticals containing the motive tripeptide arginyl-glycyl-asparatic acid (RGD) are known to target ανβ3 integrins during tumor angiogenesis. A more generic kit radiolabeling procedure accommodating Ga-68 from different generators was developed for NOTA-RGD and evaluated for its versatile use and safety in subsequent in vivo applications. The [(68)Ga]NOTA-RGD kit was further verified for its expected biodistribution and pharmacokinetics in nonhuman primates and its clinical sensitivity to detect solitary pulmonary nodules (SPN) in cancer patients. Single vial kits containing 28-56 nmol of NOTA-cyclo-Arg-Gly-Asp-d-Tyr-Lys (NOTA-RGD) and sodium acetate trihydrate buffer were formulated. Versatility of the NOTA-RGD radiolabeling performance and adaption to a TiO2- and a SnO2-based generator type, characterization and long-term storage stability of the kits were carried out. The blood clearance and urine recovery kinetics as well as the image-guided biodistribution of [(68)Ga]NOTA-RGD was studied in a vervet monkey model. [(68)Ga]NOTA-RGD kits were further tested clinically to target solitary pulmonary nodules. The kits could be successfully formulated warranting integrity over 3-4 months with a good [(68)Ga]NOTA-RGD radiolabeling performance (radiochemical purity >95 %, decay corrected yield 76-94 %, specific activity of 8.8-37.9 GBq/μmol) The kits met all quality requirements to be further tested in vivo. [(68)Ga]NOTA-RGD cleared rapidly from blood and was majorly excreted via the renal route. The liver, spleen, heart and intestines showed initial uptake with steadily declining tissue activity concentration over time. In addition, the [(68)Ga]NOTA-RGD kit allowed for delineation of SPN from non-malignant lung tissue in humans. A more versatile radiolabeling procedure using kit-formulated NOTA-RGD and different generator types was achieved. The uncompromised in vivo behavior and efficient targeting of SPN warrants further investigations on the

  13. Pharmacokinetics and safety of eszopiclone in healthy Chinese volunteers.

    PubMed

    Wu, F; Zhao, X L; Wei, M J; Wang, S M; Zhou, H; Guo, S J; Zhang, P

    2012-12-01

    The main objective of this study was to investigate the pharmacokinetic characters of eszopiclone (CAS: 138729-47-2) after single and multiple-dose oral administration in healthy adult Chinese volunteers.In single-dose study, 12 subjects were given oral administrations of 1.5, 3 and 6 mg eszopiclone in an open-label, randomized, crossover fashion. In multiple-dose study, 8 subjects were given 3 mg eszopiclone once daily consecutively for 7 days. Blood samples were collected over 24 h and plasma eszopiclone were determined using a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay. The safety and tolerability of eszopiclone was evaluated by adverse events recording, physical examination, laboratory testing, vital signs, and 12-lead ECG findings.The main pharmacokinetic parameters of eszopiclone after single-dose administration were as follows: doses of 1.5, 3 and 6 mg; Cmax of 18.08±4.65, 38.29±15.41 and 76.38±23.34 ng/ml; Tmax of 0.94±0.39, 1.04±0.63 and 1.08±0.51 h; AUC0-24 of 110.90±23.06, 227.36±62.41 and 504.10±140.13 ng*h/ml; elimination half-lives of 5.84±1.03, 5.53±1.91 and 6.17±1.23 h. After multiple-dose administration, the steady-state levels of eszopiclone were achieved by the 4th day, and the main pharmacokinetic parameters were Css_max at 33.43±5.63 ng/ml and AUCss (0-24) at 263.30±51.21 ng*h/ml. The most common adverse event was bitter or abnormal taste. All the adverse events were judged as mild to moderate and resolved without any medication.The pharmacokinetic character of eszopiclone is linear and dose-proportional over the range of 1.5-6 mg. The systemic exposure does not accumulate with once-daily administrations. Eszopiclone appears to have good safety and is well tolerated.

  14. In vivo pharmacokinetics, biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle.

    PubMed

    Rezazadeh, Mahboubeh; Emami, Jaber; Hasanzadeh, Farshid; Sadeghi, Hojjat; Minaiyan, Mohsen; Mostafavi, Abolfazl; Rostami, Mahboubeh; Lavasanifar, Afsaneh

    2016-06-01

    A water-insoluble anti-tumor agent, paclitaxel (PTX) was successfully incorporated into novel-targeted polymeric micelles based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (PTX/TS-CS-PEG-FA). The aim of the present study was to evaluate the pharmacokinetics, tissue distribution and efficacy of PTX/TS-CS-PEG-FA in comparison to Anzatax® in tumor bearing mice. The micellar formulation showed higher in vitro cytotoxicity against mice breast cancer cell line, 4T1, due to the folate receptor-mediated endocytosis. The IC50 value of PTX, a concentration at which 50% cells are killed, was 1.17 and 0.93 µM for Anzatax® and PTX/TS-CS-PEG-FA micelles, respectively. The in vivo anti-tumor efficacy of PTX/TS-CS-PEG-FA, as measured by reduction in tumor volume of 4T1 mouse breast cancer injected in Balb/c mice was significantly greater than that of Anzatax®. Pharmacokinetic study in tumor bearing mice revealed that the micellar formulation prolonged the systemic circulation time of PTX and the AUC of PTX/TS-CS-PEG-FA was obtained 0.83-fold lower than Anzatax®. Compared with Anzatax®, the Vd, T1/2ß and MRT of PTX/TS-CS-PEG-FA was increased by 2.76, 2.05 and 1.68-fold, respectively. As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Taken together, our evaluations show that PTX/TS-CS-PEG-FA micelle is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for intravenous administration of PTX.

  15. Rufinamide in children with refractory epilepsy: pharmacokinetics, efficacy, and safety.

    PubMed

    Dahlin, Maria G; Ohman, Inger

    2012-10-01

    We examined the influence of age and type of concomitant antiepileptic drugs (AEDs) on the pharmacokinetics of rufinamide (RUF) as well as its efficacy and safety in 51 children with refractory epilepsy. In a retrospective noninterventional survey, dose-to-concentration ratios of RUF and concomitant AEDs were calculated: the weight-normalized dose (mg/kg/d) divided by the steady-state trough plasma drug level, which was used as a measure of clearance. During treatment with RUF concomitantly with valproic acid (VPA) young children, aged 0 to 4.9 years, had a low clearance of RUF, which did not differ from older children. If not on VPA but on enzyme inducers, young children had a threefold higher clearance of RUF than the older ones. In young children not on VPA, those on enzyme inducers had 1.7-fold higher clearance than those on nonenzyme inducers. In children neither on VPA nor on enzyme inducers, RUF clearance was age-dependent with higher clearance in younger children. Adding RUF did not change the pharmacokinetics of concomitantly used AEDs. Seizure response after 2 to 3 months on RUF treatment was found in 12 of 51 children (23.5%), at mean plasma level of 36.9 ± 22.0 µmol/L. Adverse events were reported in 41% of the patients of which fatigue was most frequent (24%). Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  16. Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model.

    PubMed

    Quan, Ling-Dong; Yuan, Fang; Liu, Xin-Ming; Huang, Jian-Geng; Alnouti, Yazen; Wang, Dong

    2010-08-02

    N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer has been found to be arthrotropic (joint-targeting) in the adjuvant-induced arthritis (AA) rat model using magnetic resonance imaging (MRI). In this manuscript, we report the quantitative pharmacokinetics and biodistribution (PK/BD) of (125)I-labeled HPMA copolymer-dexamethasone conjugate (P-Dex) in AA rats. Structural parameters of the prodrug such as the molecular weight (MW) and Dex content were found to have strong impact on the PK/BD profiles of P-Dex. The increase of MW (14,000, 24,000, and 42,000 g/mol) and Dex content (0, 151, and 313 micromol/g) enhances the arthrotropism of P-Dex. For the conjugate with highest MW and Dex content (P-H-M(W)/Dex), the percentage of injected doses per gram (ID/g) of ankle synovial tissue at day seventh postadministration is 1% g(-1), which confirms P-Dex as an arthrotropic macromolecular prodrug. For liver and spleen, the ID/g values are 0.51 and 3.64% g(-1), respectively. As an antigen-presenting organ, the sequestration of the prodrug by spleen may be explained by its abnormal enlargement associated with the systemic inflammatory disease model. Gradual reduction of spleen weight due to the inflammation resolution effect of P-Dex may also contribute to the high ID/g values. Increase of Dex content and reduction of MW would increase P-Dex distribution to kidney. The highest ID/g value for kidney at day seventh postadministration (0.91% g(-1)) was found with P-L-M(w) (MW = 14,000 g/mol, Dex content =288 micromol/g), which may suggest kidney tubuli reabsorption of the conjugates. The P-Dex's distribution to heart and lung is minimum.

  17. Optimised nanoformulation of bromocriptine for direct nose-to-brain delivery: biodistribution, pharmacokinetic and dopamine estimation by ultra-HPLC/mass spectrometry method.

    PubMed

    Md, Shadab; Haque, Shadabul; Fazil, Mohammad; Kumar, Manish; Baboota, Sanjula; Sahni, Jasjeet K; Ali, Javed

    2014-06-01

    The present work evaluated whether the prepared nanoparticles (NPs) would be able to target the drug to the brain by a non-invasive nasal route enhancing its bioavailability. Bromocriptine (BRC) chitosan NPs (CS NPs) were prepared by ionic gelation method. The biodistribution, pharmacokinetic parameters and dopamine concentration was analysed by ultra-HPLC/mass spectrometry method. The histopathological examination in haloperidol-induced Parkinson's disease in mice model following intranasal (i.n.) administration was evaluated. BRC was found stable in all exposed conditions and the percentage accuracy observed for intra-day and inter-day batch samples ranged from 90.5 to 107% and 95.3 to 98.9% for plasma and brain homogenates, respectively. BRC-loaded CS NPs showed greater retention into the nostrils (42 ± 8.5% radioactivity) for about 4 h, whereas the 44 ± 7.5% could be retained up to 1 h for BRC solution. The brain:blood ratios of 0.96 ± 0.05 > 0.73 ± 0.15 > 0.25 ± 0.05 of BRC-loaded CS NPs (i.n.) > BRC solution (i.n.) > BRC-loaded CS NPs (intravenous), respectively, at 0.5 h indicated direct nose-to-brain transport bypassing blood-brain barrier. BRC-loaded CS NPs administered intranasally showed significantly high dopamine concentration (20.65 ± 1.08 ng/ml) as compared to haloperidol-treated mice (10.94 ± 2.16 ng/ml) (p < 0.05). Histopathology of brain sections showed selective degeneration of the dopaminergic neurons in haloperidol-treated mice which was markedly reverted by BRC-loaded CS NPs. Nanoparticulate drug delivery system could be potentially used as a nose-to-brain drug delivery carrier for the treatment of Parkinson's disease.

  18. Pharmacodynamics, pharmacokinetics and biodistribution of recombinant human N-acetylgalactosamine 4-sulfatase after 6months of therapy in cats using different IV infusion durations.

    PubMed

    Ruane, Therese; Haskins, Mark; Cheng, Alphonsus; Wang, Ping; Aguirre, Gustavo; Knox, Van W Rafe; Qi, Yulan; Tompkins, Troy; O'Neill, Charles A

    2016-02-01

    Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease characterized by an absence or marked reduction of lysosomal N-acetylgalactosamine-4-sulfatase activity. Affected individuals have widespread accumulation of unmetabolized glycosaminoglycan substrates leading to detrimental effects. Recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) is an approved enzyme replacement therapy for patients with MPS VI. Despite the known efficacy of weekly 4-h rhASB infusions, some clinicians wish to treat patients using reduced infusion times. This study compared the pharmacodynamics, pharmacokinetics, and tissue biodistribution of rhASB when administered as 2- and 4-h intravenous infusions using a feline model of MPS VI. Study animals were MPS VI-affected cats that demonstrate clinical signs and biochemical derangements similar to human MPS VI patients. Beginning at age 4weeks, animals received weekly 2-h (N=6) or 4-h (N=6) IV infusions of rhASB for 26weeks (Naglazyme® [galsulfase] Solution for Intravenous Infusion; BioMarin Pharmaceutical, Inc.). The control group consisted of untreated MPS VI-affected cats (N=6). The pharmacokinetic parameters of plasma rhASB and urinary glycosaminoglycan were determined at weeks 13 and 26. Animals were euthanized 48h after the last infusion and tissue concentration of ASB, GAG and β-glucuronidase were measured in the liver, spleen, aorta, and kidney. Skeletal and ophthalmological evaluations were performed within 2weeks of euthanasia. At week 13, the mean AUC0-t in animals treated with 4-h infusions was similar to 2-h infusions while the Cmax of the 4-h infusion was 50% of the 2-h infusion. By week 26, the mean AUC0-t of the 4-h infusion was 1.3-fold higher than the 2-h infusion (p<0.05) while Cmax of the 4-h infusion was 70% of the 2-h infusion (p<0.05). Among animals treated with 2- and 4-h infusions, there was no difference in urinary GAG excretion, tissue GAG storage, tissue galsulfase activity, and

  19. A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice

    PubMed Central

    Huang, Yu; Wei, Yumeng; Yang, Hongru; Pi, Chao; Liu, Hao; Ye, Yun; Zhao, Ling

    2016-01-01

    5-Fluorouracil (5-FU) was loaded in hollow microspheres to improve its oral bioavailability. 5-FU hollow microspheres were developed by a solvent diffusion–evaporation method. The effect of Span 80 concentration, ether/ethanol volume ratio, and polyvinyl pyrrolidone/ethyl cellulose weight ratio on physicochemical characteristics, floating, and in vitro release behaviors of 5-FU hollow microspheres was investigated and optimized. The formulation and technology composed of Span 80 (1.5%, w/v), ether/ethanol (1.0:10.0, v/v), and polyvinyl pyrrolidone/ethyl cellulose (1.0:10.0, w/w) were employed to develop three batch samples, which showed an excellent reproducibility. The microspheres were spherical with a hollow structure with high drug loading amount (28.4%±0.5%) and production yield (74.2%±0.6%); they exhibited excellent floating and sustained release characteristics in simulated gastric and intestinal fluid. Pharmacokinetic studies demonstrated that 5-FU hollow microspheres significantly enhanced oral bioavailability (area under curve, [AUC](0−t): 12.53±1.65 mg/L*h vs 7.80±0.83 and 5.82±0.83 mg/L*h) with longer elimination half-life (t1/2) (15.43±2.12 hours vs 2.25±0.22 and 1.43±0.18 hours) and mean residence time (7.65±0.97 hours vs 3.61±0.41 and 2.34±0.35 hours), in comparison with its solid microspheres and powder. In vivo distribution results from tumor-bearing nude mice demonstrated that the animals administered with 5-FU hollow microspheres had much higher drug content in tumor, plasma, and stomach at 1 and 8 hours except for 0.5 hours sample collection time point in comparison with those administered with 5-FU solid microspheres and its powder. These results suggested that the hollow microspheres would be a promising controlled drug delivery system for an oral chemotherapy agent like 5-FU. PMID:27042001

  20. A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice.

    PubMed

    Huang, Yu; Wei, Yumeng; Yang, Hongru; Pi, Chao; Liu, Hao; Ye, Yun; Zhao, Ling

    2016-01-01

    5-Fluorouracil (5-FU) was loaded in hollow microspheres to improve its oral bioavailability. 5-FU hollow microspheres were developed by a solvent diffusion-evaporation method. The effect of Span 80 concentration, ether/ethanol volume ratio, and polyvinyl pyrrolidone/ethyl cellulose weight ratio on physicochemical characteristics, floating, and in vitro release behaviors of 5-FU hollow microspheres was investigated and optimized. The formulation and technology composed of Span 80 (1.5%, w/v), ether/ethanol (1.0:10.0, v/v), and polyvinyl pyrrolidone/ethyl cellulose (1.0:10.0, w/w) were employed to develop three batch samples, which showed an excellent reproducibility. The microspheres were spherical with a hollow structure with high drug loading amount (28.4%±0.5%) and production yield (74.2%±0.6%); they exhibited excellent floating and sustained release characteristics in simulated gastric and intestinal fluid. Pharmacokinetic studies demonstrated that 5-FU hollow microspheres significantly enhanced oral bioavailability (area under curve, [AUC](0-t): 12.53±1.65 mg/L(*)h vs 7.80±0.83 and 5.82±0.83 mg/L(*)h) with longer elimination half-life (t1/2) (15.43±2.12 hours vs 2.25±0.22 and 1.43±0.18 hours) and mean residence time (7.65±0.97 hours vs 3.61±0.41 and 2.34±0.35 hours), in comparison with its solid microspheres and powder. In vivo distribution results from tumor-bearing nude mice demonstrated that the animals administered with 5-FU hollow microspheres had much higher drug content in tumor, plasma, and stomach at 1 and 8 hours except for 0.5 hours sample collection time point in comparison with those administered with 5-FU solid microspheres and its powder. These results suggested that the hollow microspheres would be a promising controlled drug delivery system for an oral chemotherapy agent like 5-FU.

  1. The Safety, Pharmacokinetics, and Efficacy of Intraocular Celecoxib

    PubMed Central

    Kim, Stephen J.; Toma, Hassanain; Shah, Rohan; Kompella, Uday B.; Vooturi, Sunil K.; Sheng, Jinsong

    2014-01-01

    Purpose. To determine safety, pharmacokinetics, and anti-inflammatory effects of intraocular celecoxib. Methods. The right eye of animals was injected with 1.5, 3, or 6 mg celecoxib prepared in dimethyl sulfoxide (DMSO). Left eyes served as controls and received 0.1 mL DMSO. Electroretinograms (ERG) were obtained at baseline and at 1, 4, and 12 weeks, and eyes were enucleated afterward for histopathologic analysis. For pharmacokinetics, 3 mg celecoxib was injected, and vitreous and retina/choroid drug levels were then analyzed at specific time points. For efficacy, 1 μg lipopolysaccharide was injected to induce inflammation; the right eye was then injected with 3 mg celecoxib (six eyes) or 2 mg triamcinolone acetonide (six eyes) and the left eye with saline. Twenty-four hours later, aqueous fluid was removed, and total leukocyte concentration and prostaglandin E2 (PGE2) concentration were determined. Results. Histologic and ERG studies demonstrated no signs of retinal or optic nerve toxicity. After a single 3-mg injection, vitreous (0.06 μg/mL) and retina/choroid (132.31 μg/g) celecoxib concentrations at 8 weeks exceeded median inhibitory concentration. Treatment with celecoxib and triamcinolone significantly reduced total leukocyte count by 40% (P = 0.02) and 31% (P = 0.01), respectively. Reduction in PGE2 levels paralleled reduction in leukocyte counts (P < 0.05). There was no increase in intraocular pressure, but cataract formation was observed at higher concentrations. Conclusions. Intraocular injection of celecoxib appeared to be nontoxic and demonstrated excellent penetration into the retina/choroid and sustained drug levels out to 8 weeks. Celecoxib demonstrated potent anti-inflammatory effects, but there was an association with cataract formation at higher doses. PMID:24458149

  2. Biodistribution and pharmacokinetics of variously sized molecular radiolabelled polyethyleneiminomethyl phosphonic acid as a selective bone seeker for therapy in the normal primate model.

    PubMed

    Dormehl, I C; Louw, W K; Milner, R J; Kilian, E; Schneeweiss, F H

    2001-01-01

    An ideal radiopharmaceutical for the treatment of neoplastic and inflammatory (benign) bone disease would be a radiolabelled compound that predominantly accumulates in bone lesions with limited access to normal bone and other organs. Neoplastic tissue's abnormal blood supply (increased permeability) and lack of lymphatics will selectively accumulate radiolabelled macromolecules. This enhanced permeability and retention effect forms the basis of this study, using various molecular sizes of the radiolabelled macromolecule polyethyleneiminomethyl phosphonic acid (PEI-MP) for increased selectivity of the bone-seeking radiopharmaceutical. PEI-MP was synthesized by condensation of polyethyleneimine, phosphonic acid and formaldehyde, followed by fractionation into different molecular sizes by membrane ultrafiltration. Labelling efficiency to 99mTc (as radiotracer) was approximately 99% with complexes stable for 24 h. The pharmacokinetics and biodistribution of various 99mTc-PEI-MP fractions were investigated using 4 experimental baboons (Papio ursinus) per fraction. Scintigraphy was performed on the baboons under general anaesthesia of pentobarbital i.v. After an i.v. bolus of 99mTc-PEI-MP (approximately 185 MBq) both dynamic studies (30 x 1 min frames), and static studies (2 min acquisition every hour for 4 h) were done, as well as blood samples and urine collected. From the results macromolecules with sizes ranging between 30-300 kDa were characterized by excessive liver (21%-57% retained activity) and kidney (40% retained activity) uptake and accompanying long residing times (t1/2 up to 24 h). The percentage bone uptake averaged at 8% for these particles excluding sizes 100-300 kDa where very little bone uptake was seen (< 1%). In this case the blood clearance was also slow (t1/2 approximately 2 h). The fraction size 10-30 kDa had comparatively low accumulation and short residence times in the liver and kidneys (resp. 20%, t1/2 = 22 +/- 4 min; 17.5%, t1/2 = 20 +/- 3

  3. Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

    PubMed Central

    Gonzalez, Daniel; Delmore, Paula; Bloom, Barry T.; Cotten, C. Michael; Poindexter, Brenda B.; McGowan, Elisabeth; Shattuck, Karen; Bradford, Kathleen K.; Smith, P. Brian; Cohen-Wolkowiez, Michael; Morris, Maurine; Yin, Wanrong; Benjamin, Daniel K.

    2016-01-01

    Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.) PMID:26926644

  4. Biodistribution, Pharmacokinetics, and Dosimetry of (177)Lu-, (90)Y-, and (111)In-Labeled Somatostatin Receptor Antagonist OPS201 in Comparison to the Agonist (177)Lu-DOTATATE: The Mass Effect.

    PubMed

    Nicolas, Guillaume P; Mansi, Rosalba; McDougall, Lisa; Kaufmann, Jens; Bouterfa, Hakim; Wild, Damian; Fani, Melpomeni

    2017-09-01

    Radiolabeled somatostatin receptor (SSTR) antagonists have shown in vivo higher uptake in SSTR-expressing tumors than agonists. In this preclinical study, the SSTR2 antagonist OPS201 (DOTA-JR11; DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH2]) labeled with (177)Lu, (90)Y, and (111)In was compared with the SSTR2 agonist (177)Lu-DOTATATE. Methods: Biodistribution, pharmacokinetics, SPECT/CT, and dosimetry studies were performed to assess the bioequivalence of all radiotracers. Use of escalated peptide mass and nephroprotective agents were systematically investigated. Results: The tumor residence time was 15.6 h (13.4-17.7) for (177)Lu-OPS201 (10 pmol) and 6.4 h (5.4-7.3) for (177)Lu-DOTATATE, resulting in a 2.5-times-higher tumor dose for the antagonist than for the agonist (0.854 vs. 0.333 mGy/MBq for a 4-cm tumor). The overall tumor-to-kidney dose ratio was approximately 24% and 32% higher for (177)Lu-OPS201 than for (90)Y-OPS201 and (177)Lu-DOTATATE, respectively. (111)In-OPS201 had a biodistribution significantly different from (90)Y-OPS201 and is therefore not a surrogate for (90)Y-OPS201 dosimetry studies. Importantly, and in contrast to (177)Lu-DOTATATE, injection of 10, 200, and 2,000 pmol of (177)Lu-OPS201 did not cause any relevant tumor saturation, with tumor uptake 4 h after injection: 23.9, 24.9, and 18.8 percentage of injected activity per gram of tissue (%IA/g), respectively, for the antagonist (P > 0.05), as compared with 17.8, 12.0, and 9.9 %IA/g for the agonist (P < 0.05). Increasing the peptide mass of (177)Lu-OPS201 from 10 to 200 pmol drastically decreased the effective dose from 0.0908 to 0.0184 mSv/MBq and decreased the uptake in the liver, bone marrow, and all SSTR2-expressing organs; thus, the therapeutic index improved considerably. Lysine and succinylated gelatine, alone or in combination, significantly reduced the renal dose of (177)Lu-OPS201 compared with the control group, by 45%, 25%, and 40%, respectively (P < 0.05). The

  5. Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients

    PubMed Central

    Robb, Adelaide S.; DelBello, Melissa; Huss, Michael; McNamara, Nora; Sarkis, Elias; Scheffer, Russell; Poulsen, Lis H.; Chen, Grace; Lemming, Ole Michael; Areberg, Johan; Auby, Philippe

    2017-01-01

    Abstract Objective: The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials. Methods: This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14–20 days with patients in the higher dose cohorts uptitrated over 2–6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing. Results: Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration–time curve from time 0 to 24 hours, was 30%–40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults. Conclusion: The results suggest that the dosages of vortioxetine evaluated (5–20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials. PMID:28333546

  6. Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients.

    PubMed

    Findling, Robert L; Robb, Adelaide S; DelBello, Melissa; Huss, Michael; McNamara, Nora; Sarkis, Elias; Scheffer, Russell; Poulsen, Lis H; Chen, Grace; Lemming, Ole Michael; Areberg, Johan; Auby, Philippe

    2017-08-01

    The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials. This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14-20 days with patients in the higher dose cohorts uptitrated over 2-6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing. Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration-time curve from time 0 to 24 hours, was 30%-40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults. The results suggest that the dosages of vortioxetine evaluated (5-20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

  7. Adenovirus encoding human platelet-derived growth factor-B delivered to alveolar bone defects exhibits safety and biodistribution profiles favorable for clinical use.

    PubMed

    Chang, Po-Chun; Cirelli, Joni A; Jin, Qiming; Seol, Yang-Jo; Sugai, James V; D'Silva, Nisha J; Danciu, Theodora E; Chandler, Lois A; Sosnowski, Barbara A; Giannobile, William V

    2009-05-01

    Platelet-derived growth factor (PDGF) gene therapy offers promise for tissue engineering of tooth-supporting alveolar bone defects. To date, limited information exists regarding the safety profile and systemic biodistribution of PDGF gene therapy vectors when delivered locally to periodontal osseous defects. The aim of this preclinical study was to determine the safety profile of adenovirus encoding the PDGF-B gene (AdPDGF-B) delivered in a collagen matrix to periodontal lesions. Standardized alveolar bone defects were created in rats, followed by delivery of matrix alone or containing AdPDGF-B at 5.5 x 10(8) or 5.5 x 10(9) plaque-forming units/ml. The regenerative response was confirmed histologically. Gross clinical observations, hematology, and blood chemistries were monitored to evaluate systemic involvement. Bioluminescence and quantitative polymerase chain reaction were used to assess vector biodistribution. No significant histopathological changes were noted during the investigation. Minor alterations in specific hematological and blood chemistries were seen; however, most parameters were within the normal range for all groups. Bioluminescence analysis revealed vector distribution at the axillary lymph nodes during the first 2 weeks with subsequent return to baseline levels. AdPDGF-B was well contained within the localized osseous defect area without viremia or distant organ involvement. These results indicate that AdPDGF-B delivered in a collagen matrix exhibits acceptable safety profiles for possible use in human clinical studies.

  8. Preclinical Biodistribution and Safety Evaluation of a pbi-shRNA STMN1 Lipoplex after Subcutaneous Delivery.

    PubMed

    Wang, Zhaohui; Jay, Christopher M; Evans, Courtney; Kumar, Padmasini; Phalon, Connor; Rao, Donald D; Senzer, Neil; Nemunaitis, John

    2017-02-01

    Stathmin-1 (STMN1) is a microtubule-destabilizing protein which is overexpressed in cancer. Its overexpression is associated with poor prognosis and also serves as a predictive marker to taxane therapy. We have developed a proprietary bi-functional shRNA (bi-shRNA) platform to execute RNA interference (RNAi)-mediated gene silencing and a liposome-carrier complex to systemically deliver the pbi-shRNA plasmids. In vitro and in vivo testing demonstrated efficacy and specificity of pbi-shRNA plasmid in targeting STMN1 (Phadke, A. P., Jay, C. M., Wang, Z., Chen, S., Liu, S., Haddock, C., Kumar, P., Pappen, B. O., Rao, D. D., Templeton, N. S., et al. (2011). In vivo safety and antitumor efficacy of bifunctional small hairpin RNAs specific for the human Stathmin 1 oncoprotein. DNA Cell Biol. 30, 715-726.). Biodistribution and toxicology studies in bio-relevant Sprague Dawley rats with pbi-shRNA STMN1 lipoplex revealed that the plasmid DNA was delivered to a broad distribution of organs after a single subcutaneous injection. Specifically, plasmid was detected within the first week using QPCR (threshold 50 copies plasmid/1 µg genomic DNA) at the injection site, lung, spleen, blood, skin, ovary (limited), lymph nodes, and liver. It was not detected in the heart, testis or bone marrow. No plasmid was detected from any organ 30 days after injection. Treatment was well tolerated. Minimal inflammation/erythema was observed at the injection site. Circulating cytokine response was also examined by ELISA. The IL-6 levels were induced within 6 h then declined to the vehicle control level 72 h after the injection. TNFα induction was transiently observed 4 days after the DNA lipoplex treatment. In summary, the pbi-shRNA STMN1 lipoplex was well tolerated and displayed broad distribution after a single subcutaneous injection. The pre-clinical data has been filed to FDA and the pbi-shRNA STMN1 lipoplex is being investigated in a phase I clinical study. © The Author 2016. Published

  9. Comparing in vivo biodistribution with radiolabeling and Franz cell permeation assay to validate the efficacy of both methodologies in the evaluation of nanoemulsions: a safety approach.

    PubMed

    Cerqueira-Coutinho, C S; De Campo, V E B; Rossi, A L; Veiga, V F; Holandino, C; Freitas, Z M F; Ricci-Junior, E; Mansur, C R E; Santos, E P; Santos-Oliveira, R

    2016-01-08

    The Franz cells permeation assay has been performed for over 25 years. However, the advent of nanotechnology created a whole new world, especially with regard to topical products. In this new global scenario an increasing number of nanostructure-based delivery systems (NDSs) have emerged and a global warning relating to the safety of these NDSs is arising. This work studied the efficacy of the Franz cells assay, comparing it with the radiolabeling biodistribution test. For this purpose a formulation of sunscreen based on an NDS was developed and characterized. The results demonstrated both that the NDS did not present in vitro cytotoxicity and that the radiolabeling biodistribution test is more precise for the evaluation of NDS cosmetics than the Franz cells assay, since it detected the permeation of the NDS at a picogram order. Due to this fact, and considering all the concerns related to NDSs and nanoparticles in general, more precise methods must be used in order to guarantee the safe use of these new classes of products.

  10. Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat(®), for age-related macular degeneration.

    PubMed

    Binley, Katie; Widdowson, Peter S; Kelleher, Michelle; de Belin, Jackie; Loader, Julie; Ferrige, Georgina; Carlucci, Marie; Esapa, Margaret; Chipchase, Daniel; Angell-Manning, Diana; Ellis, Scott; Mitrophanous, Kyriacos; Miskin, James; Bantseev, Vlad; Nork, T Michael; Miller, Paul; Naylor, Stuart

    2012-09-01

    RetinoStat(®) is an equine infectious anemia virus-based lentiviral gene therapy vector that expresses the angiostatic proteins endostatin and angiostatin that is delivered via a subretinal injection for the treatment of the wet form of age-related macular degeneration. We initiated 6-month safety and biodistribution studies in two species; rhesus macaques and Dutch belted rabbits. After subretinal administration of RetinoStat the level of human endostatin and angiostatin proteins in the vitreous of treated rabbit eyes peaked at ∼1 month after dosing and remained elevated for the duration of the study. Regular ocular examinations revealed a mild to moderate transient ocular inflammation that resolved within 1 month of dosing in both species. There were no significant long-term changes in the electroretinograms or intraocular pressure measurements in either rabbits or macaques postdosing compared with the baseline reading in RetinoStat-treated eyes. Histological evaluation did not reveal any structural changes in the eye although there was an infiltration of mononuclear cells in the vitreous, retina, and choroid. No antibodies to any of the RetinoStat vector components or the transgenes could be detected in the serum from either species, and biodistribution analysis demonstrated that the RetinoStat vector was maintained within the ocular compartment. In summary, these studies found RetinoStat to be well tolerated, localized, and capable of persistent expression after subretinal delivery.

  11. Comparing in vivo biodistribution with radiolabeling and Franz cell permeation assay to validate the efficacy of both methodologies in the evaluation of nanoemulsions: a safety approach

    NASA Astrophysics Data System (ADS)

    Cerqueira-Coutinho, C. S.; De Campo, V. E. B.; Rossi, A. L.; Veiga, V. F.; Holandino, C.; Freitas, Z. M. F.; Ricci-Junior, E.; Mansur, C. R. E.; Santos, E. P.; Santos-Oliveira, R.

    2016-01-01

    The Franz cells permeation assay has been performed for over 25 years. However, the advent of nanotechnology created a whole new world, especially with regard to topical products. In this new global scenario an increasing number of nanostructure-based delivery systems (NDSs) have emerged and a global warning relating to the safety of these NDSs is arising. This work studied the efficacy of the Franz cells assay, comparing it with the radiolabeling biodistribution test. For this purpose a formulation of sunscreen based on an NDS was developed and characterized. The results demonstrated both that the NDS did not present in vitro cytotoxicity and that the radiolabeling biodistribution test is more precise for the evaluation of NDS cosmetics than the Franz cells assay, since it detected the permeation of the NDS at a picogram order. Due to this fact, and considering all the concerns related to NDSs and nanoparticles in general, more precise methods must be used in order to guarantee the safe use of these new classes of products.

  12. Single-Dose Pharmacokinetics and Safety of Ziprasidone in Children and Adolescents

    ERIC Educational Resources Information Center

    Sallee, Floyd R.; Miceli, Jeffrey J.; Tensfeldt, Thomas; Robarge, Lisa; Wilner, Keith; Patel, Nick C.

    2006-01-01

    Objective: The purpose of this study was to provide single-dose pharmacokinetic, safety, and tolerability data for ziprasidone in youths with tic disorder, for comparison to adult studies to discern whether ziprasidone pediatric dosing could be modeled from adult data. Method: A single-dose, open-label study of ziprasidone was conducted in youths…

  13. FRAMEWORK FOR EVALUATION OF PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELS FOR USE IN SAFETY OR RISK ASSESSMENT

    EPA Science Inventory

    ABSTRACT

    Proposed applications of increasingly sophisticated biologically-based computational models, such as physiologically-based pharmacokinetic (PBPK) models, raise the issue of how to evaluate whether the models are adequate for proposed uses including safety or risk ...

  14. FRAMEWORK FOR EVALUATION OF PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELS FOR USE IN SAFETY OR RISK ASSESSMENT

    EPA Science Inventory

    ABSTRACT

    Proposed applications of increasingly sophisticated biologically-based computational models, such as physiologically-based pharmacokinetic (PBPK) models, raise the issue of how to evaluate whether the models are adequate for proposed uses including safety or risk ...

  15. Single-Dose Pharmacokinetics and Safety of Ziprasidone in Children and Adolescents

    ERIC Educational Resources Information Center

    Sallee, Floyd R.; Miceli, Jeffrey J.; Tensfeldt, Thomas; Robarge, Lisa; Wilner, Keith; Patel, Nick C.

    2006-01-01

    Objective: The purpose of this study was to provide single-dose pharmacokinetic, safety, and tolerability data for ziprasidone in youths with tic disorder, for comparison to adult studies to discern whether ziprasidone pediatric dosing could be modeled from adult data. Method: A single-dose, open-label study of ziprasidone was conducted in youths…

  16. Multiple-dose pharmacokinetics and safety of an ibuprofen-pseudoephedrine cold suspension in children.

    PubMed

    Gelotte, Cathy K; Prior, Mary Jane; Pendley, Charles; Zimmerman, Brenda; Lavins, Bernard J

    2010-07-01

    Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 + or - 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 + or - 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 + or - 2.2 mL/kg/min and Vd/F was 2.52 + or - 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.

  17. Preclinical pharmacokinetics, biodistribution, radiation dosimetry and toxicity studies required for regulatory approval of a phase I clinical trial with 111In-CP04 in medullary thyroid carcinoma patients

    PubMed Central

    Maina, Theodosia; Konijnenberg, Mark W.; KolencPeitl, Petra; Garnuszek, Piotr; Nock, Berthold A.; Kaloudi, Aikaterini; Kroselj, Marko; Zaletel, Katja; Maecke, Helmut; Mansi, Rosalba; Erba, Paola; von Guggenberg, Elisabeth; Hubalewska-Dydejczyk, Alicja; Mikolajczak, Renata; Decristoforo, Clemens

    2016-01-01

    Introduction From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of 111In-CP04 in animal models, essential for the regulatory approval of the clinical trial. Materials and methods Acute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of 111In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of 111In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing double A431-CCK2R(±) xenografts at 1, 4 and 24 h pi. Further 4-h animal groups were either additionally treated with the plasma expander gelofusine or injected with 111In-CP04 prepared by wet-labelling. Pharmacokinetics in healthy mice included the 30 min, 1, 4, 24, 48 and 72 h time points pi. Dosimetric calculations were based on extrapolation of mice data to humans adopting two scaling models. Results CP04 was well-tolerated by both mice and rats, with an LD50 > 178.5 μg/kg body weight for mice and a NOAEL (no-observed-adverse-effect-level) of 89 μg/kg body weight for rats. After labelling, 111In-CP04 remained >70% intact in peripheral mouse blood at 5 min pi. The uptake of 111In-CP04 prepared from the freeze-dried kit and by wet-labelling were comparable in the A431-CCK2R(+)-xenografts (9.24 ± 1.35%ID/g and 8.49 ± 0.39%ID/g, respectively; P > 0.05). Gelofusine-treated mice exhibited significantly reduced kidneys values (1.69 ± 0.15%ID/g vs. 5.55 ± 0.94%ID/g in controls, P < 0.001). Dosimetry data revealed very comparable effective tumour doses for the two scaling models applied, of 0.045 and 0.044 m

  18. Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin.

    PubMed

    Ye, Guo-Jie; Budzynski, Ewa; Sonnentag, Peter; Miller, Paul E; Sharma, Alok K; Ver Hoeve, James N; Howard, Kellie; Knop, David R; Neuringer, Martha; McGill, Trevor; Stoddard, Jonathan; Chulay, Jeffrey D

    2015-09-01

    Applied Genetic Technologies Corporation is developing rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus (rAAV) vector for treatment of X-linked retinoschisis (XLRS), an inherited retinal disease characterized by splitting (schisis) of retinal layers causing poor vision. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-CB-hRS1 in normal cynomolgus macaques. Three groups of male animals (n = 6 per group) received an intravitreal injection in one eye of either vehicle, or rAAV2tYF-CB-hRS1 at one of two dose levels (4 × 10(10) or 4 × 10(11) vg/eye). Half the animals were sacrificed after 14 days and the others after 91 or 115 days. The intravitreal injection procedure was well tolerated in all groups. Serial ophthalmic examinations demonstrated a dose-related anterior and posterior segment inflammatory response that improved over time. There were no test article-related effects on intraocular pressure, electroretinography, visual evoked potential, hematology, coagulation, clinical chemistry, or gross necropsy observations. Histopathological examination demonstrated minimal or moderate mononuclear infiltrates in 6 of 12 vector-injected eyes. Immunohistochemical staining showed RS1 labeling of the ganglion cell layer at the foveal slope in vector-injected eyes at both dose levels. Serum anti-AAV antibodies were detected in 4 of 6 vector-injected animals at the day 15 sacrifice and all vector-injected animals at later time points. No animals developed antibodies to RS1. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-CB-hRS1 in clinical studies in patients with XLRS.

  19. The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

    PubMed Central

    Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

    2015-01-01

    When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. PMID:25845860

  20. Ultrapure laser-synthesized Si-based nanomaterials for biomedical applications: in vivo assessment of safety and biodistribution

    PubMed Central

    Baati, Tarek; Al-Kattan, Ahmed; Esteve, Marie-Anne; Njim, Leila; Ryabchikov, Yury; Chaspoul, Florence; Hammami, Mohamed; Sentis, Marc; Kabashin, Andrei V.; Braguer, Diane

    2016-01-01

    Si/SiOx nanoparticles (NPs) produced by laser ablation in deionized water or aqueous biocompatible solutions present a novel extremely promising object for biomedical applications, but the interaction of these NPs with biological systems has not yet been systematically examined. Here, we present the first comprehensive study of biodistribution, biodegradability and toxicity of laser-synthesized Si-SiOx nanoparticles using a small animal model. Despite a relatively high dose of Si-NPs (20 mg/kg) administered intravenously in mice, all controlled parameters (serum, enzymatic, histological etc.) were found to be within safe limits 3 h, 24 h, 48 h and 7 days after the administration. We also determined that the nanoparticles are rapidly sequestered by the liver and spleen, then further biodegraded and directly eliminated in urine without any toxicity effects. Finally, we found that intracellular accumulation of Si-NPs does not induce any oxidative stress damage. Our results evidence a huge potential in using these safe and biodegradable NPs in biomedical applications, in particular as vectors, contrast agents and sensitizers in cancer therapy and diagnostics (theranostics). PMID:27151839

  1. Ultrapure laser-synthesized Si-based nanomaterials for biomedical applications: in vivo assessment of safety and biodistribution

    NASA Astrophysics Data System (ADS)

    Baati, Tarek; Al-Kattan, Ahmed; Esteve, Marie-Anne; Njim, Leila; Ryabchikov, Yury; Chaspoul, Florence; Hammami, Mohamed; Sentis, Marc; Kabashin, Andrei V.; Braguer, Diane

    2016-05-01

    Si/SiOx nanoparticles (NPs) produced by laser ablation in deionized water or aqueous biocompatible solutions present a novel extremely promising object for biomedical applications, but the interaction of these NPs with biological systems has not yet been systematically examined. Here, we present the first comprehensive study of biodistribution, biodegradability and toxicity of laser-synthesized Si-SiOx nanoparticles using a small animal model. Despite a relatively high dose of Si-NPs (20 mg/kg) administered intravenously in mice, all controlled parameters (serum, enzymatic, histological etc.) were found to be within safe limits 3 h, 24 h, 48 h and 7 days after the administration. We also determined that the nanoparticles are rapidly sequestered by the liver and spleen, then further biodegraded and directly eliminated in urine without any toxicity effects. Finally, we found that intracellular accumulation of Si-NPs does not induce any oxidative stress damage. Our results evidence a huge potential in using these safe and biodegradable NPs in biomedical applications, in particular as vectors, contrast agents and sensitizers in cancer therapy and diagnostics (theranostics).

  2. Safety and biodistribution of a double-deleted oncolytic vaccinia virus encoding CD40 ligand in laboratory Beagles

    PubMed Central

    Autio, Karoliina; Knuuttila, Anna; Kipar, Anja; Pesonen, Sari; Guse, Kilian; Parviainen, Suvi; Rajamäki, Minna; Laitinen-Vapaavuori, Outi; Vähä-Koskela, Markus; Kanerva, Anna; Hemminki, Akseli

    2014-01-01

    We evaluated adverse events, biodistribution and shedding of oncolytic vaccinia virus encoding CD40 ligand in two Beagles, in preparation for a phase 1 trial in canine cancer patients. Dog 1 received one dose of vaccinia virus and was euthanized 24 hours afterwards, while dog 2 received virus four times once weekly and was euthanized 7 days after that. Dogs were monitored for adverse events and underwent a detailed postmortem examination. Blood, saliva, urine, feces, and organs were collected for virus detection. Dog 1 had mild fever and lethargy while dog 2 experienced a possible seizure 5.5 hours after first virus administration. Viral DNA declined quickly in the blood after virus administration in both dogs but was still detectable 1 week later by quantitative polymerase chain reaction. Only samples taken directly after virus infusion contained infectious virus. Small amounts of viral DNA, but no infectious virus, were detected in a few saliva and urine samples. Necropsies did not reveal any relevant pathological changes and virus DNA was detected mainly in the spleen. The dogs in the study did not have cancer, and thus adverse events could be more common and viral load higher in dogs with tumors which allow viral amplification. PMID:27119092

  3. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy.

    PubMed

    Gabrielsson, Linda; Mattsson, Sofia; Fowler, Christopher J

    2016-10-01

    Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta-analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49 days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60 days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head-to-head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head-to-head comparisons of unmicronized vs. micronized formulations of PEA and comparisons with currently recommended treatments.

  4. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy

    PubMed Central

    Gabrielsson, Linda; Mattsson, Sofia

    2016-01-01

    Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta‐analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49 days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60 days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head‐to‐head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head‐to‐head comparisons of unmicronized vs. micronized formulations of PEA and comparisons with currently recommended treatments. PMID:27220803

  5. Pharmacokinetics, Safety, and Tolerability of Metformin in Healthy Elderly Subjects.

    PubMed

    Jang, Kyungho; Chung, Hyewon; Yoon, Jang-Soo; Moon, Seol-Joo; Yoon, Seo Hyun; Yu, Kyung-Sang; Kim, Kwangil; Chung, Jae-Yong

    2016-09-01

    Age-related physiological changes are known to alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Metformin is commonly used as first-line medication for management of diabetes in elderly patients. However, the PK and PD of metformin have not been sufficiently studied in elderly subjects. Here, 12 elderly subjects, aged 65 to 85 years, and 20 younger healthy volunteers were orally administered 750 mg of metformin 2 hours after dinner, followed by administration of a second dose (500 mg) 12 hours later. An oral glucose tolerance test (OGTT) was performed 2 hours after the second dose, with 75 g of glucose administered. Blood samples were collected at specific time points after the second metformin dose for the assessment of PK and the glucose-lowering effect of metformin. Elderly subjects exhibited 1.7 and 2.0 times higher average Cmax and AUC∞ than the younger subjects, respectively (P = .007 and .001, respectively), and t1/2 was comparable between the elderly and younger subjects. However, relative glucose level changes from baseline after metformin administration tended to be lower in elderly subjects. Systemic exposure to metformin was elevated by 50% or more in elderly subjects, whereas the glucose-lowering effect was similar compared to younger subjects after 2 doses of metformin. © 2016, The American College of Clinical Pharmacology.

  6. Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients

    PubMed Central

    Trachtman, Howard; Frymoyer, Adam; Lewandowski, Andrew; Greenbaum, Larry A.; Feig, Daniel I.; Gipson, Debbie S.; Warady, Bradley A.; Goebel, Jens W.; Schwartz, George J.; Lewis, Kenneth; Anand, Ravinder; Patel, Uptal D.

    2015-01-01

    Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options—including angiotensin-converting enzyme inhibitors—are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7–17 years) with stable kidney transplant function. Standard non-compartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n=13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30–59 ml/min per 1.73m2), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations. PMID:25807932

  7. Pharmacokinetics and Safety of Single-Dose Inhaled Loxapine in Children and Adolescents.

    PubMed

    Selim, Sally; Riesenberg, Robert; Cassella, James; Kunta, Jeevan; Hellriegel, Edward; Smith, Mark A; Vinks, Alexander A; Rabinovich-Guilatt, Laura

    2017-10-01

    This multisite open-label study sought to characterize the pharmacokinetics and safety of a single dose of inhaled loxapine in children and adolescents. Loxapine powder for oral inhalation was administered via a single-use handheld drug device to children and adolescents (aged 10-17 years) with any condition warranting chronic antipsychotic use. Patients were dosed according to body weight and cohort (<50 kg [n = 15], 2.5 or 5 mg; ≥50 kg [n = 15], 5 or 10 mg); the first 6 patients (cohort 1) enrolled in each weight group received the lower dose. Patients were enrolled in the higher-dose group (cohort 2) after an interim pharmacokinetic and safety analysis of data from cohort 1. Blood samples were collected for 48 hours after dosing to determine the pharmacokinetic profile of loxapine and its metabolites. Safety was assessed using adverse event (AE), laboratory value, physical/neurologic examination, vital sign, electrocardiogram, suicidality, and extrapyramidal symptom assessment. Thirty patients were enrolled and evaluable for pharmacokinetics. Loxapine plasma concentrations peaked by 2 to 5 minutes in most patients; systemic exposure increased with dose in both weight subgroups. Loxapine terminal elimination half-life was ∼13 to 17 hours. The most common AEs were sedation and dysgeusia. Sedation was severe in 1 patient in the <50-kg group (2.5-mg dose) and 1 patient in the ≥50-kg group (5-mg dose). No AEs indicative of bronchospasm or other serious AEs were reported. Inhaled loxapine was rapidly absorbed and generally well tolerated in pediatric patients; no new safety signals were observed. © 2017, The American College of Clinical Pharmacology.

  8. Pharmacokinetic studies of mouse monoclonal antibodies to a rat colon carcinoma: I. Comparison of biodistribution in normal rats, syngeneic tumor-bearing rats, or tumor-bearing nude mice

    SciTech Connect

    Laborda, J.; Douillard, J.Y.; Burg, C.; Lizzio, E.F.; Ridge, J.; Levenbook, I.; Hoffman, T. )

    1990-06-01

    The pharmacokinetics of two iodine-131-({sup 131}I) labeled murine anti-rat colon carcinoma monoclonal antibodies (D3 and E4) were compared in normal Sprague Dawley rats, syngeneic BDIX rats, or nude mice bearing that tumor. Results of antibody uptake after i.v. administration were analyzed in terms of accumulation and localization indices for normal tissues and tumor. Statistically significant differences between rat and mouse tissue biodistribution were found. D3, which reacts in vitro with the tumor and several normal rat tissues, cleared quickly from the blood of rats and was specifically targeted to several normal tissues, notably the lung. Virtually no targeting to the tumor was observed. Nude mice, however, showed a slower blood clearance and specific antibody targeting only in the tumor. Similar results were seen after injection of another antibody, E4, which is tumor-specific in vitro. Data suggest that studies on the xenogeneic nude mouse model may not necessarily be relevant to the choice of monoclonal antibodies for clinical diagnostic imaging or therapy.

  9. Influence of domperidone on pharmacokinetics, safety and tolerability of the dopamine agonist rotigotine

    PubMed Central

    Braun, Marina; Cawello, Willi; Boekens, Hilmar; Horstmann, Rolf

    2009-01-01

    AIMS To evaluate the influence of the antiemetic agent domperidone on steady-state pharmacokinetics, safety and tolerability of multiple-dose treatment of the transdermally applied non-ergolinic dopamine agonist rotigotine. METHODS Sixteen healthy male subjects (mean age 30.3 years) participated in a randomized, two-way crossover clinical trial. Treatment A consisted of transdermal rotigotine patch (2 mg (24 h)−1, 10 cm2, total drug content 4.5 mg) applied daily for 4 days, and concomitant oral domperidone (10 mg t.i.d.) for 5 days. For treatment B, subjects received only transdermal rotigotine treatment (daily for 4 days). Pharmacokinetic variables describing systemic exposure and renal elimination of rotigotine and metabolites, and safety and tolerability of the treatment were assessed. RESULTS The primary steady-state pharmacokinetic parameters (Cmax,ss and AUC(0–24),ss) were similar with or without co-administration of domperidone. Geometric mean ratios were close to 1 and respective 90% confidence intervals were within the acceptance range of bioequivalence (0.8, 1.25): Cmax,ss 0.96 (0.86, 1.08) and AUC(0–24),ss 0.97 (0.87, 1.08). tmax,ss, t1/2, secondary parameters calculated on days 4/5 after repeated patch application (Cmin,ss, Cave,ss, AUC(0–tz)) and renal elimination for unconjugated rotigotine and its metabolites were also similar with and without comedication of domperidone. A reduction in the dopaminergic side-effect nausea was seen with domperidone comedication. CONCLUSIONS No changes of pharmacokinetic parameters describing systemic exposure and renal elimination of rotigotine were observed when domperidone was administered concomitantly with rotigotine. The lack of pharmacokinetic interactions indicates that a dose adjustment of rotigotine transdermal patch is not necessary with concomitant use of domperidone. PMID:19094160

  10. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects.

    PubMed

    Dvorchik, Barry H; Brazier, David; DeBruin, Michael F; Arbeit, Robert D

    2003-04-01

    The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight ( approximately 20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life ( approximately 9 h), volume of distribution ( approximately 0.1 liters/kg), systemic clearance ( approximately 8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h ( approximately 54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.

  11. Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures.

    PubMed

    Mash, D C; Kovera, C A; Pablo, J; Tyndale, R F; Ervin, F D; Williams, I C; Singleton, E G; Mayor, M

    2000-09-01

    Ibogaine is an indole alkaloid found in the roots of Tabernanthe Iboga (Apocynaceae family), a rain forest shrub that is native to western Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and thirst, and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and opiates. Anecdotal reports attest that a single dose of ibogaine eliminates opiate withdrawal symptoms and reduces drug craving for extended periods of time. The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. The majority of ibogaine biotransformation proceeds via CYP2D6, including the O-demethylation of ibogaine to 12-hydroxyibogamine (noribogaine). Blood concentration-time effect profiles of ibogaine and noribogaine obtained for individual subjects after single oral dose administrations demonstrate complex pharmacokinetic profiles. Ibogaine has shown preliminary efficacy for opiate detoxification and for short-term stabilization of drug-dependent persons as they prepare to enter substance abuse treatment. We report here that ibogaine significantly decreased craving for cocaine and heroin during inpatient detoxification. Self-reports of depressive symptoms were also significantly lower after ibogaine treatment and at 30 days after program discharge. Because ibogaine is cleared rapidly from the blood, the beneficial aftereffects of the drug on craving and depressed mood may be related to the effects of noribogaine on the central nervous system.

  12. Piperaquine population pharmacokinetics and cardiac safety in Cambodia.

    PubMed

    Vanachayangkul, Pattaraporn; Lon, Chanthap; Spring, Michele; Sok, Sommethy; Ta-Aksorn, Winita; Kodchakorn, Chanikarn; Pann, Sut-Thang; Chann, Soklyda; Ittiverakul, Mali; Sriwichai, Sabaithip; Buathong, Nillawan; Kuntawunginn, Worachet; So, Mary; Youdaline, Theng; Milner, Erin; Wojnarski, Mariusz; Lanteri, Charlotte; Manning, Jessica; Prom, Satharath; Haigney, Mark; Cantilena, Louis; Saunders, David

    2017-02-13

    Despite rising resistance, dihydroartemisinin-piperaquine (DP) remains a first line therapy for uncomplicated malaria in many parts of Cambodia. While generally well-tolerated as a 3-day regimen, compressed 2-day regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine concentration on QT interval prolongation, we pooled data from 3 randomized clinical trials between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between 2-day (2DP) and 3-day (3DP) regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with 1(st) order absorption and elimination without covariates was the best fit of the data. The linear slope-intercept model in this largely male population predicted 0.05 ms QT prolongation per ng/ml of piperaquine (5 milliseconds per 100 ng/ml). Though plasma half-life was similar in both regimens, peak and total piperaquine exposure were higher in those treated with 2DP. Furthermore, the correlation between plasma piperaquine and QT interval prolongation was stronger in the 2DP population. Neither time since last meal nor baseline serum magnesium or potassium levels had additive effects on QT prolongation. As electrocardiographic monitoring is often non-existent in malaria endemic areas, 2DP regimens should be avoided, and 3DP carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3 hour fast before and after administration, and avoiding concomitant QT-prolonging medications.

  13. A Phase 1 biodistribution study of p-boronophenylalanine

    SciTech Connect

    Coderre, J.A.

    1991-01-01

    The objectives of the Phase I BPA biodistribution study are as follows: Objective 1: To establish the safety of orally administered boronophenylalanine (BPA) as determined by monitoring of patient's vital signs and by clinical analysis of blood before and after BPA administration. Objective 2: To establish BPA pharmacokinetics by monitoring the rates of boron absorption into and clearance from the blood and the rate of urinary excretion of boron. Objective 3: To measure the amount of boron incorporated into human tumors (melanoma, glioma, and breast carcinoma) using samples obtained at surgery or biopsy. This report presents the results obtained from the first thirteen patients entered into the study. Three additional glioblastoma patients have been studied recently at Stony Brook, the tissues are still being analyzed.

  14. A Phase 1 biodistribution study of p-boronophenylalanine

    SciTech Connect

    Coderre, J.A.

    1991-12-31

    The objectives of the Phase I BPA biodistribution study are as follows: Objective 1: To establish the safety of orally administered boronophenylalanine (BPA) as determined by monitoring of patient`s vital signs and by clinical analysis of blood before and after BPA administration. Objective 2: To establish BPA pharmacokinetics by monitoring the rates of boron absorption into and clearance from the blood and the rate of urinary excretion of boron. Objective 3: To measure the amount of boron incorporated into human tumors (melanoma, glioma, and breast carcinoma) using samples obtained at surgery or biopsy. This report presents the results obtained from the first thirteen patients entered into the study. Three additional glioblastoma patients have been studied recently at Stony Brook, the tissues are still being analyzed.

  15. (18)F-Tetrafluoroborate, a PET Probe for Imaging Sodium/Iodide Symporter Expression: Whole-Body Biodistribution, Safety, and Radiation Dosimetry in Thyroid Cancer Patients.

    PubMed

    O'Doherty, Jim; Jauregui-Osoro, Maite; Brothwood, Teresa; Szyszko, Teresa; Marsden, Paul K; O'Doherty, Michael J; Cook, Gary J R; Blower, Philip J; Lewington, Val

    2017-10-01

    We report the safety, biodistribution, and internal radiation dosimetry, in humans with thyroid cancer, of (18)F-tetrafluoroborate ((18)F-TFB), a novel PET radioligand for imaging the human sodium/iodide symporter (hNIS). Methods: Serial whole-body PET scans of 5 subjects with recently diagnosed thyroid cancer were acquired before surgery for up to 4 h after injection of 184 ± 15 MBq of (18)F-TFB. Activity was determined in whole blood, plasma, and urine. Mean organ-absorbed doses and effective doses were calculated via quantitative image analysis and using OLINDA/EXM software. Results: Images showed a high uptake of (18)F-TFB in known areas of high hNIS expression (thyroid, salivary glands, and stomach). Excretion was predominantly renal. No adverse effects in relation to safety of the radiopharmaceutical were observed. The effective dose was 0.0326 ± 0.0018 mSv/MBq. The critical tissues/organs receiving the highest mean sex-averaged absorbed doses were the thyroid (0.135 ± 0.079 mSv/MBq), stomach (0.069 ± 0.022 mSv/MBq), and salivary glands (parotids, 0.031 ± 0.011 mSv/MBq; submandibular, 0.061 ± 0.031 mSv/MBq). Other organs of interest were the bladder (0.102 ± 0.046 mSv/MBq) and kidneys (0.029 ± 0.009 mSv/MBq). Conclusion: Imaging using (18)F-TFB imparts a radiation exposure similar in magnitude to many other (18)F-labeled radiotracers. (18)F-TFB shows a biodistribution similar to (99m)Tc-pertechnetate, a known nonorganified hNIS tracer, and is pharmacologically and radiobiologically safe in humans. Phase 2 trials for (18)F-TFB as an hNIS imaging agent are warranted. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  16. Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects.

    PubMed

    Miller, Ann K; Harrell, Emma; Ye, Li; Baptiste-Brown, Sharon; Kleim, Jőrg-Peter; Ohrt, Colin; Duparc, Stephan; Möhrle, Jörg J; Webster, Alison; Stinnett, Sandra; Hughes, Arlene; Griffith, Sandy; Beelen, Andrew P

    2013-12-01

    The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects. © 2013 The British Pharmacological Society.

  17. Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects

    PubMed Central

    Miller, Ann K; Harrell, Emma; Ye, Li; Baptiste-Brown, Sharon; Kleim, Jőrg-Peter; Ohrt, Colin; Duparc, Stephan; Möhrle, Jörg J; Webster, Alison; Stinnett, Sandra; Hughes, Arlene; Griffith, Sandy; Beelen, Andrew P

    2013-01-01

    Aims The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Methods Healthy subjects, 18–55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1–2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. Results The coadministration of CQ + TQ had no effect on TQ AUC0–t, AUC0–∞, Tmax or t1/2. The 90% confidence intervals of CQ + TQ vs. TQ for AUC0–t, AUC0–∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0–24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. Conclusions No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects. PMID:23701202

  18. The Holy Grail of Polymer Therapeutics for Cancer Therapy: An Overview on the Pharmacokinetics and Bio Distribution.

    PubMed

    Dyawanapelly, Sathish; Junnuthula, Vijayabhaskar Reddy; Singh, AkhileshVikram

    2015-01-01

    In recent years, multifaceted clinical benefits of polymeric therapeutics have been reported. Over the past decades, cancer has been one of the leading causes of mortality in the world. Many clinically approved chemotherapeutics encounter potential challenges against deadly cancer. Moreover, safety and efficacy of anticancer agents have been limited by undesirable pharmacokinetics and biodistribution. To address these limitations, various polymer drug conjugates are being studied and developed to improve the antitumor efficacy. Among other therapeutics, polymer therapeutics are well established platforms that circumvent anticancer therapeutics from enzymatic metabolism via direct conjugation to therapeutic molecules. Interestingly, polymer therapeutics meets an unmet need of small molecules. Further clinical study showed that polymer-drug conjugation can achieve desired pharmacokinetics and biodistribution properties of several anticancer drugs. The present retrospective review mainly enlightens the most recent preclinical and clinical studies include safety, stability, pharmacokinetic behavior and distribution of polymer therapeutics.

  19. Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses.

    PubMed Central

    Barbhaiya, R H; Forgue, S T; Gleason, C R; Knupp, C A; Pittman, K A; Weidler, D J; Martin, R R

    1990-01-01

    In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min intravenous infusion) received each antibiotic, according to a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 ml/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime. PMID:2203303

  20. Pharmacokinetics, tissue distribution and safety of cinnarizine delivered in lipid emulsion.

    PubMed

    Shi, Shuai; Chen, Hao; Lin, Xia; Tang, Xing

    2010-01-04

    The aim of this study was to assess the potential of cinnarizine loaded in lipid emulsion to modify the pharmacokinetics, tissue distribution and safety of cinnarizine. The cinnarizine-loaded emulsion (CLE) which can remain stable over 18-month storage at 4+/-2 degrees C was prepared by high-pressure homogenization. Nicomp 380 particle sizing system and HPLC were used to evaluate CLE in vitro, while UPLC/MS/MS for pharmacokinetic and tissue distribution study. The pharmacokinetics and tissue distributions of CLE were assessed by comparing with the solution form after intravenous administration to rats at a dose of 2mg/kg. The CLE showed significant higher AUC and lower clearance and distribution volume than those of solution form. This helped cinnarizine to reach higher level in vessel, and circulate in the blood stream for a longer time resulting in better therapeutic effect. The tissue distribution exhibited significant lower uptake of CLE emulsion in lung and brain, indicating the advantage of CLE over the solution form in reducing drug precipitation in vivo and toxicity in CNS. Drug safety assessment studies including hemolysis test, intravenous stimulation and injection anaphylaxis revealed that the CLE was safe for intravenous injection.

  1. Safety, tolerability and pharmacokinetics of an intravenous bolus of sildenafil in patients with pulmonary arterial hypertension

    PubMed Central

    Vachiery, Jean-Luc; Huez, Sandrine; Gillies, Hunter; Layton, Gary; Hayashi, Naoto; Gao, Xiang; Naeije, Robert

    2011-01-01

    AIMS To assess pharmacokinetics and pharmacodynamics of a 10 mg intravenous sildenafil bolus in pulmonary arterial hypertension (PAH) patients stabilized on 20 mg sildenafil orally three times daily. METHODS Pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS After an acute increase, plasma concentrations stabilized within the range reported previously for a 20 mg oral tablet. At 0.5 h, mean ± SD changes from baseline were −8.4 ± 11.7 mmHg (systolic pressure), −2.6 ± 7.3 mmHg (diastolic pressure) and −3.5 ± 10.4 beats min−1 (heart rate). There was no symptomatic hypotension. CONCLUSIONS Although further research is warranted, a 10 mg sildenafil intravenous bolus appears to provide similar exposure, tolerability and safety to the 20 mg tablet. PMID:21219411

  2. (64)Cu-Labeled Trastuzumab Fab-PEG24-EGF Radioimmunoconjugates Bispecific for HER2 and EGFR: Pharmacokinetics, Biodistribution, and Tumor Imaging by PET in Comparison to Monospecific Agents.

    PubMed

    Kwon, Luke Yongkyu; Scollard, Deborah A; Reilly, Raymond M

    2017-02-06

    Heterodimerization of EGFR with HER2 coexpressed in breast cancer (BC) promotes tumor growth, and increased EGFR expression is associated with trastuzumab resistance. Our aim was to construct (64)Cu-labeled bispecific radioimmunoconjugates (bsRIC) composed of trastuzumab Fab, which binds HER2 linked through a polyethylene glycol (PEG24) spacer to EGF, and to compare their pharmacokinetic, biodistribution, and tumor imaging characteristics by positron-emission tomography (PET). bsRICs were generated by linking maleimide modified trastuzumab Fab with thiolated EGF through a thioether bond. HER2 and EGFR binding were assessed in vitro in MDA-MB-231 (EGFR(mod)/HER2(low)), MDA-MB-468 (EGFR(high)/HER2(neg)), MDA-MB-231-H2N (EGFR(mod)/HER2(mod)), and SKOV3 (EGFR(low)/HER2(high)) cells by competition and saturation cell binding assays to estimate the dissociation constant (Kd). The elimination of the (64)Cu-NOTA-trastuzumab Fab-PEG24-EGF bsRICs from the blood of Balb/c mice was compared to monospecific (64)Cu-NOTA-trastuzumab Fab and (64)Cu-NOTA-EGF. MicroPET/CT imaging was performed in NOD/SCID mice bearing subcutaneous MDA-MB-468, MDA-MB-231/H2N, or SKOV3 human BC xenografts at 24 and 48 h postinjection (p.i.) of bsRICs. Tumor and normal tissue uptake were quantified by biodistribution studies and compared to monospecific agents. The binding of bsRICs to MDA-MB-231 cells was decreased to 24.5 ± 5.2% by excess EGF, while the binding of bsRICs to SKOV3 cells was decreased to 38.6 ± 5.4% by excess trastuzumab Fab, demonstrating specific binding to both EGFR and HER2. (64)Cu-labeled bsRICs incorporating the PEG24 spacer were eliminated more slowly from the blood than (64)Cu-bsRICs without the PEG spacer and were cleared much more slowly than (64)Cu-NOTA-Fab or (64)Cu-NOTA-EGF. All three tumor xenografts were visualized by microPET/CT at 24 and 48 h p.i. of bsRICs. Biodistribution studies at 48 h p.i. in NOD/SCID mice with MDA-MB-231/H2N tumors demonstrated significantly

  3. [Comparison of the pharmacokinetics and safety of a paclitaxel injection NK and Taxol injection in breast cancer patients].

    PubMed

    Sagara, Yoshiaki; Rai, Yoshiaki; Sagara, Yoshiatsu; Matsuyama, Yoshito; Baba, Shinichi; Tamada, Shugo; Sagara, Yasuaki; Ando, Mitsutake

    2009-02-01

    A paclitaxel injection NK (NK) is a generic product containing the same amount of ingredient as a Taxol Injection. We examined the pharmacokinetics and safety of NK compared to the original product in breast cancer patients. As a result, the transition of plasma paclitaxel concentration and pharmacokinetic parameter in NK and the original drug were almost equal, which suggested that these products were bioequivalent. In adjuvant therapy, there was no significant difference in adverse events reported, and these products were approximately equally safe.

  4. Assessment of biodistribution using mesenchymal stromal cells: Algorithm for study design and challenges in detection methodologies.

    PubMed

    Reyes, Blanca; Coca, Maria Isabel; Codinach, Margarita; López-Lucas, María Dolores; Del Mazo-Barbara, Anna; Caminal, Marta; Oliver-Vila, Irene; Cabañas, Valentín; Lope-Piedrafita, Silvia; García-López, Joan; Moraleda, José M; Fontecha, Cesar G; Vives, Joaquim

    2017-09-01

    Biodistribution of candidate cell-based therapeutics is a critical safety concern that must be addressed in the preclinical development program. We aimed to design a decision tree based on a series of studies included in actual dossiers approved by competent regulatory authorities, noting that the design, execution and interpretation of pharmacokinetics studies using this type of therapy is not straightforward and presents a challenge for both developers and regulators. Eight studies were evaluated for the definition of a decision tree, in which mesenchymal stromal cells (MSCs) were administered to mouse, rat and sheep models using diverse routes (local or systemic), cell labeling (chemical or genetic) and detection methodologies (polymerase chain reaction [PCR], immunohistochemistry [IHC], fluorescence bioimaging, and magnetic resonance imaging [MRI]). Moreover, labeling and detection methodologies were compared in terms of cost, throughput, speed, sensitivity and specificity. A decision tree was defined based on the model chosen: (i) small immunodeficient animals receiving heterologous MSC products for assessing biodistribution and other safety aspects and (ii) large animals receiving homologous labeled products; this contributed to gathering data not only on biodistribution but also on pharmacodynamics. PCR emerged as the most convenient technique despite the loss of spatial information on cell distribution that can be further assessed by IHC. This work contributes to the standardization in the design of biodistribution studies by improving methods for accurate assessment of safety. The evaluation of different animal models and screening of target organs through a combination of techniques is a cost-effective and timely strategy. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  5. Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

    PubMed

    Glue, Paul; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, Cheung-Tak; Friedhoff, Lawrence

    2015-02-01

    Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers.

  6. Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants.

    PubMed

    Salerno, Sara; Hornik, Christoph P; Cohen-Wolkowiez, Michael; Smith, P Brian; Ku, Lawrence C; Kelly, Matthew S; Clark, Reese; Gonzalez, Daniel

    2017-09-01

    Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking. To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Using a previously published population pharmacokinetic model in the target population, we simulated piperacillin steady state area under the concentration versus time curve from zero to τ (AUCss,0-τ) and steady state maximal drug concentration (Cmaxss). Next, we used multivariable logistic regression to evaluate the association between simulated AUCss,0-τ and Cmaxss with clinical AEs (seizure and rash) and laboratory AEs controlling for gestational age. The odds ratios (95% confidence intervals) comparing the third versus the first tertiles for AUCss,0-τ and Cmaxss were reported. We identified 746 infants with a median (interquartile range) gestational age of 30 weeks (26-33) and postnatal age of 11 days (6-25). The median (interquartile range) piperacillin dose was 225 mg/kg/d (176-300). No significant associations were found between simulated piperacillin exposure (AUCss,0-τ and Cmaxss) and clinical and laboratory AEs. We found no associations between predicted piperacillin exposures and the occurrence of AEs. This study confirms the feasibility of using population pharmacokinetics and EHR to relate drug exposure with safety.

  7. Randomized clinical trial: pharmacokinetics and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis

    PubMed Central

    Cuffari, Carmen; Pierce, David; Korczowski, Bartosz; Fyderek, Krzysztof; Van Heusen, Heather; Hossack, Stuart; Wan, Hong; Edwards, Alena YZ; Martin, Patrick

    2016-01-01

    Background Limited data are available on mesalamine (5-aminosalicylic acid; 5-ASA) use in pediatric ulcerative colitis (UC). Aim To evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC. Methods Participants (5–17 years of age; 18–82 kg, stratified by weight) with UC received multi-matrix mesalamine 30, 60, or 100 mg/kg/day once daily (to 4,800 mg/day) for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model. Results Fifty-two subjects (21 [30 mg/kg]; 22 [60 mg/kg]; 9 [100 mg/kg]) were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60 mg/kg/day cohorts. For 30, 60, and 100 mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%–45%, respectively) were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were reported by ten subjects. Events were similar among different doses and age groups with no new safety signals identified. Conclusion Children and adolescents with UC receiving multimatrix mesalamine demonstrated 5-ASA and Ac-5-ASA pharmacokinetic profiles similar to historical adult data. Multimatrix mesalamine was well tolerated across all dose and age groups. ClinicalTrials.gov Identifier: NCT01130844. PMID:26893546

  8. Fructus Ligustri Lucidi in Osteoporosis: A Review of its Pharmacology, Phytochemistry, Pharmacokinetics and Safety.

    PubMed

    Chen, Beibei; Wang, Lili; Li, Lin; Zhu, Ruyuan; Liu, Haixia; Liu, Chenyue; Ma, Rufeng; Jia, Qiangqiang; Zhao, Dandan; Niu, Jianzhao; Fu, Min; Gao, Sihua; Zhang, Dongwei

    2017-09-05

    Background: Fructus Ligustri Lucidi (FLL) has now attracted increasing attention as an alternative medicine in the prevention and treatment of osteoporosis. This study aimed to provide a general review of traditional interpretation of the actions of FLL in osteoporosis, main phytochemical constituents, pharmacokinetics, pharmacology in bone improving effect, and safety. Materials and Methods: Several databases, including PubMed, China National Knowledge Infrastructure, National Science and Technology Library, China Science and Technology Journal Database, and Web of Science were consulted to locate publications pertaining to FLL. The initial inquiry was conducted for the presence of the following keywords combinations in the abstracts: Fructus Ligustri Lucidi, osteoporosis, phytochemistry, pharmacokinetics, pharmacology, osteoblasts, osteoclasts, salidroside. About 150 research papers and reviews were consulted. Results: FLL is assumed to exhibit anti-osteoporotic effects by improving liver and kidney deficiencies and reducing lower back soreness in Traditional Chinese Medicine (TCM). The data from animal and cell experiments demonstrate that FLL is able to improve bone metabolism and bone quality in ovariectomized, growing, aged and diabetic rats through the regulation of PTH/FGF-23/1,25-(OH)₂D₃/CaSR, Nox4/ROS/NF-κB, and OPG/RANKL/cathepsin K signaling pathways. More than 100 individual compounds have been isolated from this plant. Oleanolic acid, ursolic acid, salidroside, and nuzhenide have been reported to exhibit the anti-osteoporosis effect. The pharmacokinetics data reveals that salidroside is one of the active constituents, and that tyrosol is hard to detect under physiological conditions. Acute and subacute toxicity studies show that FLL is well tolerated and presents no safety concerns. Conclusions: FLL provides a new option for the prevention and treatment of osteoporosis, which attracts rising interests in identifying potential anti

  9. The pharmacokinetics and safety of desvenlafaxine in subjects with chronic renal impairment.

    PubMed

    Nichols, A I; Richards, L S; Behrle, J A; Posener, J A; McGrory, S B; Paul, J

    2011-01-01

    Desvenlafaxine (administered as desvenlafaxine succinate), the major active metabolite of venlafaxine, is a new serotonin-norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD). To assess the pharmacokinetics, safety, and tolerability of desvenlafaxine in healthy volunteers vs. those with renal impairment. A single, oral, 100 mg dose of desvenlafaxine was administered to healthy subjects (n = 8) and subjects with mild (n = 9), moderate (n = 9), or severe (n = 7) renal impairment (24-h creatinine clearance, ml/min: 50 - 80, 30 - 50, or < 30 ml/min, respectively) or end-stage renal disease (ESRD; on dialysis.

  10. Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers.

    PubMed

    Chow, A T; Fowler, C; Williams, R R; Morgan, N; Kaminski, S; Natarajan, J

    2001-07-01

    The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation.

  11. Pharmacokinetics and safety of the sesame lignans, sesamin and episesamin, in healthy subjects.

    PubMed

    Tomimori, Namino; Tanaka, Yasuhiro; Kitagawa, Yoshinori; Fujii, Wataru; Sakakibara, Yutaka; Shibata, Hiroshi

    2013-11-01

    A single-blind, placebo-controlled, parallel-group and multiple oral dose study was conducted in 48 healthy subjects to investigate the pharmacokinetics and safety of multiple oral doses of sesame lignans (sesamin and episesamin). Subjects were randomly divided into two groups. Each subject was administered 50 mg of sesame lignans (sesamin/episesamin=1/1) or placebo once daily for 28 days. The pharmacokinetics of the sesame lignans were investigated using 10 of the 24 subjects in the sesame lignans group. No serious adverse events were observed in this study. Sesamin was absorbed with a peak plasma concentration at 5.0 h. The plasma concentration of the main metabolite, SC-1, reached a peak at 5.0 h and decreased rapidly with a terminal half-life of 2.4 h. Episesamin was also absorbed with a peak plasma concentration at 5.0 h and decreased with a terminal half-life of 7.1 h. The plasma concentration of the main metabolite, EC-1, reached a peak at 5.0 h and decreased rapidly with a terminal half-life of 3.4 h. The plasma concentrations of sesamin and episesamin reached a steady state by day 7. Sesame lignans were confirmed to be safe and tolerable in healthy subjects. The results of the pharmacokinetic study demonstrate that no accumulation was observed following multiple 50 mg doses of sesame lignans.

  12. Pharmacokinetics and safety of tanaproget, a nonsteroidal progesterone receptor agonist, in healthy women.

    PubMed

    Bapst, Jody L; Ermer, James C; Ferron, Geraldine M; Foss, Deborah; Orczyk, Gayle P

    2006-11-01

    This study aimed to evaluate the pharmacokinetics, pharmacodynamics and safety of the nonsteroidal progesterone receptor agonist, tanaproget. A randomized, double-blind, placebo-controlled, sequential-group study of ascending single doses of tanaproget was conducted in healthy, 25- to 45-year-old women on cycle days 8 to 12. Eight subjects (six active, two placebo) per cohort received a dose of 0.1, 0.3, 1, 3, 7 (+/-high-fat meal) or 15 mg. The maximum concentration (C(max)) of tanaproget occurred approximately 2 to 3 h after administration. The elimination half-life (t(1/2)) ranged from 12 to 30 h, and the oral clearance was approximately 70 L/h. The pharmacokinetics of tanaproget was not noticeably altered with a high-fat meal. All doses of tanaproget decreased cervical mucus scores (using a modified Insler method), indicating poor production and poor quality of cervical mucus. The most frequent treatment-emergent adverse events were vaginal bleeding/spotting, abdominal cramping and vomiting; their incidence was not dose related and most events were mild. Tanaproget was safe and well tolerated, decreased cervical mucus scores and had a pharmacokinetic profile acceptable for use as a once-daily oral contraceptive.

  13. Safety, Tolerability, and Pharmacokinetics of Intravenous Nemonoxacin in Healthy Chinese Volunteers

    PubMed Central

    Cao, Guo-ying; Zhang, Ying-yuan; Guo, Bei-ning; Yu, Ji-cheng; Wu, Xiao-jie; Chen, Yuan-cheng; Wu, Ju-Fang; Shi, Yao-guo

    2014-01-01

    Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (Cmax) values were 4.826 μg/ml, 7.152 μg/ml, and 11.029 μg/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC0–72 h) were 17.05 μg · h/ml, 39.30 μg · h/ml, and 61.98 μg · h/ml. The mean elimination half-life (t1/2) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. Volunteers treated with 250 to 750 mg nemonoxacin exhibited a linear dose-response relationship between the AUC0–72 h and AUC0–∞. These findings provide further support for the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.) PMID:25092690

  14. Galantamine pharmacokinetics, safety, and tolerability profiles are similar in healthy Caucasian and Japanese subjects.

    PubMed

    Zhao, Qinying; Brett, Martin; Van Osselaer, Nancy; Huang, Fenglei; Raoult, Alain; Van Peer, Achiel; Verhaeghe, Tom; Hust, Rita

    2002-09-01

    The aim of this study was to compare the pharmacokinetics of galantamine in healthy Japanese and Caucasian subjects and assess the safety and tolerability of galantamine in both ethnic groups. Parallel groups of healthy Japanese (n = 13; 6 males and 7 females)and Caucasian (n = 12; 6 males and 6 females) subjects matched for weight and age received single oral doses of galantamine 4 mg, or galantamine 8 mg, or placebo in a double-blind, three-way crossover trial according to a randomized dosing schedule. Concentrations of galantamine and norgalantamine were determined in plasma and urine samples taken up to 48 and 24 hours after dosing, respectively. Safety and tolerability were monitored throughout the trial by recording adverse events, laboratory tests, and cardiovascular parameters. The mean plasma concentration-time profiles of galantamine were very similar after single doses of galantamine (4 and 8 mg), and there was an approximate dose proportionality of galantamine pharmacokinetic parameters in both Caucasian and Japanese ethnic groups. The mean (+/- SD) pharmacokinetic parameters in the two ethnic groups did not show any clinically relevant differences. The ratios for the area under the plasma-concentration curve from time zero to infinity (AUC)0-infinity) in Japanese:Caucasian subjects with 4 and 8 mg doses were 103% (90% confidence interval [CII = 92-116) and 107% (90% CI = 94-121), respectively. Ratios for maximum plasma concentration (Cmax) values were 107% (90% CI= 90-127) and 108% (90% CI= 95-123), respectively. These ratios and associated 90% CIs were within the 80% to 125% range limit of bioequivalence. Analysis of variance (ANOVA) showed that these ratio values demonstrated no statistically significant difference between the two ethnic groups. There was no overt difference in the adverse event profile in Japanese subjects compared with Caucasian subjects. There were no serious adverse events, and no subjects discontinued from the study because of

  15. Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women
.

    PubMed

    Schultze-Mosgau, Marcus-Hillert; Schuett, Barbara; Hafner, Frank-Thorsten; Zollmann, Frank; Kaiser, Andreas; Hoechel, Joachim; Rohde, Beate

    2017-01-01

    Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids. In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and - after a wash-out period - daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28). Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 - 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 µg/L (1 mg) to 68.6 µg/L (30 mg) and 58.5 µg×h/L to 1,590 µg×h/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0-24)md/AUC(0-24)sd ratios: 1.9 to 3.2). The ratio AUC(0-24)md/AUCsd increased with dose from ~ 1 (1 mg) to 1.5 (30 mg). Exposure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t1/2, indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range.
.

  16. Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents

    PubMed Central

    Gonzalez, Daniel; Palazzi, Debra L.; Bhattacharya-Mithal, Leena; Al-Uzri, Amira; James, Laura P.; Bradley, John; Neu, Natalie; Jasion, Theresa; Hornik, Christoph P.; Smith, P. Brian; Benjamin, Daniel K.; Keedy, Kara; Fernandes, Prabhavathi

    2016-01-01

    We assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 μg/ml (0.61 μg/ml) and 9.28 μg · h/ml (6.30 μg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01966055.) PMID:26883693

  17. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety.

    PubMed

    Badros, A Z; Vij, R; Martin, T; Zonder, J A; Kunkel, L; Wang, Z; Lee, S; Wong, A F; Niesvizky, R

    2013-08-01

    This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80 ml/min, 50-80 ml/min, 30-49 ml/min, <30 ml/min and chronic hemodialysis. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: 15 mg/m(2) (Cycle 1), 20 mg/m(2) (Cycle 2) and 27 mg/m(2) (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events (AEs) included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%) and fatigue (14.0%). AEs were similar among groups. At 15 mg/m(2), proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy.

  18. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis.

    PubMed

    Ogura, Takashi; Taniguchi, Hiroyuki; Azuma, Arata; Inoue, Yoshikazu; Kondoh, Yasuhiro; Hasegawa, Yoshinori; Bando, Masashi; Abe, Shinji; Mochizuki, Yoshiro; Chida, Kingo; Klüglich, Matthias; Fujimoto, Tsuyoshi; Okazaki, Kotaro; Tadayasu, Yusuke; Sakamoto, Wataru; Sugiyama, Yukihiko

    2015-05-01

    A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone.

  19. Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability

    PubMed Central

    Usach, Iris; Melis, Virginia; Peris, José-Esteban

    2013-01-01

    Introduction Human immunodeficiency virus (HIV) type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection. Discussion First-generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second-generation NNRTIs, etravirine (ETR) and rilpivirine (RPV) have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next-generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK-4965, MK-1439 and MK-6186. Conclusions This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research. PMID:24008177

  20. In Vivo Safety, Biodistribution and Antitumor Effects of uPAR Retargeted Oncolytic Measles Virus in Syngeneic Cancer Models

    PubMed Central

    Jing, Yuqi; Zaias, Julia; Duncan, Robert; Russell, Stephen J.; Merchan, Jaime R.

    2014-01-01

    The urokinase receptor (uPAR) is a clinically relevant target for novel biological therapies. We have previously rescued oncolytic measles viruses fully retargeted against human (MV-h-uPA) or murine (MV-m-uPA) uPAR. Here, we investigated the in vivo effects of systemic administration of MV-m-uPA in immunocompetent cancer models. MV-m-uPA induced in vitro cytotoxicity and replicated in a receptor dependent manner in murine mammary (4T1), and colon (MC-38 and CT-26) cancer cells. Intravenous administration of MV-m-uPA to 4T1 tumor bearing mice was not associated with significant clinical or laboratory toxicity. Higher MV-N RNA copy numbers were detected in primary tumors, and viable viral particles were recovered from tumor bearing tissues only. Non-tumor bearing organs did not show histological signs of viral induced toxicity. Serum anti-MV antibodies were detected at day 14 of treatment. Immunohistochemistry and immunofluorescence studies confirmed successful tumor targeting and demonstrated enhanced MV-m-uPA induced tumor cell apoptosis in treated, compared to control mice. Significant antitumor effects and prolonged survival were observed after systemic administration of MV-m-uPA in colon (CT-26) and mammary (4T1) cancer models. The above results demonstrate safety and feasibility of uPAR targeting by an oncolytic virus, and confirm significant antitumor effects in highly aggressive syngeneic immunocompetent cancer models. PMID:24430235

  1. Safety, tolerability and pharmacokinetics of phenoprolamine hydrochloride floating sustained-release tablets in healthy Chinese subjects.

    PubMed

    Zhao, Libo; Yang, Xiaoyan; Xu, Rong; Wu, Jianhong; Gu, Shifen; Zhang, Li; Gong, Peili; Chen, Hui; Zeng, Fandian

    2009-07-30

    The present study was designed to assess the safety, tolerability and pharmacokinetics of phenoprolamine hydrochloride floating sustained tablets (PHFST) in healthy Chinese subjects. 116 volunteers were randomized into single- or multiple-dose groups for oral administration 30-240 mg of PHFST once or 60-120 mg twice daily. Safety and tolerability were appraised by monitoring adverse events and laboratory parameters. Pharmacokinetics was assessed by determining the plasma concentrations of phenoprolamine hydrochloride with a validated HPLC method. In single-dose studies, no severe adverse events were observed in volunteers, and all adverse events were mild; the percentages of treatment-emergent events judged to be possibly related to the drug were 3/6 in the 240 mg dose group, 1/6 in the 180-210 mg dose groups, and none in the 30-150 mg dose groups; system exposure (AUC, C(max)) increased with respect to dose at 30-120 mg, whereas AUC raised disproportionately with dose escalating from 120 to 240 mg; the absorption of phenoprolamine hydrochloride was unaffected by food. In multiple studies, no safety concerns were revealed up to 7 days; steady-state plasma concentration was achieved after approximately 4-5 days of repeated twice-daily dosing. PHFST is safe and well tolerated in healthy Chinese subjects. The mean C(max) of PHFST is proportional to dose, but not the AUC. Oral dosing regimen selected for subsequent Phase II/III clinical trials was 60 mg of PHFST, b.i.d., and dose up to 120 mg, b.i.d. - may be used to achieve better antihypertensive effect.

  2. Voriconazole Pharmacokinetics and Safety in Immunocompromised Children Compared to Adult Patients ▿

    PubMed Central

    Michael, Claudia; Bierbach, Uta; Frenzel, Katrin; Lange, Thoralf; Basara, Nadezda; Niederwieser, Dietger; Mauz-Körholz, Christine; Preiss, Rainer

    2010-01-01

    The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. Trough voriconazole levels in blood over 10 days of therapy and regular voriconazole levels in blood for up to 12 h postdose on day 3 were examined. Wide intra- and interindividual variations in plasma voriconazole levels were noted in each dose group and were most pronounced in the children receiving the 7-mg/kg dose. Five (56%) of them frequently had trough voriconazole levels in plasma below 1 μg/ml or above 6 μg/ml. The recommended dose of 7 mg/kg i.v. in children provides exposure (area under the concentration-time curve) comparable to that observed in adults receiving 4 mg/kg i.v. The children had significantly higher Cmax values; other pharmacokinetic parameters were not significantly different from those of adults. Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years. PMID:20547816

  3. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

    SciTech Connect

    Vuillemenot, Brian R.; Kennedy, Derek; Reed, Randall P.; Boyd, Robert B.; Butt, Mark T.; Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O'Neill, Charles A.

    2014-05-15

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

  4. Safety and Pharmacokinetics of Repeat-Dose Micafungin in Young Infants

    PubMed Central

    Benjamin, Daniel K; Smith, P Brian; Arrieta, Antonio; Castro, Lisa; Sánchez, Pablo J; Kaufman, David; Arnold, Leah J; Kovanda, Laura L; Sawamoto, Taiji; Buell, Donald N; Hope, William W; Walsh, Thomas J

    2010-01-01

    Due to the risk of central nervous system infection, relatively high weight-based echinocandin dosages may be required for successful treatment of invasive candidiasis and candidemia in young infants. This open-label study assessed safety and pharmacokinetics of micafungin in 13 young infants (> 48 hours of age and < 120 days of life) with suspected candidemia or invasive candidiasis. Infants weighing ≥ 1,000 g and < 1,000 g received 7 and 10 mg/kg/day, respectively, for a minimum of 4 to 5 days. Mean baseline weight and gestational age were 2101 g and 688 g, and 30 weeks and 25 weeks, in the 7 and 10 mg/kg/day groups, respectively. Median pharmacokinetic values for the 7 and 10 mg/kg/day groups, respectively, were: AUC0–24, 258.1 and 291.2 μg•h/ml; Clss/wt, 0.45 and 0.57 ml/min/kg; Cmax, 23.3 and 24.9 μg/ml; and Vdss/wt, 341.4 and 542.8 ml/kg. No deaths or discontinuations from treatment occurred. These data suggest that micafungin dosages of 7 and 10 mg/kg/day were well tolerated and provided exposure that was demonstrated in animal model to be adequate for central nervous system coverage. PMID:19890251

  5. Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males.

    PubMed

    Shen, Zancong; Rowlings, Colin; Kerr, Brad; Hingorani, Vijay; Manhard, Kimberly; Quart, Barry; Yeh, Li-Tain; Storgard, Chris

    2015-01-01

    Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration-time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated.

  6. Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males

    PubMed Central

    Shen, Zancong; Rowlings, Colin; Kerr, Brad; Hingorani, Vijay; Manhard, Kimberly; Quart, Barry; Yeh, Li-Tain; Storgard, Chris

    2015-01-01

    Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration–time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated. PMID:26170627

  7. Multiple-dose pharmacokinetics and safety of desloratadine in subjects with moderate hepatic impairment.

    PubMed

    Gupta, Samir K; Kantesaria, Bhavna; Wang, Zaiqi

    2007-10-01

    Desloratadine, a nonsedating histamine H(1)-receptor antagonist, is metabolized to 3-hydroxy (3-OH) desloratadine. Impaired hepatic function could result in increased exposure to desloratadine. This study assessed possible differences in the pharmacokinetics and safety of desloratadine and 3-OH desloratadine in subjects (N = 21) with moderate hepatic dysfunction or normal liver function. Subjects were given desloratadine 5 mg once daily for 10 days and were assessed in several pharmacokinetic parameters. A similar degree of plasma protein binding to desloratadine and 3-OH desloratadine was observed in healthy volunteers and subjects with moderate hepatic impairment. All subjects with hepatic impairment were normal metabolizers. Three subjects with normal liver function, all African American, were identified as poor metabolizers. Exposure to desloratadine in the poor metabolizers was 2.6- to 6.5-fold greater than in other subjects with normal liver function. Eleven treatment-related adverse events, all mild to moderate in severity, were reported. Results suggest that subjects with moderate hepatic impairment experienced a greater increase in desloratadine exposure than subjects with normal liver function. Poor metabolizers had more exposure to desloratadine than normal metabolizers with or without hepatic impairment. Desloratadine administered at a daily dose of 5 mg was well tolerated.

  8. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.

    PubMed

    Wang, Xiaoli; Tirucherai, Giridhar; Marbury, Thomas C; Wang, Jessie; Chang, Ming; Zhang, Donglu; Song, Yan; Pursley, Janice; Boyd, Rebecca A; Frost, Charles

    2016-05-01

    An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in apixaban concentration. A single 5-mg oral dose of apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on apixaban clearance.

  9. Safety, pharmacokinetics and pharmacodynamics of the anti‐hepcidin Spiegelmer lexaptepid pegol in healthy subjects

    PubMed Central

    Boyce, M; Warrington, S; Cortezi, B; Zöllner, S; Vauléon, S; Swinkels, D W; Summo, L; Schwoebel, F

    2016-01-01

    Background and Purpose Anaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l‐oligoribonucleotide, binds and inactivates hepcidin. Experimental Approach We conducted a placebo‐controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg−1. Key Results After treatment with lexaptepid, serum iron concentration and transferrin increased dose‐dependently. Iron increased from approximately 20 μmol·L−1 at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg−1 lexaptepid. The pharmacokinetics showed dose‐proportional increases in peak plasma concentrations and moderately over‐proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti‐drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg−1 and with local injection site reactions after s.c. but not after i.v. administration. Conclusions and Implications Lexaptepid pegol inhibited hepcidin and dose‐dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease. PMID:26773325

  10. Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis.

    PubMed

    Zuurmond, Anne-Marie; Koudijs, Angela; van El, Benno; Doornbos, Robert P; van Manen-Vernooij, Babs C T; Bastiaans, Jacqueline H M W; Penninks, André H; van Bilsen, Jolanda H M; Cnubben, Nicole H P; Degroot, Jeroen

    2011-04-01

    Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure.

  11. Safety, Tolerability, and Pharmacokinetics of Micafungin (FK463) in Febrile Neutropenic Pediatric Patients

    PubMed Central

    Seibel, Nita L.; Schwartz, Cindy; Arrieta, Antonio; Flynn, Patricia; Shad, Aziza; Albano, Edith; Keirns, James; Lau, Wendi M.; Facklam, David P.; Buell, Donald N.; Walsh, Thomas J.

    2005-01-01

    Micafungin (FK463) is a new parenteral echinocandin. A multicenter, phase I, open-label, sequential-group dose escalation study was conducted to assess the safety, tolerability, and pharmacokinetics of micafungin in neutropenic pediatric patients. A total of 77 patients stratified by age (2 to 12 and 13 to 17 years) received micafungin. Therapy was initiated at 0.5 mg/kg per day and escalated to higher dose levels of 1.0, 1.5, 2.0, 3.0, and 4.0 mg/kg per day. Micafungin was administered within 24 h of initiating broad-spectrum antibacterial antibiotics for the new onset of fever and neutropenia. The most common overall adverse events in the study population were diarrhea (19.5%), epistaxis (18.2%), abdominal pain (16.9%), and headache (16.9%). Nine patients (12%) experienced adverse events considered by the investigator to be possibly related to the study drug. The most common related events were diarrhea, vomiting, and headache, all occurring in two patients each. There was no evidence of a dose-limiting toxicity as defined within the prespecified criteria of this clinical protocol. There was one death during the study due to septic shock. The pharmacokinetic profiles for micafungin over the 0.5- to 4.0-mg/kg dose range demonstrated dose linearity. Clearance, volume of distribution, and half-life remained relatively constant over the dose range and did not change with repeated administration. The overall plasma pharmacokinetic profile was similar to that observed in adults. However, there was an inverse relation between age and clearance. For patients 2 to 8 years old, clearance was approximately 1.35 times that of patients ≥9 years of age. In summary, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age. PMID:16048942

  12. Pharmacokinetics and Safety of Famciclovir in Children with Herpes Simplex or Varicella-Zoster Virus Infection▿

    PubMed Central

    Sáez-Llorens, X.; Yogev, R.; Arguedas, A.; Rodriguez, A.; Spigarelli, M. G.; De León Castrejón, T.; Bomgaars, L.; Roberts, M.; Abrams, B.; Zhou, W.; Looby, M.; Kaiser, G.; Hamed, K.

    2009-01-01

    Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (∼12.5 mg/kg of body weight [BW] for children weighing <40 kg and 500 mg for children weighing ≥40 kg). The average systemic exposure to penciclovir was similar (6- to 12-year-olds) or slightly lower (1- to <6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW0.696. An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose. PMID:19273678

  13. Pharmacokinetics, efficacy, and safety of intravesical formulation of oxybutynin in patients with detrusor overactivity.

    PubMed

    Lehtoranta, Kari; Tainio, Hanna; Lukkari-Lax, Eeva; Hakonen, Tiina; Tammela, Teuvo L J

    2002-02-01

    To determine the pharmacokinetics of oxybutynin and its main active metabolite, N-desethyloxybutynin, after multiple dosage (5 mg/30 ml three times daily) of intravesical oxybutynin formulation. Furthermore, to determine the efficacy and safety of intravesical oxybutynin in the symptomatic relief of urge incontinence or urgency in adult patients with detrusor hyperreflexia or instability. Nine patients were randomly allocated to treatment with a special bladder instillation formulation of oxybutynin or placebo for two 14-day treatment periods in a double-blind, cross-over manner. The third, open study period was designed for pharmacokinetic purposes with all patients on the active drug. The pharmacokinetics was depicted by AUC0-24, Cmax, Cmin, and t(max), The efficacy was evaluated from the data collected from urinary voiding diaries and cystometries. The safety was measured by recording adverse events on questionnaires. Patients who were willing to continue with the intravesical oxybutynin treatment entered the 1-year extension part of the study. Oxybutynin was absorbed from the bladder with a geometric mean Cmax of 9.4 ng/ml and AUC0-24 of 92 ng x h/ml. For N-desethyloxybutynin, the geometric mean Cmax was 14.4 ng/ml and AUC0-24 186 ng x h/ml. Elimination of the drug was protracted, as there were detectable serum concentrations of both oxybutynin and N-desethyloxybutynin even 24 hours post-dose. The mean number of toilet visits/day decreased from the baseline value of 6.9 to 5.7 during oxybutynin treatment, whereas during the placebo period the value increased to 7.4 (p = 0.022). It remained at the same decreased level during the one-year follow-up period. Oxybutynin is readily absorbed from the bladder after intravesical administration. The serum concentrations of oxybutynin after single 5 mg intravesical doses are at least as high as those reported after oral drug intake, but the parent drug/metabolite ratio is much higher after intravesical administration. The

  14. Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects.

    PubMed

    Chen, Xia; Hu, Pei; Vaccaro, Nicole; Polidori, David; Curtin, Christopher R; Stieltjes, Hans; Sha, Sue; Weiner, Sveta; Devineni, Damayanthi

    2015-07-01

    Canagliflozin, an orally active sodium-glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of canagliflozin in healthy Chinese subjects. In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of canagliflozin 100 mg, canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. All participants are healthy Chinese adults. Mean AUC and Cmax of canagliflozin increased in a dose-dependent manner after single-dose administration (AUC0-∞, 10,521 ng · h/mL for 100 mg, 33,583 ng · h/mL for 300 mg; Cmax, 1178 ng/mL for 100 mg, 4113 ng/mL for 300 mg). The mean apparent t½ and the median Tmax of canagliflozin were independent of dose (t½, 16.0 hours for 100 mg, 16.2 hours for 300 mg; Tmax, ~1 hour). Mean CL/F and renal clearance of canagliflozin were comparable between the 2 doses. Mean plasma metabolite to parent molar ratios for Cmax and AUC0-∞ were similar with both doses. Canagliflozin decreased the 24-hour mean renal threshold for glucose, calculated by using measured creatinine clearance to estimate the glomerular filtration rate (67.9 and 60.7 mg/dL for canagliflozin 100 and 300 mg, respectively) and 24-hour increased urinary glucose excretion (33.8 and 42.9 g for canagliflozin 100 and 300 mg, respectively) in a dose-dependent manner; the 24-hour plasma glucose profile remained largely unchanged. No deaths, hypoglycemic events, or discontinuations due to adverse events were observed. Pharmacokinetics (AUC and Cmax) of canagliflozin increased in a dose-dependent manner after single oral doses of canagliflozin (100 and 300 mg) in

  15. Preclinical testing of the safety and tolerability of LV-mediated above normal alpha-L-iduronidase expression in murine and human hematopoietic cells using toxicology and biodistribution GLP studies.

    PubMed

    Visigalli, Ilaria; Delai, Stefania; Ferro, Francesca; Cecere, Francesca; Vezzoli, Michela; Sanvito, Francesca; Chanut, Franck; Benedicenti, Fabrizio; Spinozzi, Giulio; Wynn, Rob; Calabria, Andrea; Naldini, Luigi; Montini, Eugenio; Cristofori, Patrizia; Biffi, Alessandra

    2016-07-18

    In order to support the clinical application of hematopoietic stem cell (HSC) gene therapy for Mucopolysaccharidosis I (MPS I), we conducted biosafety studies to assess the toxicity and tumorigenic potential, as well as the biodistribution of HSCs and progenitor cells (HSPCs) transduced with lentiviral vectors (LV) encoding the cDNA of the alpha-iduronidase (IDUA) gene, which is mutated in MPS I patients. To this goal, toxicology and biodistribution studies were conducted employing Good Laboratory Practice (GLP) study practices. Vector integration sites studies were applied in order to predict adverse consequences of vector gene transfer and obtain HSC-related information. Overall, the results obtained in these studies provided robust evidence to support the safety and tolerability of high-efficiency LV-mediated gene transfer and above normal IDUA enzyme expression in both murine and human HSPCs and their in vivo progeny. Taken together these investigations provide essential safety data to support clinical testing of HSC gene therapy in MPS I patients. These studies have also underlined criticisms associated to the use of currently available models and highlighted the value of surrogate markers of tumorigenicity that may be further explored in the future. Notably, biological evidence supporting the efficacy of gene therapy on MPS I disease was also generated and the clonal contribution of LV-transduced HSPCs to hematopoiesis along serial transplantation was quantified in a minimum of 200-300 clones, with the different level of repopulating cells in primary recipients being reflected in the secondary.

  16. Pharmacokinetics and safety of 0.5% ivermectin lotion for head louse infestations.

    PubMed

    Hazan, Lydie; Berg, Jeffrey E; Bowman, James P; Murray, John V; Ryan, William G

    2013-01-01

    The safety of a novel 0.5% ivermectin lotion (IVL) and potential for ivermectin absorption after application was investigated in an open-label study in young children, and a human repeat insult patch test (HRIPT) and cumulative irritation test (CIT) assessed any potential for cumulative dermal irritation and contact sensitization. In the pharmacokinetic and safety study, 30 head louse-infested children ages 6 months to 3 years received a 10-minute application of IVL on day 1. Blood was collected before application; 0.5, 1, and 6 hours after rinsing; and on days 2 and 8. Samples from 20 subjects were assayed for ivermectin (test sensitivity 0.05 ng/mL). Liver panel and complete blood counts were completed for all subjects. For the HRIPT/CIT, occlusive patches containing IVL or vehicle control lotion (CL) were repeatedly applied to 220 healthy adult subjects to assess contact sensitization; for cumulative dermal irritation testing, additional patches with normal saline and sodium dodecyl sulfate (SDS) were applied to 36 subjects. In the open-label study, all detected ivermectin plasma concentrations were <1 ng/mL. No safety signals emerged, and treatment was well tolerated. In the HRIPT/CIT, IVL was significantly less irritating than normal saline and SDS, with no evidence of dermal irritation or sensitization in human skin. IVL was safe when applied topically, absorption was de minimus, there was no evidence of irritation or sensitization from repeated exposures, and results support the safety of topical IVL use in children as young as 6 months. © 2012 Wiley Periodicals, Inc.

  17. Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects.

    PubMed

    Kersemaekers, Wendy M; van Iersel, Thijs; Nassander, Ulla; O'Mara, Edward; Waskin, Hetty; Caceres, Maria; van Iersel, Marlou L P S

    2015-02-01

    This study evaluated the safety, tolerability, and pharmacokinetics of a posaconazole i.v. (intravenous) solution. This was a single-center, 2-part, randomized, rising single- and multiple-dose study in healthy adults. In part 1, subjects received 0 (vehicle), 50, 100, 200, 250, or 300 mg posaconazole in a single dose i.v. by 30-min peripheral infusion (6 cohorts of 12 subjects each [9 active and 3 placebo], making a total of 72 subjects). Blood samples were collected until 168 h postdose. In part 2, subjects were to receive 2 peripheral infusions at a 12-h interval on day 1 followed by once-daily infusion for 9 days. However, part 2 was terminated early because of high rates of infusion site reactions with multiple dosing at the same infusion site. The pharmacokinetics results for part 1 (n=45 subjects) showed that the mean posaconazole exposure (area under the concentration-time curve from time zero to infinity [AUC0-∞]) ranged from 4,890 to 46,400 ng · h/ml (range of coefficient of variation values, 26 to 50). The dose-proportionality slope estimate (90% confidence interval) for AUC0-∞ was 1.30 (1.19 to 1.41), indicating a greater-than-dose-proportional increase. The data for safety in part 1 show that 29/72 subjects had ≥1 adverse event. Infusion site reactions were reported in 2/9 vehicle subjects, 0/18 placebo subjects, and 7/45 i.v. posaconazole subjects. The data for safety in part 2 show that infusion site reactions were reported in 1/4 (25%) placebo subjects, 3/9 (33%) vehicle control subjects, and 4/5 (80%) i.v. posaconazole (100 mg) subjects (3 posaconazole recipients subsequently developed thrombophlebitis and were discontinued from treatment). In conclusion, the posaconazole i.v. solution showed a greater-than-dose-proportional increase in exposure, primarily at doses below 200 mg. When administered peripherally at the same infusion site, multiple dosing of i.v. posaconazole led to unacceptably high rates of infusion site reactions. Intravenous

  18. Raltegravir for HIV-1 infected children and adolescents: efficacy, safety, and pharmacokinetics

    PubMed Central

    Larson, Kajal B; King, Jennifer R; Acosta, Edward P

    2013-01-01

    Raltegravir was the first HIV integrase strand-transfer inhibitor to be approved by the US FDA, in October 2007, for the treatment of HIV-1 infection in combination with other antiretroviral agents. Raltegravir can be used in treatment-naïve and -experienced patients, as well as for the treatment of multidrug-resistant infection. Raltegravir exists in two formulations: a film-coated tablet administered orally at 400 mg twice daily, and a chewable tablet administered orally at 300 mg twice daily. In 2011, raltegravir was also approved for the treatment of children and adolescents, ages 2–18 years. For adolescents (ages 12–18 years), the recommended dose is 400 mg twice daily (film-coated tablet). If children (ages 6–12 years) weigh at least 25 kg, the film-coated tablet is recommended at 400 mg twice daily. Otherwise, patients receive the chewable tablet according to weight-based dosing at approximately 6 mg/kg/dose. Studies are ongoing for children ages 4 weeks to 2 years, and preliminary efficacy and safety data are promising. This article reviews current studies on the efficacy, safety, and pharmacokinetics of raltegravir in the pediatric population and the challenges of treating HIV in children and adolescents. PMID:24600298

  19. Safety and Pharmacokinetics of Multiple Dose myo-Inositol in Preterm Infants

    PubMed Central

    Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Nolen, Tracy L.; Watterberg, Kristi L.; Oh, William; Goedecke, Michael; Ehrenkranz, Richard A.; Fennell, Timothy; Poindexter, Brenda B.; Cotten, C. Michael; Hallman, Mikko; Frantz, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; Lacy, Conra Backstrom; Walsh, Michele C.; Carlo, Waldemar A.; Sánchez, Pablo J.; Bell, Edward F.; Shankaran, Seetha; Carlton, David P.; Chess, Patricia R.; Higgins, Rosemary D.

    2016-01-01

    BACKGROUND Preterm infants with RDS given inositol had reduced BPD, death and severe ROP. We assessed the safety and pharmacokinetics(PK) of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS Infants ≤29wks GA (n=122, 14 centers) were randomized and treated with placebo or inositol at 10, 40 or 80mg/kg/day. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 weeks, 34weeks PMA or discharge. Serum collection employed a sparse sampling population PK design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS At 80mg/kg/day mean serum levels reached 140mg/L, similar to Hallman’s findings. Levels declined after 2 weeks, converging in all groups by 6 wks. Analyses showed a mean volume of distribution 0.657 L/kg, clearance 0.058 L/kg/hr, and half-life 7.90 hr. Adverse events and co-morbidities were fewer in the inositol groups, but not significantly so. CONCLUSIONS Multiple dose inositol at 80mg/kg/day was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a Phase 3 trial. PMID:27074126

  20. Safety and Pharmacokinetics of the Oral Iron Chelator SP-420 in β-thalassemia.

    PubMed

    Taher, Ali T; Saliba, Antoine N; Kuo, Kevin H; Giardina, Patricia J; Cohen, Alan R; Neufeld, Ellis J; Aydinok, Yesim; Kwiatkowski, Janet L; Jeglinski, Brenda I; Pietropaolo, Keith; Berk, Gregory; Viprakasit, Vip

    2017-09-22

    Our Phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent β-thalassemia. SP-420 was administered as a single dose of 1.5 (n=3), 3 (n=3), 6 (n=3), 12 (n=3), and 24 (n=6) mg/kg or as a twice-daily dose of 9 mg/kg (n=6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for Cmax and AUC0-τ over the dose range evaluated. The median tmax ranged from 0.5 - 2.25 h and was not dose-dependent. The study was prematurely terminated by the sponsor due to renal adverse events including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal adverse events observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  1. Concomitant administration of bevacizumab, irinotecan, 5-fluorouracil, and leucovorin: nonclinical safety and pharmacokinetics.

    PubMed

    Gaudreault, Jacques; Shiu, Vanessa; Bricarello, Ann; Christian, Brian J; Zuch, Christina L; Mounho, Barbara

    2005-01-01

    Bevacizumab (Avastin) is a humanized monoclonal antibody against vascular endothelial growth factor approved for use in combination with 5-fluorouracil (5-FU)-based chemotherapy for first-line treatment of metastatic colorectal cancer. The Saltz regimen (irinotecan/5-FU/leucovorin [LV]) is a first-line treatment for this indication. The objective of this study was to evaluate the safety of bevacizumab when administered concomitantly with the Saltz regimen to cynomolgus monkeys, and to determine if the pharmacokinetics of bevacizumab, irinotecan, SN38 (the active metabolite of irinotecan), or 5-FU were affected by combined administration. Male cynomolgus monkeys were intravenously administered the Saltz regimen (125 mg/m2 irinotecan, 500 mg/m2 5-FU, 20 mg/m2 LV) alone (n = 4) or concomitantly with 10 mg/kg bevacizumab (n = 5) on days 1 and 8. All animals survived to euthanasia on day 15. Adverse effects associated with the Saltz regimen included diarrhea and neutropenia. Macroscopically, two animals from each group had small thymus glands that correlated microscopically with lymphoid depletion. Myeloid hypoplasia and/or erythroid hyperplasia was observed in the sternal bone marrow of most animals. These effects were considered to be associated with the Saltz regimen; concomitant bevacizumab administration did not alter the severity of these findings. Irinotecan and 5-FU were observed to be rapidly eliminated (t1/2 = 1 h and 0.5 h, respectively). Although the number of animals in each group was small and no statistical comparison between groups was performed, bevacizumab did not affect the disposition of either agent. These results indicate that bevacizumab can be safely administered in combination with the Saltz regimen without pharmacokinetic interaction.

  2. Pharmacodynamics, pharmacokinetics and safety profile of the new platelet-activating factor antagonist apafant in man.

    PubMed

    Brecht, H M; Adamus, W S; Heuer, H O; Birke, F W; Kempe, E R

    1991-01-01

    Platelet-activating factor (PAF) is a unique phospholipid mediator with multifunctional properties. Evidence generated in experimental studies suggests that PAF plays a pathogenetic role in anaphylactic, inflammatory and immunogenic reactions. Apafant (WEB 2086, CAS 105219-56-5), a novel synthetic PAF receptor antagonist, was administered to a total of 101 healthy volunteers within 5 studies to investigate its pharmacologic activity, pharmacokinetic behaviour and safety profile. Pharmacologic activity was monitored by inhibition of 5 x 10(-8) mol/l PAF-induced platelet aggregation ex vivo. The following treatment schedules were studied: oral single dose 1.25 to 400 mg; oral multiple dose 100 mg t.i.d. over 7 days; i.v. infusion 0.5 to 50 mg (over 30 min); inhalative administration up to 1.0 mg. PAF induced platelet aggregation was virtually completely inhibited by single oral doses of 20 mg upwards, throughout during the multiple oral dose study, at all dose levels tested in the i.v. study and (significantly but not completely) at 0.5 and 1.0 mg in the inhalative study. Following oral administrations (capsules) apafant is absorbed rapidly (tmax 1 to 2 h), there is linear pharmacokinetics for the mean plasma concentrations of apafant measured by RIA as well as for the areas under the curve (AUCs). Approximately 60% of apafant is bound to plasma protein, the mean volume of distribution is 28 l, about 44% of an oral dose is excreted in the urine, the mean renal clearance is 192 ml/min. No accumulation of the drug occurred in volunteers with normal kidney function. No clinically relevant drug related adverse events or changes in laboratory or vital parameters such as blood pressure, heart rate, respiratory rate and ECG were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants.

    PubMed

    Migoya, Elizabeth M; Mistry, Goutam C; Stone, Julie A; Comisar, Wendy; Sun, Peng; Norcross, Alisha; Bi, Sheng; Winchell, Gregory A; Ghosh, Kalyan; Uemera, Naoto; Deutsch, Paul J; Wagner, John A

    2011-02-01

    Caspofungin was the first in a new class of antifungal agents (echinocandins) indicated for the treatment of primary and refractory fungal infections. Higher doses of caspofungin may provide another option for patients who have failed caspofungin or other antifungal therapy. This study evaluated the safety, tolerability, and pharmacokinetics of single 150- and 210-mg doses of caspofungin in 16 healthy participants and 100 mg/d for 21 days in 20 healthy participants. Other than infusion site reactions and 1 reversible elevation in alanine aminotransferase (≥2× and <4× upper limit of normal), caspofungin was generally well tolerated. Geometric mean AUC(0-∞) after single 150- and 210-mg doses was 279.7 and 374.9 µg·h/mL, respectively; peak concentrations were 29.4 and 33.5 µg/mL, respectively; and 24-hour postdose concentrations were 2.8 and 4.2 µg/mL, respectively. Steady state was achieved in the third week of dosing. Following multiple 100-mg doses of caspofungin, day 21 geometric mean AUC(0-24) was 227.4 µg·h/mL, peak concentration was 20.9 µg/mL, and trough concentration was 4.7 µg/mL. Beta-phase t(1/2) was ~8 to ~13 hours. Caspofungin pharmacokinetics at these higher doses were dose proportional to and consistent with those observed at lower doses, suggesting a modest nonlinearity of increased accumulation with dose, which was considered not clinically meaningful.

  4. Safety, tolerability and pharmacokinetic properties of coadministered azithromycin and piperaquine in pregnant Papua New Guinean women.

    PubMed

    Moore, Brioni R; Benjamin, John M; Auyeung, Siu On; Salman, Sam; Yadi, Gumul; Griffin, Suzanne; Page-Sharp, Madhu; Batty, Kevin T; Siba, Peter M; Mueller, Ivo; Rogerson, Stephen J; Davis, Timothy Me

    2016-07-01

    The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of coadministered azithromycin (AZI) and piperaquine (PQ) for treating malaria in pregnant Papua New Guinean women. Thirty pregnant women (median age 22 years; 16-32 weeks' gestation) were given three daily doses of 1 g AZI plus 960 mg PQ tetraphosphate with detailed monitoring/blood sampling over 42 days. Plasma AZI and PQ were assayed using liquid chromatography-mass spectrometry and high-performance liquid chromatography, respectively. Pharmacokinetic analysis was by population-based compartmental models. The treatment was well tolerated. The median (interquartile range) increase in the rate-corrected electrocardiographic QT interval 4 h postdose [12 (6-26) ms(0) (.5) ] was similar to that found in previous studies of AZI given in pregnancy with other partner drugs. Six women with asymptomatic malaria cleared their parasitaemias within 72 h. Two apararasitaemic women developed late uncomplicated Plasmodium falciparum infections on Days 42 and 83. Compared with previous pregnancy studies, the area under the concentration-time curve (AUC0-∞ ) for PQ [38818 (24354-52299) μg h l(-1) ] was similar to published values but there was a 52% increase in relative bioavailability with each dose. The AUC0-∞ for AZI [46799 (43526-49462) μg h l(-1) ] was at least as high as reported for higher-dose regimens, suggesting saturable absorption and/or concentration-dependent tissue uptake and clearance from the central compartment. AZI-PQ appears to be well tolerated and safe in pregnancy. Based on the present/other data, total AZI doses higher than 3 g for the treatment and prevention of malaria may be unnecessary in pregnant women, while clearance of parasitaemia could improve the relative bioavailability of PQ. © 2016 The British Pharmacological Society.

  5. Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: a randomized controlled trial.

    PubMed

    Ahmed, Amir I A; van den Elsen, Geke A H; Colbers, Angela; van der Marck, Marjolein A; Burger, David M; Feuth, Ton B; Rikkert, Marcel G M Olde; Kramers, Cornelis

    2014-09-01

    There is a great concern about the safety of THC-based drugs in older people (≥65 years), as most of THC-trials did not include such group. In this phase 1, randomized, double-blind, double-dummy, placebo-controlled, cross-over trial, we evaluated the safety and pharmacokinetics of three oral doses of Namisol(®), a novel THC in tablet form, in older subjects. Twelve healthy older subjects (6 male; mean age 72±5 years) randomly received a single oral dose of 3mg, 5mg, or 6.5mg of THC or matching placebo, in a crossover manner, on each intervention day. The data for 11 subjects were included in the analysis. The data of 1 subject were excluded due to non-compliance to study medication. THC was safe and well tolerated. The most frequently reported adverse events (AEs) were drowsiness (27%) and dry mouth (11%). Subjects reported more AEs with THC 6.5mg than with 3mg (p=0.048), 5mg (p=0.034) and placebo (p=0.013). There was a wide inter-individual variability in plasma concentrations of THC. Subjects for whom the Cmax fell within the sampling period (over 2h), Cmax was 1.42-4.57ng/mL and Tmax was 67-92min. The AUC0-2h (n=11) was 1.67-3.51ng/mL. Overall, the pharmacodynamic effects of THC were smaller than effects previously reported in young adults. In conclusion, THC appeared to be safe and well tolerated by healthy older individuals. Data on safety and effectiveness of THC in frail older persons are urgently required, as this population could benefit from the therapeutic applications of THC.

  6. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans

    PubMed Central

    Manini, Alex F.; Yiannoulos, Georgia; Bergamaschi, Mateus M.; Hernandez, Stephanie; Olmedo, Ruben; Barnes, Allan J.; Winkel, Gary; Sinha, Rajita; Jutras-Aswad, Didier; Huestis, Marilyn A.; Hurd, Yasmin L.

    2015-01-01

    Objectives Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. Methods This double-blind, placebo-controlled cross-over study of CBD co-administered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21–65 years with prior opioid exposure, regardless of route. Blood samples were obtained before and after 400 or 800 mg CBD pretreatment, followed by a single 0.5 (Session 1) or 1.0mcg/Kg (Session 2) intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. Results SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. Following low dose CBD, tmax occurred at 3 and 1.5h (Sessions 1 and 2, respectively). Following high dose CBD, tmax occurred at 3 and 4h in Sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC p=NS) between sessions. Conclusions CBD does not exacerbate adverse effects associated with intravenous fentanyl administration. Co-administration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse. PMID:25748562

  7. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects.

    PubMed

    Guzzo, Cynthia A; Furtek, Christine I; Porras, Arturo G; Chen, Cong; Tipping, Robert; Clineschmidt, Coleen M; Sciberras, David G; Hsieh, John Y K; Lasseter, Kenneth C

    2002-10-01

    Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 34 7-594 microg/kg) also received a single dose with food after a 1-week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with t(max) approximately 4 hours and t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.

  8. Influence of age, gender, and race on pharmacokinetics, pharmacodynamics, and safety of fesoterodine.

    PubMed

    Malhotra, B K; Wood, N; Sachse, R

    2009-09-01

    Fesoterodine, a new antimuscarinic agent for overactive bladder, undergoes immediate and extensive hydrolysis by nonspecific esterases to 5-hydroxymethyl tolterodine (5-HMT), the metabolite principally responsible for its antimuscarinic activity. Formation of 5-HMT does not require cytochrome P450 (CYP)-mediated metabolism, but its further metabolism and inactivation involves CYP3A4 and CYP2D6 isoenzymes. Subject age, gender, and race can play a key role in inter-subject variability in pharmacokinetics and thus efficacy and safety of drugs. This article examines the effects of age, gender, and race on the pharmacokinetics and pharmacodynamics of fesoterodine. Data from two randomized, double-blind, placebo-controlled, parallel-group trials in healthy subjects are presented: Study 1 investigated the effects of race (white vs. black men) and Study 2 investigated the effects of age (young vs. old men) and gender (elderly men vs. elderly women) on the pharmacokinetics and pharmacodynamics of single doses of fesoterodine 8 mg. In both studies, the primary endpoints were area under the concentration-time curve up to the last sample (AUC0-tz) and maximum concentration (Cmax) of 5-HMT in plasma. Pharmacodynamic variables included spontaneous salivary secretion (Studies 1 and 2) and residual urine volume (Study 2 only). The two studies included 5 groups of 16 subjects each (randomized 3 : 1 to fesoterodine or placebo): white men aged 18 - 45 years, black men aged 18 - 45 years (Study 1); young white men aged 18 - 40 years, elderly white men aged > 65 years, and elderly white women aged > 65 years (Study 2). There were no clinically meaningful differences in the primary endpoints between white and black subjects or between young white men, elderly white men, and elderly white women. Mean AUC0-tz was 70.7 ng/ml x h in whites and 64.1 ng/ml x h in blacks; mean Cmax was 6.1 and 5.5 ng/ml in whites and blacks, respectively. Mean AUC0-tz in young white men, elderly white men, and

  9. The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development

    PubMed Central

    Walker, D K

    2004-01-01

    The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially. PMID:15563358

  10. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers.

    PubMed

    Gota, Vikram S; Maru, Girish B; Soni, Tejal G; Gandhi, Tejal R; Kochar, Nitin; Agarwal, Manish G

    2010-02-24

    Curcumin is the lipid-soluble antioxidant compound obtained from the rhizome of Curcuma longa Linn, also known as turmeric. Curcumin targets multiple chemotherapeutic and inflammatory pathways and has demonstrated safety and tolerability in humans, supporting its potential as a therapeutic agent; however, the clinical literature lacks conclusive evidence supporting its use as a therapeutic agent due to its low bioavailability in humans. The purpose of this study was to quantify plasma levels of free curcumin after dosing of a solid lipid curcumin particle (SLCP) formulation versus unformulated curcumin in healthy volunteers and to determine its tolerability and dose-plasma concentration relationship in late-stage osteosarcoma patients. Doses of 2, 3, and 4 g of SLCP were evaluated in 11 patients with osteosarcoma. Plasma curcumin levels were measured using a validated high-performance liquid chromatography method. The limit of detection of the assay was 1 ng/mL of curcumin. In healthy subjects, the mean peak concentration of curcumin achieved from dosing 650 mg of SLCP was 22.43 ng/mL, whereas plasma curcumin from dosing an equal quantity of unformulated 95% curcuminoids extract was not detected. In both healthy individuals and osteosarcoma patients, high interindividual variability in pharmacokinetics and nonlinear dose dependency was observed, suggesting potentially complex absorption kinetics. Overall, good tolerability was noted in both healthy and osteosarcoma groups.

  11. Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor▿

    PubMed Central

    Jordan, Robert; Tien, Deborah; Bolken, Tove' C.; Jones, Kevin F.; Tyavanagimatt, Shanthakumar R.; Strasser, Josef; Frimm, Annie; Corrado, Michael L.; Strome, Phoebe G.; Hruby, Dennis E.

    2008-01-01

    ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis, not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman primates in which ST-246 protected animals from lethal orthopoxvirus infection. PMID:18316519

  12. Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor.

    PubMed

    Jordan, Robert; Tien, Deborah; Bolken, Tove' C; Jones, Kevin F; Tyavanagimatt, Shanthakumar R; Strasser, Josef; Frimm, Annie; Corrado, Michael L; Strome, Phoebe G; Hruby, Dennis E

    2008-05-01

    ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis, not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman primates in which ST-246 protected animals from lethal orthopoxvirus infection.

  13. Pharmacokinetics, pharmacodynamics and safety of CKD-519, a CETP inhibitor, in healthy subjects

    PubMed Central

    Kim, Choon Ok; Oh, Eun Sil; Choi, Chungam; Kim, Yeonjoo; Lee, Sera; Kim, Semi; Park, Min Soo

    2016-01-01

    CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of dyslipidemia to raise high-density lipoprotein cholesterol. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of CKD-519 in healthy adult subjects. A randomized, double-blinded, placebo-controlled, single ascending dose study was performed. Eight healthy subjects were enrolled in each CKD-519 dose group (25, 50, 100, 200, or 400 mg) and randomized to CKD-519 (n=6) or matching placebo (n=2). CKD-519 reached the maximum plasma concentration (Cmax) at 5–6 h post-dose, and had a long terminal half-life ranging between 40–70 h. The area under the plasma concentration–time curve (AUC) and Cmax increased with the dose, however, Cmax and AUC normalized by dose decreased with each incremental dose. CETP activity decreased with dose, and the maximum decrease (63%–83%) was observed at 6–8 h post-dose. A sigmoid Emax model best described the relationship between CKD-519 plasma concentrations and CETP activity with an EC50 of 17.3 ng/mL. Overall, 11 adverse events (AEs) were observed. All AEs were mild or moderate in intensity, and resolved without any complications. There were no clinically significant effects on blood pressure. In conclusion, single doses of CKD-519 up to 400 mg were well tolerated and showed potent inhibition of CETP activity. PMID:27895466

  14. Alfuzosin: overview of pharmacokinetics, safety, and efficacy of a clinically uroselective alpha-blocker.

    PubMed

    Roehrborn, C G

    2001-12-01

    Efficacy and safety of alfuzosin administered as 3-times-daily and 2-times-daily formulations have been previously demonstrated in placebo-controlled studies, and these formulations have been commercially available in many countries. A once-daily formulation of alfuzosin administered through a novel prolonged-release system has been recently developed to improve the convenience of dosing and to provide optimal pharmacokinetic coverage over 24 hours. The results of 2 double-blind, placebo-controlled phase 3 studies in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia suggests that 10 mg of alfuzosin administered once daily without dose titration is superior to placebo in terms of symptom and urinary flow rate improvement. Orthostatic hypotension and first-dose phenomenon related to the alpha-blocking property were rare. The incidences of asthenia and fatigue were comparable to those seen with placebo. Ejaculatory disorders were very rare. The most frequently reported adverse event potentially related to alpha blockade was dizziness, which occurred in 5.0% of patients treated with 10 mg alfuzosin compared with 2.1% of patients given placebo.

  15. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability.

    PubMed

    Citrome, Leslie

    2013-02-01

    Cariprazine is an atypical antipsychotic in clinical development for the treatment of schizophrenia and bipolar mania/mixed episodes. The purpose of this review is to describe the chemistry, pharmacodynamic profile, pharmacokinetics, and clinical profile of cariprazine. Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist. Doses ≥ 1.5 mg/d yielded 69 - 75% D2/D3 receptor occupancy as measured in positron emission tomography scans. Mean half-life for cariprazine was 2 - 5 d over a dose range of 1.5 - 12.5 mg. Cariprazine produces two clinically relevant metabolites: desmethyl-cariprazine and didesmethyl-cariprazine, the latter having a longer half-life than cariprazine. Exposure to didesmethyl-cariprazine exceeded that of the parent drug. Cariprazine is metabolized by CYP3A4 and to a lesser extent by CYP2D6. The efficacy and safety of cariprazine have been so far investigated only in a few short-term (unpublished) clinical trials; however, three studies in schizophrenia and three studies in bipolar mania/mixed episodes evidenced a statistically significant therapeutic effect compared to placebo for cariprazine at doses ranging from 1.5 to 12 mg/d. There does not appear to be clinically relevant adverse effects of cariprazine on metabolic variables. Commonly encountered adverse events associated with cariprazine include insomnia, extrapyramidal symptoms, akathisia, sedation, nausea, dizziness, and constipation.

  16. Efficacy, safety and pharmacokinetics of a novel subcutaneous immunoglobulin, Evogam®, in primary immunodeficiency.

    PubMed

    Empson, Marianne B; Tang, Mimi L K; Pearce, Lisa K C; Rozen, Leon; Gold, Michael S; Katelaris, Constance H; Langton, David; Smart, Joanne; Smith, William B; Steele, Richard H; Ziegler, John B; Maher, Darryl

    2012-10-01

    This phase III, open-label, multi-centre study investigated the efficacy, safety, pharmacokinetics and quality of life impact of Evogam(®), a new chromatographically fractionated 16% subcutaneous immunoglobulin, utilising a 1:1 dose transition ratio from previous immunoglobulin therapy. Thirty-five previously treated patients with primary immunodeficiency received weekly Evogam over 36 weeks. Primary endpoints were rate of serious bacterial infections (SBIs) and steady-state serum immunoglobulin G (IgG) trough concentrations. No SBIs were reported during the study. Evogam produced significantly higher mean trough IgG concentrations with 1:1 dose conversion compared to previous immunoglobulin treatment (8.94 versus 8.27 g/L, p = 0.0063). Evogam was efficacious in the prevention of infections and maintenance of trough levels using a 1:1 dose conversion. It was well tolerated with no withdrawals due to adverse events and was preferred to IVIg by the majority of patients.

  17. Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects.

    PubMed

    Bozik, Michael E; Mather, James L; Kramer, William G; Gribkoff, Valentin K; Ingersoll, Evan W

    2011-08-01

    Dexpramipexole (KNS-760704; [6R]-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) is a novel synthetic amino-benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single-dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half-life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%-90% of dose). Food had no effect on the single-dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases.

  18. Pharmacokinetics, safety, and tolerability of faldaprevir in patients with renal impairment.

    PubMed

    Huang, Fenglei; Moschetti, Viktoria; Lang, Benjamin; Halabi, Atef; Petersen-Sylla, Marc; Yong, Chan-Loi; Elgadi, Mabrouk

    2015-01-01

    Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC0-∞) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.).

  19. Pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults.

    PubMed

    Pavliv, Leo; Voss, Bryan; Rock, Amy

    2011-01-01

    The pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults were evaluated. Methods In this randomized, double-blind, placebo-controlled, single-dose, crossover study, 12 healthy subjects age 18-65 years were randomized to receive a single dose of either 800 mg i.v. ibuprofen (infused over five to seven minutes) concomitantly with an oral placebo or 800 mg oral ibuprofen with concomitant i.v. placebo (0.9% sodium chloride injection). After a six-day washout period, subjects received the treatment not previously received. Blood samples were taken 1 hour before each dose of study medication was administered and throughout the 12 hours thereafter. Plasma ibuprofen concentrations were determined using validated liquid chromatography-tandem mass spectrometry methods. The frequency and severity of treatment-emergent adverse effects were monitored throughout the study. The maximum plasma concentration (C(max)) of i.v. ibuprofen was approximately twice that of oral ibuprofen, and the (t(max)) of i.v. ibuprofen was 0.11 hour, compared with 1.5 hours for oral ibuprofen. However, the elimination half-life of i.v. and oral ibuprofen did not differ, both of which were approximately 2 hours. Oral ibuprofen was 100% bioavailable; therefore, the area under the concentration-time curve did not differ between i.v. and oral ibuprofen. In addition, i.v. ibuprofen infused over five to seven minutes did not differ in terms of safety or tolerability when compared with oral ibuprofen. I.V. ibuprofen, when administered over five to seven minutes in healthy subjects, achieved a higher C(max) and a more-rapid t(max) than did oral ibuprofen and was found to be safe and well tolerated.

  20. Investigation of the safety of topical metronidazole from a pharmacokinetic perspective.

    PubMed

    Iida, Junichi; Kudo, Toshiyuki; Shimada, Kento; Yatsuno, Yoshiyuki; Yamagishi, Saori; Hasegawa, Satoshi; Ike, Hideyuki; Sato, Toru; Kagaya, Hajime; Ito, Kiyomi

    2013-01-01

    Metronidazole (MTZ) ointment has been used widely as a hospital preparation against cancerous malodor. Although cancerous tissue with ulcer-like symptoms is likely to have a higher capacity to absorb drugs than normal skin, the extent to which MTZ is absorbed when a topical preparation is applied to cancerous tissue remains unclear. Furthermore, few studies have investigated the drug interactions involving MTZ despite its long use in clinical practice. In the present study, plasma concentration of MTZ was measured in a breast cancer patient using MTZ ointment for cancerous malodor and basic research was also conducted with the objective of investigating the safety of topical MTZ from a pharmacokinetic perspective. 4.75 µg/mL (27.8 µM) of MTZ was detected in the patient's plasma, which was close to the plasma concentration after oral dosage of MTZ. In a metabolic inhibition study using human liver microsomes, cytochrome P450 (CYP) 2C9-mediated hydroxylation of S-warfarin was almost unaffected by MTZ at the corresponding concentrations. In addition, 3-d repeated oral administration of MTZ (200 mg/kg/d) to rats did not show any significant effects on the hepatic mRNA levels of various CYP isozymes and CYP2C protein levels. These results suggest that the reported interaction of oral MTZ and S-warfarin was not due to CYP2C9 inhibition and that drug interactions via inhibition of CYP2C9 is unlikely to occur when MTZ ointment is applied to ulcerous skin. This information should be valuable for assessing the safety of MTZ ointment used for mitigating cancerous malodor.

  1. Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis.

    PubMed

    Thomsen, Edward K; Sanuku, Nelly; Baea, Manasseh; Satofan, Samson; Maki, Elit; Lombore, Bart; Schmidt, Mark S; Siba, Peter M; Weil, Gary J; Kazura, James W; Fleckenstein, Lawrence L; King, Christopher L

    2016-02-01

    Available treatments for lymphatic filariasis (LF) are limited in their longterm clearance of microfilaria from the blood. The safety and efficacy of a single-dose triple-drug therapy of the antifilarial drugs diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB) for LF are unknown. We performed a pilot study to test the efficacy, safety, and pharmacokinetics of single-dose DEC, IVM, and ALB in Wuchereria bancrofti-infected Papua New Guineans. Adults were randomized into 2 treatment arms, DEC 6 mg/kg + ALB 400 mg (N = 12) or DEC 6 mg/kg + ALB 400 mg + IVM 200 μg/kg (N = 12), and monitored for microfilaria, parasite antigenemia, adverse events (AEs), and serum drug levels. Triple-drug therapy induced >2-log reductions in microfilaria levels at 36 and 168 hours after treatment compared with approximately 1-log reduction with 2 drugs. All 12 individuals who received 3 drugs were microfilaria negative 1 year after treatment, whereas 11 of 12 individuals in the 2-drug regimen were microfilaria positive. In 6 participants followed 2 years after treatment, those who received 3 drugs remained microfilaria negative. AEs, particularly fever, myalgias, pruritus, and proteinuria/hematuria, occurred in 83% vs 50% of those receiving triple-drug compared to 2-drug treatment respectively (P = .021); all resolved within 7 days after treatment. No serious AEs were observed in either group. There was no significant effect of IVM on DEC or ALB drug levels. Triple-drug therapy is safe and more effective than DEC + ALB for Bancroftian filariasis and has the potential to accelerate elimination of lymphatic filariasis. NCT01975441. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  2. Safety and Pharmacokinetics of CD101 IV, a Novel Echinocandin, in Healthy Adults

    PubMed Central

    Ong, Voon; Lee, Jonathan; Thye, Dirk

    2016-01-01

    ABSTRACT CD101 IV is a novel echinocandin with distinctive pharmacokinetic properties that is being developed as a once-weekly treatment for candidemia and invasive candidiasis. CD101 has potent in vitro activity and in vivo efficacy against a broad range of Candida and Aspergillus species. The primary objective of two randomized, double-blind, placebo-controlled, dose-escalation studies in healthy adults was to determine the safety and tolerability of CD101 IV. Sequential cohorts of 8 subjects (n = 6, active; n = 2, placebo) were administered single (50, 100, 200, 400 mg) or multiple once-weekly (100 mg given once weekly for two weeks [×2], 200 mg ×2, 400 mg ×3) doses of CD101 IV infused over 1 h. There were no deaths, serious adverse events (SAEs), severe adverse events (AEs), or withdrawals from the study due to an AE. The majority of AEs were mild, and all completely resolved. There was a higher incidence of total AEs and mild transient infusion reactions in the 400-mg ×3 dose group. There were no clinically meaningful trends in postbaseline laboratory abnormalities and no safety issues related to electrocardiograms, vital signs, or physical exams. CD101 showed dose-proportional plasma exposures, minor accumulation (30% to 55%), low apparent clearance (<0.28 liter/h), long half-life (t1/2) (>80 h), and minimal urine excretion. CD101 IV was safe and well tolerated at single and multiple doses of up to 400 mg given once weekly for 3 weeks and exhibited a long t1/2, minimal accumulation over several weeks, negligible renal excretion, and high plasma exposures enabling once-weekly dosing. PMID:27919901

  3. Pharmacokinetics, safety and tolerability of an oral suspension of fexofenadine for children with allergic rhinitis.

    PubMed

    Segall, Nathan; Grubbe, Robert E; Levy, Arden L; Maloney, Michael J; Nayak, Anjuli S; Kittner, Barbara; Quesada, Javier T

    2008-01-01

    Allergic rhinitis (AR) is a common chronic condition in children and may impact a child's quality of life. Increasing treatment compliance may improve quality of life. An oral suspension of fexofenadine hydrochloride (HCl) has been developed to ease administration to children and may, therefore, improve treatment compliance. The purpose of this study was to assess the pharmacokinetic behavior, safety, and tolerability of a single dose of fexofenadine HCl oral suspension administered to children aged 2-5 years with allergic rhinitis. Children (aged 2-5 years) with AR were recruited in a multicenter, open-label, single-dose study. Fexofenadine HCl (30 mg) was administered as a 6-mg/mL suspension (5 mL). Plasma samples were collected up to 24 hours postdose. Adverse events (AEs); electrocardiograms (ECGs); vital signs; and clinical laboratory tests for hematology, blood chemistry, and urinalysis were analyzed to evaluate safety and tolerability. Fifty subjects completed the study. Mean maximum plasma concentration of fexofenadine was 224 ng/mL, and mean area under the plasma concentration curve was 898 ng . hour/mL. Treatment-emergent AEs were mild in intensity and reported in a total of seven subjects. No trends or clinically meaningful changes in mean ECG, vital sign, or clinical laboratory test data occurred during the study. In children aged 2-5 years, the exposure after a 30-mg dose of fexofenadine HCl suspension was similar to the exposures previously seen after a 30- and 60-mg dose of fexofenadine HCl in children aged 6-11 years and in adults, respectively. The suspension was also well tolerated.

  4. The pharmacokinetics and safety profile of oral ganciclovir in combination with trimethoprim in HIV- and CMV-seropositive patients

    PubMed Central

    Jung, Donald; AbdelHameed, Magdy H; Hunter, John; Teitelbaum, Philip; Dorr, Albert; Griffy, Kay

    1999-01-01

    Aims We investigated the pharmacokinetics and safety profile of oral ganciclovir coadministered with trimethoprim in HIV-and CMV-seropositive patients. Methods In an open-label, randomized, 3-way crossover study, 12 adult males received oral ganciclovir 1000 mg every 8h, oral trimethoprim 200 mg once daily, or both drugs concomitantly in a sequence of three 7-day treatment periods. Pharmacokinetic parameters were determined and adverse events recorded for each treatment. Results The presence of trimethoprim significantly decreased CLr (12.9%, P = 0.0068) and increased t1/2 (18.1%, P = 0.0378) of ganciclovir. However, these changes are unlikely to be clinically meaningful. There were no statistically significant changes in trimethoprim pharmacokinetic parameters in the presence of ganciclovir, with the exception of a 12.7% increase in Cmin. Ganciclovir was well tolerated when administered alone or in combination with trimethoprim. Conclusions There was no clinically significant pharmacokinetic interaction between oral ganciclovir and trimethoprim when coadministered. PMID:10215748

  5. Single-dose pharmacokinetics and safety of pegylated interferon-alpha2b in patients with chronic renal dysfunction.

    PubMed

    Gupta, Samir K; Pittenger, Amy L; Swan, Suzanne K; Marbury, Thomas C; Tobillo, Emlyn; Batra, Vijay; Sack, Marshall; Glue, Paul; Jacobs, Sheila; Affrime, Melton

    2002-10-01

    This study evaluates the pharmacokinetics and safety of pegylated interferon-alpha2b (PEG-Intron) following a single-dose subcutaneous injection into subjects with normal renal function, subjects with chronic renal impairment, and patients on hemodialysis. In this open-label, single-dose, parallel group study, subjects were divided into five groups according to their degree of renal function: four groups as defined by measured creatinine clearance and a fifth hemodialysis dependent group. They received 1 microg/kg PEG-Intron subcutaneously after a 10-hour fast. Pharmacokinetic and safety assessments were performed up to 168 hours postdose. Hemodialysis patients had a second PEG-Intron dose 12 hours prior to a hemodialysis session. PEG-Intron pharmacokinetic parameters (AUCtf, Cmax, and t1/2) increased progressively as CL(CR) declined. All subjects reported at least one adverse event, which were typical of those reported after alpha-interferon administration (e.g., flu-like symptoms, headache). Single-dose PEG-Intron administration to volunteers with normal renal function and chronic renal impairment was safe and well tolerated. In patients with CL(CR) < 30 ml/min, AUCand Cmax values were increased 90% compared with controls, while half-life was increased by up to 40% over controls. Based on the relationship between PEG-Intron apparent clearance and CL(CR), renal clearance accountsfor less than half of its total clearance. Hemodialysis did not affect PEG-Intron apparent clearance.

  6. The efficacy, pharmacokinetics, and safety of a nevirapine to rilpivirine switch in virologically suppressed HIV-1-infected patients.

    PubMed

    Rokx, Casper; Blonk, Maren; Verbon, Annelies; Burger, David; Rijnders, Bart J A

    2015-01-01

    : This prospective, open-label nonrandomized controlled trial evaluated the efficacy, safety, and pharmacokinetics of substituting nevirapine/emtricitabine/tenofovir for rilpivirine/emtricitabine/tenofovir in 50 suppressed HIV-1 switchers. One hundred thirty-nine nonswitchers remained on nevirapine as controls. Week 12 HIV-1 RNA was <50 copies per milliliter in 92.0% of switchers and was <50 copies per milliliter at week 24 in 88.0% of switchers and 90.6% of nonswitchers (difference 2.6%, 95% confidence interval: -7.6% to 12.8%). Week 3 geometric mean nevirapine concentration was undetectable and week 1 geometric mean rilpivirine concentration (0.083 mg/L) was comparable with phase 3 trial (P = 0.747). Substituting nevirapine for rilpivirine resulted in ongoing virological suppression and did not have clinically relevant pharmacokinetic effects by cytochrome P450 interactions.

  7. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban--an oral, direct factor Xa inhibitor--are not affected by aspirin.

    PubMed

    Kubitza, Dagmar; Becka, Michael; Mueck, Wolfgang; Zuehlsdorf, Michael

    2006-09-01

    Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. This was a randomized, 2-way crossover study in healthy male subjects, with an aspirin run-in period, to examine whether aspirin influences the safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban. All treatments were well tolerated; drug-related adverse events were mild and transient. Aspirin did not alter the effects of rivaroxaban on Factor Xa activity or clotting tests. Platelet aggregation and bleeding time were not affected by rivaroxaban, and rivaroxaban did not influence the effects of aspirin on these parameters to a clinically relevant extent. Aspirin did not affect the pharmacokinetics of rivaroxaban, including the fraction unbound. This study suggests that there is no clinically relevant interaction between rivaroxaban and aspirin and that the 2 drugs could be administered concomitantly at the doses used in this study.

  8. Multiple-Dose Safety and Pharmacokinetics of Oral Garenoxacin in Healthy Subjects

    PubMed Central

    Gajjar, D. A.; Bello, A.; Ge, Z.; Christopher, L.; Grasela, D. M.

    2003-01-01

    Garenoxacin (T-3811ME, BMS-284756) is a novel des-F(6) quinolone that has been shown to be effective in vitro against a wide range of clinically important pathogens, including gram-positive and gram-negative aerobes and anaerobes. This study was conducted to evaluate the safety and tolerability of multiple oral doses (100 to 1,200 mg/day) of garenoxacin in healthy subjects and to determine its multiple-dose pharmacokinetics. Forty healthy male and female subjects (18 to 45 years of age) were enrolled in this randomized, double-blind, placebo-controlled, sequential, multiple- and ascending-dose study. Each subject received a once-daily oral dose of garenoxacin (100, 200, 400, 800, or 1,200 mg) or a placebo for 14 days. Blood and urine samples were collected for measurements of garenoxacin by validated liquid chromatography with dual mass spectrometry, and plasma garenoxacin concentration-time data were analyzed by noncompartmental methods. The effects of garenoxacin on Helicobacter pylori, psychometric test performance, and electrocardiograms were assessed, as was drug safety. Over the 14 days of dosing, geometric mean peak concentrations of garenoxacin in plasma (Cmax) at the 100- and 1,200-mg doses were within the ranges of 1.2 to 1.6 and 16.3 to 24 μg/ml, respectively. The corresponding values for the geometric mean area under the concentration-time curve over the dosing interval (AUCτ) for garenoxacin in plasma at the 100- and 1,200-mg doses were within the ranges of 11.5 to 15.7 and 180 to 307 μg · h/ml, respectively. Increases in systemic exposure to garenoxacin in terms of AUC and Cmax were approximately dose proportional over the 100- to 400-mg dose range but demonstrated increases that were somewhat greater than the dose increments at the 800- and 1,200-mg doses. Median values for the time to achieve Cmax were in the range of 1.13 to 2.50 h for all doses. The mean elimination half-life for garenoxacin in plasma appeared to be independent of dose and

  9. Ocular Safety and Pharmacokinetics Study of FK506 Suspension Eye Drops After Corneal Transplantation

    PubMed Central

    Yuan, Jin; Zhai, Jia-jie; Huang, Xi; Zhou, Shi-you

    2012-01-01

    Abstract Purpose The aim of this study was to investigate the sensitization, pharmacokinetics, and absorption of FK506 after corneal transplantation. Methods New Zealand albino rabbits were divided into normal and corneal transplantation groups. Each group was divided into 5 subgroups—saline, blank matrix, high-dose, medium-dose, and low-dose, respectively. There were 10 rabbits in each subgroup. One drop (25 μL) of FK506 was administered topically to both eyes of the rabbits 4 times daily for 30 days. Thirty days later, 5 rabbits of each subgroup were sacrificed after the administration of the last dose. Both eyes were enucleated; the left eye was used for pathologic examination and the right eye for the determination of FK506 distribution. The other 5 rabbits in each subgroup were sacrificed 14 days after the former 5 rabbits were sacrificed, and their eyes were enucleated for pathologic examination and tissue distribution determination as the former 5 rabbits in each subgroup (the second batch). Results Fluorescein staining and local ocular reaction provided evidence that there were no significant differences between control and FK506-instilled eyes in the rabbit model at any of the tested doses. Histologic examination revealed no ocular abnormality in the rabbits instilled with any doses of FK506 eyedrop. The peak serum concentration (Cmax) of systemic absorption ranged from 4.31±0.79 ng/mL to 14.89±6.85 ng/mL. Conclusion Our study suggests that up to 0.1% FK506 administered 4 times a day (q.i.d.) topically is safe for the rabbit eye. However, further safety studies are required in view of systemic adverse effects. PMID:22136074

  10. Pharmacokinetic, partial pharmacodynamic and initial safety analysis of (−)-Epicatechin in healthy volunteers

    PubMed Central

    Barnett, Christopher F.; Moreno-Ulloa, Aldo; Shiva, Sruti; Ramirez-Sanchez, Israel; Taub, Pam R.; Su, Yongxuan; Ceballos, Guillermo; Dugar, Sundeep; Schreiner, George; Villarreal, Francisco

    2015-01-01

    (−)-Epicatechin ((−)-EPI), a naturally occurring flavanol has emerged as a likely candidate for cocoa-based product reported reductions in cardiometabolic risk. The present study aimed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of purified (−)-EPI administered to healthy volunteers. In this phase I, open-label, two-part single- and multiple-dose study subjects received either a single dose (n=9) of 50, 100 or 200 mg or multiple doses (n=8) of 50 mg daily (q.d.) or twice daily (b.i.d) for 5 days. Blood was collected at 0, 0.5, 1, 2, 4 and 6 hrs after (−)-EPI administration in the single and multiple dose groups (blood collection repeated in day 5). Samples were analyzed by HPLC-HR-ESI-MS for EPI and metabolites quantification. In the q.d. and b.i.d. groups, blood samples were analyzed for NO surrogates, follistatin, platelet mitochondrial complex I, V and citrate synthase level determinations. (−)-EPI was well tolerated and readily absorbed with further phase 2 metabolism. On day 5, in the q.d. and b.i.d. groups, there were significant increases in plasma nitrite of 30 % and 17 %, respectively. In the q.d. group on day 5 vs. day 1, platelet mitochondria complexes I, IV and citrate synthase activities demonstrated a significant increase of ~ 92, 62 and 8 %, respectively. Average day 5 follistatin AUC levels were ~2.5 fold higher vs. day 1 AUC levels in the b.i.d. group. (−)-EPI was safe with no observed adverse effects and our findings suggest that increases in NO metabolites, mitochondrial enzyme function and plasma follistatin levels may underlie some of the beneficial effects of cocoa products or (−)-EPI as reported in other studies. PMID:25598082

  11. Pharmacokinetic modeling as an approach to assessing the safety of residual formaldehyde in infant vaccines.

    PubMed

    Mitkus, Robert J; Hess, Maureen A; Schwartz, Sorell L

    2013-06-07

    Formaldehyde is a one-carbon, highly water-soluble aldehyde that is used in certain vaccines to inactivate viruses and to detoxify bacterial toxins. As part of the manufacturing process, some residual formaldehyde can remain behind in vaccines at levels less than or equal to 0.02%. Environmental and occupational exposure, principally by inhalation, is a continuing risk assessment focus for formaldehyde. However, exposure to formaldehyde via vaccine administration is qualitatively and quantitatively different from environmental or occupational settings and calls for a different perspective and approach to risk assessment. As part of a rigorous and ongoing process of evaluating the safety of biological products throughout their lifecycle at the FDA, we performed an assessment of formaldehyde in infant vaccines, in which estimates of the concentrations of formaldehyde in blood and total body water following exposure to formaldehyde-containing vaccines at a single medical visit were compared with endogenous background levels of formaldehyde in a model 2-month-old infant. Formaldehyde levels were estimated using a physiologically-based pharmacokinetic (PBPK) model of formaldehyde disposition following intramuscular (IM) injection. Model results indicated that following a single dose of 200 μg, formaldehyde is essentially completely removed from the site of injection within 30 min. Assuming metabolism at the site of injection only, peak concentrations of formaldehyde in blood/total body water were estimated to be 22 μg/L, which is equivalent to a body burden of 66 μg or <1% of the endogenous level of formaldehyde. Predicted levels in the lymphatics were even lower. Assuming no adverse effects from endogenous formaldehyde, which exists in blood and extravascular water at background concentrations of 0.1 mM, we conclude that residual, exogenously applied formaldehyde continues to be safe following incidental exposures from infant vaccines. Published by Elsevier Ltd.

  12. Pharmacokinetics, efficacy, and safety of caspofungin in Japanese pediatric patients with invasive candidiasis and invasive aspergillosis.

    PubMed

    Mori, Masaaki; Imaizumi, Masue; Ishiwada, Naruhiko; Kaneko, Takashi; Goto, Hiroaki; Kato, Koji; Hara, Junichi; Kosaka, Yoshiyuki; Koike, Kazutoshi; Kawamoto, Hiroshi; Maeda, Naoko; Yoshinari, Tomoko; Kishino, Hiroyuki; Takahashi, Kenichi; Kawahara, Shizuko; Kartsonis, Nicholas A; Komada, Yoshihiro

    2015-06-01

    The antifungal agents approved in Japan for pediatric use are limited and many unapproved drugs are actually used without clear instruction for dosage. We investigated the pharmacokinetics of caspofungin for the treatment of invasive candidiasis and invasive aspergillosis in 20 Japanese pediatric patients using a pediatric-specific dosage based on body surface area. Caspofungin was administered intravenously over 60 min as 70 mg/m(2) on Day 1, followed by 50 mg/m(2) per day. Five or 4 point blood sampling were done in 15 patients on Day 4-5 to calculate AUC0-24 h. The geometric means (95% confidence interval) of C24 h and AUC0-24 h in the pediatric patients were 3.3(2.5, 4.4) μg/mL and 175.1 (139.3, 220.1) μg hr/mL, respectively, which were comparable to those in Japanese adult patients [3.2 (2.8, 3.5) μg/mL and 144.9 (131.7, 159.3) μg hr/mL, respectively]. Among the 20 patients, 10 (50%) had at least 1 drug-related adverse event which was considered related to caspofungin therapy. No drug-related serious adverse event and no death occurred. The most common drug-related adverse events were events relating to hepatic function (mainly increases in ALT and AST). The overall success in efficacy was observed in 13 of 20 patients. In conclusion, once daily administration of caspofungin (70 mg/m(2) on Day 1, followed by 50 mg/m(2) [maximum daily dose not to exceed 70 mg]), which is the same dosage being used in overseas, achieved sufficient drug exposure and a favorable efficacy and acceptable safety profile in Japanese pediatric patients with invasive fungal infections.

  13. Antiparasitic drugs for paediatrics: systematic review, formulations, pharmacokinetics, safety, efficacy and implications for control.

    PubMed

    Keiser, Jennifer; Ingram, Katrin; Utzinger, Jürg

    2011-10-01

    Drug development for paediatric applications entails a number of challenges, such as the wide age spectrum covered - from birth to adolescence - and developmental changes in physiology during biological maturation that influence the efficacy and toxicity of drugs. Safe and efficacious antiparasitic drugs for children are of pivotal importance given the large proportion of burden attributable to parasitic diseases in this age group, and growing efforts to administer, as widely as possible, antiparasitic drugs to at-risk populations, such as infants and school-aged children, often without prior diagnosis. The purpose of this review is to investigate whether antiparasitic drugs have been adequately studied for use in paediatrics. We approached this issue through a systematic review using PubMed and the Cochrane Central Register of Trials covering a period of 10 years and 8 months until the end of August 2010 to identify trials that investigated efficacy, safety and pharmacokinetic (PK) parameters of antiparasitic drugs for paediatrics. Overall, 269 clinical drug trials and 17 PK studies met our inclusion criteria. Antimalarial drugs were the most commonly studied medicines (82·6%). Most trials were carried out in Africa and children aged 2-11 years were the age group most often investigated. Additionally, we critically examined available drug formulations for anthelminthics and identified a number of shortcomings that are discussed. Finally, we shed new light on current proposals to expand 'preventive chemotherapy' to preschool-aged children and emphasise that new research, including risk-benefit analyses, are needed before such a strategy can be adopted more widely.

  14. Ocular safety and pharmacokinetics study of FK506 suspension eye drops after corneal transplantation.

    PubMed

    Yuan, Jin; Zhai, Jia-jie; Huang, Xi; Zhou, Shi-you; Chen, Jia-qi

    2012-04-01

    The aim of this study was to investigate the sensitization, pharmacokinetics, and absorption of FK506 after corneal transplantation. New Zealand albino rabbits were divided into normal and corneal transplantation groups. Each group was divided into 5 subgroups--saline, blank matrix, high-dose, medium-dose, and low-dose, respectively. There were 10 rabbits in each subgroup. One drop (25 μL) of FK506 was administered topically to both eyes of the rabbits 4 times daily for 30 days. Thirty days later, 5 rabbits of each subgroup were sacrificed after the administration of the last dose. Both eyes were enucleated; the left eye was used for pathologic examination and the right eye for the determination of FK506 distribution. The other 5 rabbits in each subgroup were sacrificed 14 days after the former 5 rabbits were sacrificed, and their eyes were enucleated for pathologic examination and tissue distribution determination as the former 5 rabbits in each subgroup (the second batch). Fluorescein staining and local ocular reaction provided evidence that there were no significant differences between control and FK506-instilled eyes in the rabbit model at any of the tested doses. Histologic examination revealed no ocular abnormality in the rabbits instilled with any doses of FK506 eyedrop. The peak serum concentration (C(max)) of systemic absorption ranged from 4.31±0.79 ng/mL to 14.89±6.85 ng/mL. Our study suggests that up to 0.1% FK506 administered 4 times a day (q.i.d.) topically is safe for the rabbit eye. However, further safety studies are required in view of systemic adverse effects.

  15. The pharmacokinetics of phenylethyl alcohol (PEA): safety evaluation comparisons in rats, rabbits, and humans.

    PubMed

    Politano, Valerie T; Diener, Robert M; Christian, Mildred S; Hawkins, David R; Ritacco, Gretchen; Api, Anne Marie

    2013-01-01

    The present studies were conducted to compare the dermal absorption, plasma pharmacokinetics, and excretion of phenylethyl alcohol (PEA) by pregnant and nonpregnant rats, rabbits, and humans. The PEA is a natural fragrance material that is widely used in perfumes, soaps, and lotions and is a major ingredient of natural rose oil. Following dermal (430, 700, or 1400 mg/kg body weight [bw]), gavage (430 mg/kg bw), or dietary (430 mg/kg bw) administration of PEA to rats, plasma concentrations of PEA were found to be low regardless of the route of administration. The plasma concentrations of phenylacetic acid (PAA, the major metabolite of PEA) greatly exceeded the concentrations of PEA and were highest after gavage, followed by dermal then dietary administration. Absorption, distribution, metabolism, and excretion were compared following topical application of ¹⁴C-labeled PEA to rats, rabbits, and humans (specific activities of dosing solutions: 58-580, 164, and 50 µCi/mL, respectively). In rabbits, the plasma concentration-time profile for PAA was markedly prolonged compared to rats or humans. In humans, only 7.6% of the applied dose of PEA was absorbed, versus 77% in rats and 50% in rabbits. Based on a human dermal systemic exposure of 0.3 mg/kg per day from the use of multiple consumer personal care products containing PEA, a rat dermal no observed adverse effect level of 70 mg/kg per day, and the percentage of dose absorbed in humans, the margin of safety exceeds 2600 concluding that, under normal fragrance use conditions, PEA is not a developmental toxicity hazard for humans.

  16. Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial.

    PubMed

    Stasyshyn, O; Djambas Khayat, C; Iosava, G; Ong, J; Abdul Karim, F; Fischer, K; Veldman, A; Blackman, N; St Ledger, K; Pabinger, I

    2017-04-01

    Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile.

  17. Pharmacokinetics, Pharmacodynamics, and Safety of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus.

    PubMed

    Iijima, Hiroaki; Kifuji, Takayuki; Maruyama, Nobuko; Inagaki, Nobuya

    2015-08-01

    Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved worldwide for the treatment of patients with type 2 diabetes mellitus (T2DM). The present study evaluated pharmacokinetics, pharmacodynamics, and safety of canagliflozin in Japanese patients with T2DM. Canagliflozin, at doses of 25, 100, 200, or 400 mg, was administered as a single dose and, after a washout of 1 day, in repeated doses for 14 consecutive days to 61 subjects in a randomized, double-blind, placebo-controlled study. Plasma concentrations of canagliflozin and urinary glucose excretion (UGE) were measured, and renal threshold for glucose excretion (RTG) was calculated. Safety was evaluated on the basis of adverse event (AE) reports, blood and urine laboratory parameters, and vital signs. Plasma canagliflozin maximum concentration and area under the concentration-time curve (AUC) values increased in a dose-dependent manner with the time to maximum concentration (t max) of 1.0 h and elimination half-life (t 1/2) of 10.22-13.26 h on Day 1. No significant changes in t max and t 1/2 were observed after multiple-dose administration. The linearity factors, as calculated from the ratios of AUC0-24h on Day 16 to AUC0-∞ on Day 1, were close to 1 in all canagliflozin groups. Canagliflozin increased UGE0-24h (80-110 g/day with canagliflozin ≥100 mg) and decreased RTG from the first day of treatment; these effects were sustained during the entire period of multiple administration. No significant AEs were noted. Urine volume was slightly increased on Day 1, but subsequent changes after repeated doses for 14 days were small. Urinary sodium tended to be higher in the early treatment period, whereas no particular change was observed in serum osmolality and hematocrit. Canagliflozin increased UGE, decreased RTG, and was well tolerated throughout the entire period of multiple administrations in Japanese patients with T2DM. Mitsubishi Tanabe Pharma Corporation. ClinicalTrials.gov#NCT00707954.

  18. Pharmacokinetic study and evaluation of the safety of taurolidine for dogs with osteosarcoma

    PubMed Central

    2013-01-01

    Background Osteosarcoma in dogs and humans share many similarities and the dog has been described as an excellent model to study this disease. The median survival in dogs has not improved in the last 25 years. Taurolidine has been shown to be cytotoxic to canine and human osteosarcoma in vitro. The goals of this study were to determine the pharmacokinetics and safety of taurolidine in healthy dogs and the safety of taurolidine in combination with doxorubicin or carboplatin in dogs with osteosarcoma. Methods Two percent taurolidine was infused into six healthy dogs (150 mg/kg) over a period of two hours and blood samples were taken periodically. One dog received taurolidine with polyvinylpyrrolidone (PVP) as its carrier and later received PVP-free taurolidine as did all other dogs in this study. Serum taurolidine concentrations were determined using high-performance liquid chromatography (HPLC) online coupled to ESI-MS/MS in the multiple reaction monitoring mode. Subsequently, the same dose of taurolidine was infused to seven dogs with osteosarcoma also treated with doxorubicin or carboplatin. Results Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects. Maximum taurolidine serum concentrations ranged between 229 to 646 μM. The dog that received taurolidine with PVP had an immediate allergic reaction but recovered fully after the infusion was stopped. Three additional dogs with osteosarcoma received doxorubicin and taurolidine without PVP. Toxicities included dilated cardiomyopathy, protein-losing nephropathy, renal insufficiency and vasculopathy at the injection site. One dog was switched to carboplatin instead of doxorubicin and an additional 4 dogs with osteosarcoma received taurolidine-carboplatin combination. One incidence of ototoxicity occurred with the taurolidine- carboplatin combination. Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone

  19. Pharmacokinetics of internally labeled monoclonal antibodies as a gold standard: comparison of biodistribution of /sup 75/Se-, /sup 111/In-, and /sup 125/I-labeled monoclonal antibodies in osteogenic sarcoma xenografts in nude mice

    SciTech Connect

    Koizumi, M.; Endo, K.; Watanabe, Y.; Saga, T.; Sakahara, H.; Konishi, J.; Yamamuro, T.; Toyama, S.

    1989-04-01

    In order to know the true biodistribution of anti-tumor monoclonal antibodies, three monoclonal antibodies (OST6, OST7, and OST15) against human osteosarcoma and control antibody were internally labeled with 75Se by incubating (75Se)methionine and hybridoma cells. 75Se-labeled monoclonal antibodies were evaluated both in vitro and in vivo using the human osteogenic sarcoma cell line KT005, and the results were compared with those of 125I- and 111In-labeled antibodies. 75Se-, 125I- and 111In-labeled monoclonal antibodies had identical binding activities to KT005 cells, and the immunoreactivity was in the decreasing order of OST6, OST7, and OST15. On the contrary, in vivo tumor uptake (% injected dose/g) of 75Se- and 125I-labeled antibodies assessed using nude mice bearing human osteosarcoma KT005 was in the order of OST7, OST6, and OST15. In the case of 111In, the order was OST6, OST7, and OST15. High liver uptake was similarly seen with 75Se- and 111In-labeled antibodies, whereas 125I-labeled antibodies showed the lowest tumor and liver uptake. These data indicate that tumor targeting of antibody conjugates are not always predictable from cell binding studies due to the difference of blood clearance of labeled antibodies. Furthermore, biodistribution of both 111In- and 125I-labeled antibodies are not identical with internally labeled antibody. Admitting that internally labeled antibody is a ''gold standard'' of biodistribution of monoclonal antibody, high liver uptake of 111In-radiolabeled antibodies may be inherent to antibodies. Little, if any, increase in tumor-to-normal tissue ratios of antibody conjugates will be expected compared to those of 111In-labeled antibodies if stably coupled conjugates are administered i.v.

  20. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years.

    PubMed

    Nachman, Sharon; Zheng, Nan; Acosta, Edward P; Teppler, Hedy; Homony, Brenda; Graham, Bobbie; Fenton, Terence; Xu, Xia; Wenning, Larissa; Spector, Stephen A; Frenkel, Lisa M; Alvero, Carmelita; Worrell, Carol; Handelsman, Edward; Wiznia, Andrew

    2014-02-01

    IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥ 3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥ 1 log10 reduction between baseline and week 24. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/µL (4.6%). Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥ 25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses. NCT00485264.

  1. Safety and pharmacokinetics of a single 1500-mg dose of famciclovir in adolescents with recurrent herpes labialis.

    PubMed

    Block, Stan L; Yogev, Ram; Waldmeier, Felix; Hamed, Kamal

    2011-06-01

    An open-label study evaluated the safety (n = 53) and pharmacokinetics (n = 8) of single-dose therapy with 1500 mg famciclovir (prodrug of penciclovir) for recurrent herpes labialis in adolescents. Mean Cmax, mean AUC0-∞, and clearance for penciclovir were 9.37 μg/mL, 31.8 μg · h/mL, and 38.2 L/h, respectively, and within the range extrapolated from data in adults. Adverse events were generally mild and transient.

  2. [Undesirable pharmacokinetic drug-to-drug interactions affecting the effectiveness and safety of anti-infectious pharmacotherapy].

    PubMed

    Dworacka, Marzena; Nowocień, Tamara

    2017-02-20

    The occurence of pharmacokinetic drug-to-drug interactions is the serious clinical problem in the course of pharmacotherapy of infections. Its essential part is the influence of such interactions on the effectiveness and safety of antimicrobial therapy. The aim of study was to present, the most significant on clinical hand, examples of interactions and their mechanisms between antimicrobial agents and other drugs on stages of absorption, distribution, biotransformation and elimination, leading to the decreased antimicrobial activity and ineffective pharmacotherapy or to the increased antimicrobial activity and to the increased risk of adverse effects due to agents used for anti-infectious pharmacotherapy.

  3. Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Umeclidinium and Vilanterol Alone and in Combination: A Randomized Crossover Trial

    PubMed Central

    Kelleher, Dennis L.; Mehta, Rashmi S.; Jean-Francois, Bernadette M.; Preece, Andrew F.; Blowers, James; Crater, Glenn D.; Thomas, Paul

    2012-01-01

    Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting β2 agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 µg) and vilanterol (50 µg) when administered separately and in combination using a novel dry powder inhaler (NDPI). Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol) followed by rapid elimination with median tlast of 4–5 h for umeclidinium and median tlast of 1.5–2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone. Trial Registration Clinicaltrials.gov NCT00976144 PMID:23284643

  4. Safety and biodistribution of 111In-amatuximab in patients with mesothelin expressing cancers using single photon emission computed tomography-computed tomography (SPECT-CT) imaging.

    PubMed

    Lindenberg, Liza; Thomas, Anish; Adler, Stephen; Mena, Esther; Kurdziel, Karen; Maltzman, Julia; Wallin, Bruce; Hoffman, Kimberly; Pastan, Ira; Paik, Chang Hum; Choyke, Peter; Hassan, Raffit

    2015-02-28

    Amatuximab is a chimeric high-affinity monoclonal IgG1/k antibody targeting mesothelin that is being developed for treatment of mesothelin-expressing cancers. Considering the ongoing clinical development of amatuximab in these cancers, our objective was to characterize the biodistribution, and dosimetry of 111Indium (111In) radiolabelled amatuximab in mesothelin-expressing cancers. Between October 2011 and February 2013, six patients including four with malignant mesothelioma and two with pancreatic adenocarcinoma underwent Single Photon Emission Computed Tomography-Computed Tomography (SPECT/CT) imaging following administration of 111In amatuximab. SPECT/CT images were obtained at 2-4 hours, 24-48 hours and 96-168 hours after radiotracer injection. In all patients, tumor to background ratios (TBR) consistently met or exceeded an uptake of 1.2 (range 1.2-62.0) which is considered the minimum TBR that can be visualized. TBRs were higher in tumors of patients with mesothelioma than pancreatic adenocarcinoma. 111In-amatuximab uptake was noted in both primary tumors and metastatic sites. The radiotracer dose was generally well-tolerated and demonstrated physiologic uptake in the heart, liver, kidneys and spleen. This is the first study to show tumor localization of an anti-mesothelin antibody in humans. Our results show that 111In-amatuximab was well tolerated with a favorable dosimetry profile. It localizes to mesothelin expressing cancers with a higher uptake in mesothelioma than pancreatic cancer.

  5. Pharmacokinetics, safety, and hydrolysis of oral pyrroloquinazolinediamines administered in single and multiple doses in rats.

    PubMed

    Li, Qigui; Kozar, Michael P; Shearer, Todd W; Xie, Lisa H; Lin, Ai J; Smith, Kirsten S; Si, Yuanzheng; Anova, Lalaine; Zhang, Jing; Milhous, Wilbur K; Skillman, Donald R

    2007-08-01

    Pyrroloquinazolinediamine (PQD) derivatives such as tetra-acetamide PQD (PQD-A4) and bis-ethylcarbamyl PQD (PQD-BE) were much safer (with therapeutic indices of 80 and 32, respectively) than their parent compound, PQD (therapeutic index, 10). Further evaluation of PQD-A4 and PQD-BE in single and multiple pharmacokinetic (PK) studies as well as corresponding toxicity studies was conducted with rats. PQD-A4 could be converted to two intermediate metabolites (monoacetamide PQD and bisacetamide PQD) first and then to the final metabolite, PQD, while PQD-BE was directly hydrolyzed to PQD without precursor and intermediate metabolites. Maximum tolerant doses showed that PQD-A4 and PQD-BE have only 1/12 and 1/6, respectively, of the toxicity of PQD after a single oral dose. Compared to the area under the concentration-time curve for PQD alone (2,965 ng.h/ml), values measured in animals treated with PQD-A4 and PQD-BE were one-third (1,047 ng.h/ml) and one-half (1,381 ng.h/ml) as high, respectively, after an equimolar dosage, suggesting that PQD was the only agent to induce the toxicity. Similar results were also shown in multiple treatments; PQD-A4 and PQD-BE generated two-fifths and three-fifths, respectively, of PQD concentrations, with 8.8-fold and 3.8-fold safety margins, respectively, over the parent drug. PK data indicated that the bioavailability of oral PQD-A4 was greatly limited at high dose levels, that PQD-A4 was slowly converted to PQD via a sequential three-step process of conversion, and that PQD-A4 was significantly less toxic than the one-step hydrolysis drug, PQD-BE. It was concluded that the slow and smaller release of PQD was the main reason for the reduction in toxicity and that the active intermediate metabolites can still maintain antimalarial potency. Therefore, the candidate with multiple-step hydrolysis of PQD could be developed as a safer potential agent for malaria treatment.

  6. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease.

    PubMed

    Gill, Joan C; Castaman, Giancarlo; Windyga, Jerzy; Kouides, Peter; Ragni, Margaret; Leebeek, Frank W G; Obermann-Slupetzky, Ortrun; Chapman, Miranda; Fritsch, Sandor; Pavlova, Borislava G; Presch, Isabella; Ewenstein, Bruce

    2015-10-22

    This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII : C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII : C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII : C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227.

  7. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease

    PubMed Central

    Gill, Joan C.; Castaman, Giancarlo; Windyga, Jerzy; Kouides, Peter; Ragni, Margaret; Leebeek, Frank W. G.; Obermann-Slupetzky, Ortrun; Chapman, Miranda; Fritsch, Sandor; Pavlova, Borislava G.; Presch, Isabella

    2015-01-01

    This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII:C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII:C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII:C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227. PMID:26239086

  8. Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and Its Cardiovascular Effects in Healthy Volunteers.

    PubMed

    Belmonte, Carmen; Ochoa, Dolores; Román, Manuel; Cabaleiro, Teresa; Talegón, Maria; Sánchez-Rojas, Sergio Daniel; Abad-Santos, Francisco

    2016-12-01

    The aim of this study was the evaluation of the possible relationship between pharmacokinetics and the safety of aripiprazole as well as its influence on blood pressure (BP), heart rate (HR), and corrected QT (QTc) interval. The study population comprised 157 healthy volunteers from 6 bioequivalence clinical trials. Subjects were administered a single 10-mg oral dose of each formulation separated by a 28-day washout period. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. Blood pressure was measured at the following times: predose and 0.5, 2, 4, 6, and 8 hours postdose. An electrocardiogram was recorded at predose, 4, and 8 hours postdose. Area under the curve (AUC), maximum plasma concentration, half-life, and distribution volume corrected for weight were higher in women. Aripiprazole treatment produced a decrease of BP (9.3 mm Hg on systolic and 6.2 mm Hg on diastolic pressure) and an increase in HR (12.1 beats per minute) and QTc interval (9.1 milliseconds). There were sex differences in BP, HR, and QTc interval. Women and subjects with higher AUC and maximum plasma concentration values were more prone to experience adverse drug reactions and gastrointestinal adverse reactions. The AUC was related with systolic BP and diastolic BP decrease and HR increase but there was no relationship between aripiprazole concentrations and QTc increase. Aripiprazole decreases BP and increases HR and QTc interval. Pharmacokinetics, pharmacodynamics, and safety of aripiprazole are affected by sex. There is a directly proportional relationship between pharmacokinetic parameters and adverse drug reactions and effect on BP and HR.

  9. Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers

    PubMed Central

    Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

    2013-01-01

    Aim The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Methods Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. Results ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Conclusions Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. PMID:23016924

  10. Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers

    PubMed Central

    Abel, Samantha; van der Ryst, Elna; Rosario, Maria C; Ridgway, Caroline E; Medhurst, Christine G; Taylor-Worth, Richard J; Muirhead, Gary J

    2008-01-01

    Aims To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers. Methods Three double-blind, placebo-controlled, dose-escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed. Results Maraviroc is rapidly absorbed following oral administration, and plasma Tmax is achieved within 0.5–4.0 h postdose. Steady-state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3–1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10–12 l h−1 and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose-limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses. Conclusions Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug-metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate. PMID:18333861

  11. Pharmacokinetics of 2 dapivirine vaginal microbicide gels and their safety vs. Hydroxyethyl cellulose-based universal placebo gel.

    PubMed

    Nel, Annalene M; Smythe, Shanique C; Habibi, Sepideh; Kaptur, Paulina E; Romano, Joseph W

    2010-10-01

    Dapivirine, a nonnucleoside reverse transcriptase inhibitor, is in development as a microbicide for the protection of women against HIV infection. A randomized, double-blind, phase 1 trial was conducted in 36 healthy HIV-negative women to compare the pharmacokinetics of 2 dapivirine vaginal gel formulations (0.05% each) and their safety with the hydroxyethyl cellulose-based universal placebo gel. Gel was self-administered once daily for a total of 11 days. Blood and vaginal fluid samples were collected sequentially over 24 days for pharmacokinetic analysis. Safety was evaluated by pelvic examination, colposcopy, adverse events, and clinical laboratory assessments. Adverse event profiles were similar for the 3 gels. Most events were mild and not related to study gel. Headache and vaginal hemorrhage (any vaginal bleeding) were most common. Plasma concentrations of dapivirine did not exceed 1.1 ng/mL. Steady-state conditions were reached within approximately 10 days. Dapivirine concentrations in vaginal fluids were slightly higher for Gel 4789, but Cmax values on days 1 and 14 were not significantly different. Terminal half-life was 72-73 hours in plasma and 15-17 hours in vaginal fluids. Both formulations of dapivirine gel were safe and well tolerated. Dapivirine was delivered to the lower genital tract at concentrations at least 5 logs greater than in vitro inhibitory concentrations.

  12. [Pharmacokinetics and safety of aripiprazole long-acting injection, following multiple deltoid administrations in schizophrenia patients in Japan].

    PubMed

    Ishigooka, Jun; Noda, Takamasa; Nishiyama, Kosuke; Tamaru, Noriko; Shima, Tomoko; Yamasaki, Yumiko; Tadori, Yoshihiro

    2016-06-01

    Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre-study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady-state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 μg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues.

  13. Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects.

    PubMed

    Nomoto, Maiko; Pastino, Gina; Rege, Bhaskar; Aluri, Jagadeesh; Ferry, Jim; Han, David

    2017-03-24

    Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects. Administration with food did not alter the rate or extent of avatrombopag absorption but substantially reduced pharmacokinetic variability relative to the fasted state. CYP2C9 polymorphism (*2, *3) was associated with higher pharmacokinetic variability but not with any clinically important effect on variability in platelet response. Plasma exposures of avatrombopag increased in a dose-proportional manner over the dose range tested. After a single dose, platelet count increased in a dose-related manner, reaching a maximum by day 11 and returning to baseline levels by day 27. No clinically important differences were found when avatrombopag pharmacokinetics and pharmacodynamics were compared between Japanese and white subjects. Administration of avatrombopag was generally well tolerated. © 2017, The American College of Clinical Pharmacology.

  14. Effectiveness, Safety, and Pharmacokinetics of Quetiapine in Aggressive Children with Conduct Disorder

    ERIC Educational Resources Information Center

    Findling, Robert L.; Reed, Michael D.; O'Riordan, Mary Ann; Demeter, Christine A.; Stansbrey, Robert J.; McNamara, Nora K.

    2006-01-01

    Objective: To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). Method: This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale…

  15. Effectiveness, Safety, and Pharmacokinetics of Quetiapine in Aggressive Children with Conduct Disorder

    ERIC Educational Resources Information Center

    Findling, Robert L.; Reed, Michael D.; O'Riordan, Mary Ann; Demeter, Christine A.; Stansbrey, Robert J.; McNamara, Nora K.

    2006-01-01

    Objective: To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). Method: This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale…

  16. Recombinant human hemoglobin does not affect renal function in humans: analysis of safety and pharmacokinetics.

    PubMed

    Viele, M K; Weiskopf, R B; Fisher, D

    1997-04-01

    Recombinant human hemoglobin (OptroD; rHb1.1) is a genetically engineered protein produced in Escherichia coli. The two alpha-globin polypeptides are genetically joined, resulting in a stable tetramer that does not dissociate into dimers or monomers. Historically, infusion in humans of acellular hemoglobin preparations has resulted in renal toxicity. This study was performed to evaluate the safety and pharmacokinetics of rHb1.1 when infused in humans. After giving informed consent, 48 healthy male volunteers were randomly assigned to receive either 0.015-0.32 g/kg 5% rHb1.1 (n = 34) or an equivalent amount of 5% human serum albumin (HSA; n = 14) infused intravenously over 0.8-1.9 h. Serum creatinine, creatinine clearance, urine N-acetyl-beta-glucosaminidase, and serum rHb1.1 concentrations were measured before and at timed intervals after infusion. Postinfusion urine N-acetyl-beta-glucosaminidase activity did not exceed preinfusion values at any interval in either group. Serum creatinine did not differ from preinfusion values at 1 day, 2-3 days, or 7 days after infusion for either group. Creatinine clearance increased significantly for the HSA group 12 h after infusion (138 +/- 16 ml/min, means +/- SE) and in the rHb1.1 group 1 day after infusion (112 +/- 5 ml/min; P < 0.05). Values for creatinine clearance did not differ from preinfusion values for either group at any other postinfusion interval; serum creatinine and creatinine clearance did not differ between groups at any time. The amount of hemoglobin excreted in the urine did not exceed approximately 0.04% of the administered rHb1.1 dose in any volunteer. Plasma clearance of rHb1.1 decreased and half-life increased as a function of increasing plasma concentration (e.g., the half-life was 2.8 h at a plasma concentration of 0.5 mg/ml and 12 h at 5 mg/ml). The incidence of gastrointestinal symptoms, fever, and chills was greater after infusion of rHb1.1 than after HSA (P < 0.05). No evidence for rHb1.1-mediated

  17. Insulin receptor antibody-iduronate 2-sulfatase fusion protein: pharmacokinetics, anti-drug antibody, and safety pharmacology in Rhesus monkeys.

    PubMed

    Boado, Ruben J; Ka-Wai Hui, Eric; Zhiqiang Lu, Jeff; Pardridge, William M

    2014-11-01

    Mucopolysaccharidosis (MPS) Type II is caused by mutations in the gene encoding the lysosomal enzyme, iduronate 2-sulfatase (IDS). The majority of MPSII cases affect the brain. However, enzyme replacement therapy with recombinant IDS does not treat the brain, because IDS is a large molecule drug that does not cross the blood-brain barrier (BBB). To enable BBB penetration, IDS has been re-engineered as an IgG-IDS fusion protein, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, and the HIRMAb domain of the fusion protein acts as a molecular Trojan horse to ferry the fused IDS into brain from blood. The present study reports on the first safety pharmacology and pharmacokinetics study of the HIRMAb-IDS fusion protein. Juvenile male Rhesus monkeys were infused intravenously (IV) weekly for 26 weeks with 0, 3, 10, or 30 mg/kg of the HIRMAb-IDS fusion protein. The plasma clearance of the fusion protein followed a linear pharmacokinetics profile, which was equivalent either with measurements of the plasma concentration of immunoreactive HIRMAb-IDS fusion protein, or with assays of plasma IDS enzyme activity. Anti-drug antibody (ADA) titers were monitored monthly, and the ADA response was primarily directed against the variable region of the HIRMAb domain of the fusion protein. No infusion related reactions or clinical signs of immune response were observed during the course of the study. A battery of safety pharmacology, clinical chemistry, and tissue histopathology showed no signs of adverse events, and demonstrate the safety profile of chronic treatment of primates with 3-30 mg/kg weekly IV infusion doses of the HIRMAb-IDS fusion protein. © 2014 Wiley Periodicals, Inc.

  18. Liraglutide's safety, tolerability, pharmacokinetics, and pharmacodynamics in pediatric type 2 diabetes: a randomized, double-blind, placebo-controlled trial.

    PubMed

    Klein, David J; Battelino, Tadej; Chatterjee, D J; Jacobsen, Lisbeth V; Hale, Paula M; Arslanian, Silva

    2014-10-01

    The prevalence of type 2 diabetes (T2D) in youth is increasing. Treatment options beyond metformin and insulin are needed. The safety, tolerability, pharmacokinetics, and pharmacodynamics of liraglutide once daily in youth (10-17 years old) with T2D were investigated in a randomized, double-blind, placebo-controlled trial. Youth treated with diet/exercise alone or with metformin and having a hemoglobin A1c (HbA1c) level of 6.5-11% were randomized to liraglutide (n=14) or placebo (n=7). Starting at 0.3 mg/day, doses were escalated weekly to 0.6, 0.9, 1.2, and 1.8 mg/day (or placebo equivalent) for 5 weeks. Nineteen participants completed the trial. Baseline characteristics were similar between groups, with mean (SD) values for age of 14.8 (2.2) years, weight of 113.2 (35.6) kg (range, 57-214 kg), diabetes duration of 1.7 (1.4) years, and HbA1c level of 8.1% (1.2%). No serious adverse events (AEs), including severe hypoglycemia, occurred. Transient gastrointestinal AEs were most common at lower liraglutide doses during dose escalation. No significant changes in safety and tolerability parameters occurred. There was no evidence of pancreatitis or lipase elevations above three times the upper normal limit; calcitonin levels remained within the normal range. For liraglutide 1.8 mg, mean half-life was 12 h, and clearance was 1.7 L/h. After 5 weeks, the decline in HbA1c level was greater with liraglutide versus placebo (-0.86 vs. 0.04%, P=0.0007), whereas mean body weight remained stable (-0.50 vs. -0.54 kg, P=0.9703). Liraglutide was well tolerated in youth with T2D, with safety, tolerability, and pharmacokinetic profiles similar to profiles in adults.

  19. A randomized safety and pharmacokinetic trial of daily tenofovir 1% gel in term and near-term pregnancy

    PubMed Central

    Beigi, Richard H; Noguchi, Lisa M; Montgomery, Elizabeth; Biggio, Joseph; Hendrix, Craig W; Marzinke, Mark A; Dai, James Y; Pan, Jason; Na Ayudhya, Ratiya Kunjara; Schwartz, Jill L; Isaacs, Karen; Piper, Jeanna M; Watts, D Heather

    2016-01-01

    Introduction Vaginal tenofovir (TFV) 1% gel may reduce incident HIV-1 and herpes simplex virus 2 infection. Pregnancy may increase risk of HIV acquisition, and incident HIV in pregnancy potentiates perinatal HIV transmission. Our objective was to investigate the safety and pharmacokinetics of seven days of TFV 1% vaginal gel in term and near-term pregnancy. Methods Ninety-eight healthy pregnant women, stratified to a term cohort followed by a near-term cohort, were enrolled into a 2:1 randomized, double-blinded, placebo-controlled trial. Women received TFV or placebo gel for seven consecutive days with pharmacokinetic sampling on days 0 and 6. Maternal and cord blood were collected at delivery. Primary end points included laboratory and genital adverse events, adverse pregnancy and neonatal outcomes, and maternal TFV levels. Results Most adverse events were grade 1 and none of the grade 3 or 4 adverse events were related to study product. There was no significant difference in safety end points between the two pregnancy cohorts (p=0.18); therefore, their data were combined. Primary safety end point rates were similar for mothers randomized to the TFV gel vs placebo arm (72.7 and 68.8%, p=0.81). The same was true for newborns in the TFV gel vs placebo arms (4.5% vs 6.3%, p=0.66). All women randomized to TFV had quantifiable serum levels within eight hours of dosing, with low overall median (interquartile range) day 0 and day 6 peak values (3.8 (2.0 to 7.0) and 5.8 (2.6 to 9.4) ng/mL, respectively). Conclusions Daily TFV 1% vaginal gel use in term and near-term pregnancy appears to be safe and produces low serum drug levels. PMID:27658440

  20. Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia.

    PubMed

    Ye, Guo-jie; Budzynski, Ewa; Sonnentag, Peter; Nork, T Michael; Miller, Paul E; Sharma, Alok K; Ver Hoeve, James N; Smith, Leia M; Arndt, Tara; Calcedo, Roberto; Gaskin, Chantelle; Robinson, Paulette M; Knop, David R; Hauswirth, William W; Chulay, Jeffrey D

    2016-03-01

    Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated viral (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in cynomolgus macaques. Three groups of animals (n = 2 males and 2 females per group) received a subretinal injection in one eye of 300 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two concentrations (4 × 10(11) or 4 × 10(12) vector genomes/ml) and were evaluated over a 3-month period before being euthanized. Administration of rAAV2tYF-PR1.7-hCNGB3 was associated with a dose-related anterior and posterior segment inflammatory response that was greater than that observed in eyes injected with the vehicle control. Most manifestations of inflammation improved over time except that vitreous cells persisted in vector-treated eyes until the end of the study. One animal in the lower vector dose group was euthanized on study day 5, based on a clinical diagnosis of endophthalmitis. There were no test article-related effects on intraocular pressure, visual evoked potential responses, hematology or clinical chemistry parameters, or gross necropsy observations. Histopathological examination demonstrated minimal mononuclear infiltrates in all vector-injected eyes. Serum anti-AAV antibodies developed in all vector-injected animals. No animals developed antibodies to CNGB3. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.

  1. Safety and Biodistribution Evaluation in CNGB3-Deficient Mice of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia.

    PubMed

    Ye, Guo-jie; Budzynski, Ewa; Sonnentag, Peter; Nork, T Michael; Miller, Paul E; McPherson, Leslie; Ver Hoeve, James N; Smith, Leia M; Arndt, Tara; Mandapati, Savitri; Robinson, Paulette M; Calcedo, Roberto; Knop, David R; Hauswirth, William W; Chulay, Jeffrey D

    2016-03-01

    Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in CNGB3-deficient mice. Three groups of animals (n = 35 males and 35 females per group) received a subretinal injection in one eye of 1 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two dose concentrations (1 × 10(12) or 4.2 × 10(12) vg/ml) and were euthanized 4 or 13 weeks later. There were no test-article-related changes in clinical observations, body weights, food consumption, ocular examinations, clinical pathology parameters, organ weights, or macroscopic observations at necropsy. Cone-mediated electroretinography (ERG) responses were detected after vector administration in the treated eyes in 90% of animals in the higher dose group and 31% of animals in the lower dose group. Rod-mediated ERG responses were reduced in the treated eye for all groups, with the greatest reduction in males given the higher dose of vector, but returned to normal by the end of the study. Microscopic pathology results demonstrated minimal mononuclear cell infiltrates in the retina and vitreous of some animals at the interim euthanasia and in the vitreous of some animals at the terminal euthanasia. Serum anti-AAV antibodies developed in most vector-injected animals. No animals developed antibodies to hCNGB3. Biodistribution studies demonstrated high levels of vector DNA in vector-injected eyes but little or no vector DNA in nonocular tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.

  2. Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma

    SciTech Connect

    Puntel, Mariana; Ghulam, Muhammad A.K.M.; Farrokhi, Catherine; VanderVeen, Nathan; Paran, Christopher; Appelhans, Ashley; Kroeger, Kurt M.; Salem, Alireza; Lacayo, Liliana; Pechnick, Robert N.; Kelson, Kyle R.; Kaur, Sukhpreet; Kennedy, Sean; Palmer, Donna; Ng, Philip; and others

    2013-05-01

    Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression “on” or “off” according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1 × 10{sup 8}, 1 × 10{sup 9}, or 1 × 10{sup 10} viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1 × 10{sup 9} vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma. - Highlights: ► High capacity Ad vectors elicit sustained therapeutic gene expression in the brain. ► HC-Ad-TK/TetOn-Flt3L encodes two therapeutic genes and a transcriptional switch. ► We performed a dose escalation study at

  3. Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia.

    PubMed

    Ye, Guo-Jie; Budzynski, Ewa; Sonnentag, Peter; Nork, T Michael; Miller, Paul E; Sharma, Alok K; Ver Hoeve, James N; Smith, Leia; Arndt, Tara; Calcedo, Roberto; Gaskin, Chantelle; Robinson, Paulette; Knop, David R; Hauswirth, William W; Chulay, Jeffrey David

    2016-03-08

    AGTC is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity and absence of color discrimination. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in cynomolgus macaques. Three groups of animals (n=2 males and 2 females per group) received a subretinal injection in one eye of 300 µL containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two concentrations (4 × 1011 or 4 × 1012 vg/mL) and were evaluated over a 3 month period prior to being euthanized. Administration of rAAV2tYF-PR1.7-hCNGB3 was associated with a dose-related anterior and posterior segment inflammatory response that was greater than that observed in eyes injected with the vehicle control. Most manifestations of inflammation improved over time except that vitreous cells persisted in vector-treated eyes until the end of the study. One animal in the lower vector dose group was euthanized on Study Day 5 based on a clinical diagnosis of endophthalmitis. There were no test article-related effects on intraocular pressure, visual evoked potential responses, hematology or clinical chemistry parameters, or gross necropsy observations. Histopathological examination demonstrated minimal mononuclear infiltrates in all vector-injected eyes. Serum anti-AAV antibodies developed in all vector-injected animals. No animals developed antibodies to CNGB3. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.

  4. Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

    PubMed Central

    Ye, Guo-jie; Budzynski, Ewa; Sonnentag, Peter; Nork, T. Michael; Miller, Paul E.; Sharma, Alok K.; Ver Hoeve, James N.; Smith, Leia M.; Arndt, Tara; Calcedo, Roberto; Gaskin, Chantelle; Robinson, Paulette M.; Knop, David R.; Hauswirth, William W.; Chulay, Jeffrey D.

    2016-01-01

    Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated viral (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in cynomolgus macaques. Three groups of animals (n = 2 males and 2 females per group) received a subretinal injection in one eye of 300 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two concentrations (4 × 1011 or 4 × 1012 vector genomes/ml) and were evaluated over a 3-month period before being euthanized. Administration of rAAV2tYF-PR1.7-hCNGB3 was associated with a dose-related anterior and posterior segment inflammatory response that was greater than that observed in eyes injected with the vehicle control. Most manifestations of inflammation improved over time except that vitreous cells persisted in vector-treated eyes until the end of the study. One animal in the lower vector dose group was euthanized on study day 5, based on a clinical diagnosis of endophthalmitis. There were no test article-related effects on intraocular pressure, visual evoked potential responses, hematology or clinical chemistry parameters, or gross necropsy observations. Histopathological examination demonstrated minimal mononuclear infiltrates in all vector-injected eyes. Serum anti-AAV antibodies developed in all vector-injected animals. No animals developed antibodies to CNGB3. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations. PMID:27003753

  5. Safety, pharmacokinetic and pharmacodynamic properties of TV-1106, a long-acting GH treatment for GH deficiency.

    PubMed

    Cohen-Barak, Orit; Sakov, Anat; Rasamoelisolo, Michele; Bassan, Merav; Brown, Kurt; Mendzelevski, Boaz; Spiegelstein, Ofer

    2015-11-01

    TV-1106 (Teva Pharmaceuticals) is a genetically fused recombinant protein of human GH (hGH) and human serum albumin, in development for treatment of GH deficiency (GHD). TV-1106 is expected to have an extended duration of action compared to daily GH treatment and may enable a reduction in the frequency of injections and improve compliance and quality of life for adults and children requiring GHD therapy. To assess the safety, local tolerability, pharmacokinetics and pharmacodynamics of TV-1106 following single s.c. injections in healthy male volunteers. Subjects (n=56) were assigned to one of seven ascending dose groups (3-100 mg) and received either a single dose of TV-1106 (n=6) or placebo (n=2) by s.c. injection. Eighteen subjects reported 43 adverse effects (AEs), which were mild to moderate; no serious AEs (SAEs) occurred. In 50, 70 and 100 mg groups there were mild to moderate increases in heart rate and systolic blood pressure that significantly correlated with higher levels of IGF1. TV-1106 showed pharmacokinetic characteristics of a long-acting hGH as demonstrated by a terminal elimination half-life of 23-35 h, delayed time of peak concentration, and systemic levels seen up to 7 days after dosing. IGF1 levels increased in a dose-dependent manner, before reaching a plateau, with levels above baseline extending beyond 7 days post dose. Single administration of TV-1106 up to 100 mg was safe in healthy volunteers. Pharmacokinetics and pharmacodynamics support once-weekly administration in patients with GHD. © 2015 The authors.

  6. Pharmacokinetics and safety of 3,4-diaminopyridine base in healthy Japanese volunteers.

    PubMed

    Ishida, Natsuko; Kobayashi, Erina; Kondo, Yuya; Matsushita, Ryo; Komai, Kiyonobu

    2015-08-01

    3,4-diaminopyridine (3,4-DAP) is commonly used for treating neuromuscular diseases, such as the Lambert-Eaton myasthenic syndrome, but the pharmacokinetics of 3,4-DAP base have not been investigated. We therefore studied 3,4-DAP base pharmacokinetics in healthy Japanese volunteers. In this crossover study, we administered a single oral dose of 10 or 20 mg 3,4-DAP base to healthy Japanese volunteers (n = 5) after food intake, or 10 mg 3,4-DAP to fasting individuals. We measured serum 3,4-DAP concentrations, performed electrocardiography (ECG), and administered questionnaires. After administration of 10 or 20 mg 3,4-DAP following food intake, the maximum serum concentrations (Cmax) were 8.09 ± 4.47 ng/mL and 35.8 ± 15.7 ng/mL, respectively (mean ± standard deviation; SD), and the areas under the serum concentration-time curve (extrapolated to infinity) were 639 ± 213 ng x min/mL and 2,097 ± 936 ng x min/mL (mean ± SD), respectively. Administration to fasted individuals indicated that food intake did not significantly alter 3,4-DAP pharmacokinetics. ECG showed no clinically significant changes, but PR intervals were prolonged in all cases. Two out of 5 subjects showed perioral paresthesia symptoms after administration of 20 mg 3,4-DAP. This study indicated that 3,4-DAP base pharmacokinetics were non-linear. Although no clinically significant changes in ECG were observed, it is advisable to perform ECG periodically during 3,4-DAP administration in order to monitor cardiac function. Moreover, the development of perioral paresthesia may be dependent on the dose of 3,4-DAP used.

  7. Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects.

    PubMed

    Harrell, Robert E; Karim, Aziz; Zhang, Wencan; Dudkowski, Caroline

    2016-05-01

    Azilsartan medoxomil (AZL-M) is an angiotensin II receptor blocker approved to treat hypertension. After oral dosing, AZL-M is quickly hydrolyzed to azilsartan (AZL). The aims of this study were to assess the effects of age, sex, and race on the pharmacokinetics of AZL-M in healthy subjects, as well as safety and tolerability. Sixty-one healthy adults were enrolled in this phase I, single-blind, randomized placebo-controlled study (placebo control was for assessment of safety/tolerability only). Subjects were stratified by age (18-45 vs. 65-85 years), sex, and race (black vs. white) and given oral AZL-M 60 mg (3 × 20 mg capsules) or placebo as a single dose (Day 1) and consecutive daily doses (Days 4-8) (6:2 ratio for AZL-M:placebo per group). Pharmacokinetics were evaluated (AZL-M patients only) on Days 1-3 and 8-9 and safety/tolerability was monitored. Age, sex, and race had no clinically meaningful effect on AZL exposures after single or multiple dosing. Pharmacokinetic parameters remained similar between Days 1 and 8 for each age, sex, and race subgroup. The frequency of adverse events was similar for AZL-M (32%) and placebo (29%). No discontinuations or serious adverse events occurred. Based on these pharmacokinetic and safety/tolerability findings, no AZL-M dose adjustments are required based on age, sex, or race (black/white).

  8. Safety and biodistribution assessment of sc-rAAV2.5IL-1Ra administered via intra-articular injection in a mono-iodoacetate-induced osteoarthritis rat model

    PubMed Central

    Wang, Gensheng; Evans, Christopher H; Benson, Janet M; Hutt, Julie A; Seagrave, JeanClare; Wilder, Julie A; Grieger, Joshua C; Samulski, R Jude; Terse, Pramod S

    2016-01-01

    Interleukin-1 (IL-1) plays an important role in the pathophysiology of osteoarthritis (OA), and gene transfer of IL-1 receptor antagonist (IL-1Ra) holds promise for OA treatment. A preclinical safety and biodistribution study evaluated a self-complementary adeno-associated viral vector carrying rat IL-1Ra transgene (sc-rAAV2.5rIL-1Ra) at 5 × 108, 5 × 109, or 5 × 1010 vg/knee, or human IL-1Ra transgene (sc-rAAV2.5hIL-1Ra) at 5 × 1010 vg/knee, in Wistar rats with mono-iodoacetate (MIA)–induced OA at days 7, 26, 91, 180, and 364 following intra-articular injection. The MIA-induced OA lesions were consistent with the published data on this model. The vector genomes persisted in the injected knees for up to a year with only limited vector leakage to systemic circulation and uptake in tissues outside the knee. Low levels of IL-1Ra expression and mitigation of OA lesions were observed in the vector-injected knees, albeit inconsistently. Neutralizing antibodies against the vector capsid developed in a dose-dependent manner, but only the human vector induced a small splenic T-cell immune response to the vector capsid. No local or systemic toxicity attributable to vector administration was identified in the rats as indicated by clinical signs, body weight, feed consumption, clinical pathology, and gross and microscopic pathology through day 364. Taken together, the gene therapy vector demonstrated a favorable safety profile. PMID:26817025

  9. Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers.

    PubMed

    Frey, Reiner; Mück, Wolfgang; Unger, Sigrun; Artmeier-Brandt, Ulrike; Weimann, Gerrit; Wensing, Georg

    2008-12-01

    Preclinical data indicate that the nitric oxide-independent soluble guanylate cyclase activator cinaciguat (BAY 58-2667), which is a new drug in development for patients with heart failure, induces vasodilation preferentially in diseased vessels. This study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinaciguat. Seventy-six healthy volunteers were included in this randomized, placebo-controlled study. Cinaciguat (50-250 microg/h) was administered intravenously for up to 4 hours in a maximum of 6 individuals per dose group. No serious adverse events were reported. Four-hour infusions (50-250 microg/h) decreased diastolic blood pressure and increased heart rate (all P values < .05) versus placebo, without significantly reducing systolic blood pressure (P between 0.07 and 0.56). At higher doses (150-250 microg/h), 4-hour infusions decreased mean arterial pressure and increased plasma cyclic guanosine monophosphate levels (all P values < .05). Pharmacokinetics showed dose-proportionality with low interindividual variability. Plasma concentrations declined below 1.0 microg/L within 30 minutes of cessation of infusion. Cinaciguat had potent cardiovascular effects reducing preload and afterload, warranting further investigation in patients with heart failure.

  10. Psychomotor effects, pharmacokinetics and safety of the orexin receptor antagonist suvorexant administered in combination with alcohol in healthy subjects.

    PubMed

    Sun, Hong; Yee, Ka Lai; Gill, Sean; Liu, Wen; Li, Xiaodong; Panebianco, Deborah; Mangin, Eric; Morrison, Dennis; McCrea, Jacqueline; Wagner, John A; Troyer, Matthew D

    2015-11-01

    A double-blind crossover study investigated psychomotor effects, pharmacokinetics, and safety of the orexin receptor antagonist suvorexant with and without alcohol. Healthy adults (n=31) were randomized to receive placebo or suvorexant (40 mg) plus placebo solution or alcohol (0.7 g/kg) in each of four treatments (single doses; morning administration). The US Food and Drug Administration approved suvorexant dose is 10 mg (up to 20 mg) daily. Pharmacodynamic effects were assessed using tests of digit vigilance (DVT; primary endpoint), choice reaction time, digit symbol substitution, numeric working memory, immediate/delayed word recall, body sway and subjective alertness. Suvorexant alone did not significantly affect DVT reaction time, but did impact some pharmacodynamic tests. Suvorexant with alcohol increased reaction time versus either alone (mean difference at 2 h: 44 ms versus suvorexant, p<0.001; 24 ms, versus alcohol, p<0.05) and had additive negative effects on tests of vigilance, working/episodic memory, postural stability and alertness. No effects of suvorexant alone or with alcohol were observed by 9 h. No important changes in pharmacokinetic parameters were observed upon co-administration. All treatments were generally well tolerated without serious adverse events. In conclusion, co-administration of 40 mg suvorexant and 0.7 g/kg alcohol had additive negative psychomotor effects. Patients are advised not to consume alcohol with suvorexant.

  11. Safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors: results of a phase 1 trial.

    PubMed

    Awada, Ahmad; Gil, Thierry; Whenham, Nicolas; Van Hamme, Julie; Besse-Hammer, Tatiana; Brendel, Erich; Delesen, Heinz; Joosten, Miranda C; Lathia, Chetan D; Loembé, Bienvenu A; Piccart-Ghebart, Martine; Hendlisz, Alain

    2011-12-01

    Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m(2) bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m(2) bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (C(max) and AUC(0-12)) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m(2) bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m(2) bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid, as scheduled above.

  12. Safety and pharmacokinetics of the antiorthopoxvirus compound ST-246 following repeat oral dosing in healthy adult subjects.

    PubMed

    Jordan, Robert; Chinsangaram, Jarasvech; Bolken, Tove' C; Tyavanagimatt, Shanthakumar R; Tien, Deborah; Jones, Kevin F; Frimm, Annie; Corrado, Michael L; Pickens, Margaret; Landis, Patrick; Clarke, Jean; Marbury, Thomas C; Hruby, Dennis E

    2010-06-01

    ST-246, a novel compound that inhibits egress of orthopoxvirus from infected cells, is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, placebo-controlled, escalating multiple-dose study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose of 250, 400, or 800 mg for 21 days to nonfasting healthy human volunteers. ST-246 appeared to be well tolerated, with no serious adverse events (AEs). Headache, for which one subject in the 800-mg group discontinued the study, was the most commonly reported AE in all treatment groups. The multiple-dose pharmacokinetics of ST-246 was well characterized. The day 21 mean elimination half-lives were calculated at 18.8, 19.8, and 20.7 h for each of the 250-, 400-, and 800-mg/day dose groups, respectively. Steady state was reached by day 6 (within 3 to 5 half-lives), saturable absorption was observed at the 800-mg dose level, and the fraction of parent drug excreted in the urine was very low. Based on these results, administration of 400 mg/day ST-246 can be expected to provide plasma concentrations above the efficacious concentration demonstrated in nonhuman primate models in earlier studies.

  13. Safety and Pharmacokinetics of the Antiorthopoxvirus Compound ST-246 following Repeat Oral Dosing in Healthy Adult Subjects▿

    PubMed Central

    Jordan, Robert; Chinsangaram, Jarasvech; Bolken, Tove' C.; Tyavanagimatt, Shanthakumar R.; Tien, Deborah; Jones, Kevin F.; Frimm, Annie; Corrado, Michael L.; Pickens, Margaret; Landis, Patrick; Clarke, Jean; Marbury, Thomas C.; Hruby, Dennis E.

    2010-01-01

    ST-246, a novel compound that inhibits egress of orthopoxvirus from infected cells, is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, placebo-controlled, escalating multiple-dose study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose of 250, 400, or 800 mg for 21 days to nonfasting healthy human volunteers. ST-246 appeared to be well tolerated, with no serious adverse events (AEs). Headache, for which one subject in the 800-mg group discontinued the study, was the most commonly reported AE in all treatment groups. The multiple-dose pharmacokinetics of ST-246 was well characterized. The day 21 mean elimination half-lives were calculated at 18.8, 19.8, and 20.7 h for each of the 250-, 400-, and 800-mg/day dose groups, respectively. Steady state was reached by day 6 (within 3 to 5 half-lives), saturable absorption was observed at the 800-mg dose level, and the fraction of parent drug excreted in the urine was very low. Based on these results, administration of 400 mg/day ST-246 can be expected to provide plasma concentrations above the efficacious concentration demonstrated in nonhuman primate models in earlier studies. PMID:20385870

  14. Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
.

    PubMed

    Kulmatycki, Kenneth M; Langenickel, Thomas; Ng, Wai Hong; Pal, Parasar; Zhou, Wei; Lin, Tsu-Han; Rajman, Iris; Chandra, Priyamvada; Sunkara, Gangadhar

    2017-09-01

    To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.
.

  15. Safety, Pharmacokinetics, and Pharmacodynamic Effects of a Selective TGR5 Agonist, SB-756050, in Type 2 Diabetes.

    PubMed

    Hodge, Rebecca J; Lin, Jiang; Vasist Johnson, Lakshmi S; Gould, Elizabeth P; Bowers, Gary D; Nunez, Derek J

    2013-07-01

    TGR5 is a bile acid receptor and a potential target for the treatment of type 2 diabetes (T2D). We report here the safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in patients with T2D. Fifty-one subjects were randomized to receive either placebo or one of four doses of SB-756050 for 6 days. A single 100 mg dose of sitagliptin was co-administered on Day 6 to all subjects. SB-756050 was well-tolerated; it was readily absorbed, exhibited nonlinear pharmacokinetics with a less than dose-proportional increase in plasma exposure above 100 mg, and demonstrated no significant changes in exposure when co-administered with sitagliptin. SB-756050 demonstrated highly variable pharmacodynamic effects both within dose groups and between doses, with increases in glucose seen at the two lowest doses and no reduction in glucose seen at the two highest doses. The glucose effects of SB-756050 + sitagliptin were comparable to those of sitagliptin alone, even though gut hormone plasma profiles were different. This study was registered at ClinicalTrials.gov (NCT00733577).

  16. Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials

    PubMed Central

    Miyasaka, Nobuyuki; Kawai, Shinichi; Yuasa, Hirotoshi; Yamashita, Noriaki; Sugiyama, Noriko; Wagerle, Lorin Craig; Vlahos, Bonnie; Wajdula, Joseph

    2015-01-01

    Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA. PMID:24842477

  17. Pharmacokinetics and preliminary safety data of a single oral dose of bosentan, a dual endothelin receptor antagonist, in cats.

    PubMed

    Puza, N; Papich, M G; Reinero, C; Chang, C H; Yu, D-H; Sharp, C; DeClue, A

    2014-04-01

    The objective of this study was to evaluate the pharmacokinetic properties and adverse effect profile of single-dose oral bosentan, a dual endothelin receptor antagonist, in healthy cats. Pharmacokinetic parameters were determined following a single mean ± SD oral dose of 3.2 ± 0.6 mg/kg of bosentan in 6 adult cats. Blood was collected for quantification of bosentan via high-performance liquid chromatography with ultraviolet detection. Blood and urine were evaluated for CBC, plasma biochemical profile, and urinalysis, and repeat physical examinations were performed to evaluate for adverse effects. The mean terminal half-life of bosentan was 20.4 ± 17.2 h. The mean peak plasma concentration was 0.49 ± 0.24 g/mL, and the mean time to maximum plasma concentration was 6.8 ± 8.6 h. The area under the curve was 5.14 ± 3.81 h·μg/mL. Oral bosentan tablets were absorbed in cats, and no clinically important adverse events were noted. Further evaluation of repeat dosing, investigation into the in vivo efficacy of decreasing endothelin-1 concentrations in cats, as well as safety in conjunction with other medications is warranted.

  18. Effect of food on the pharmacokinetics of TAS-102 and its efficacy and safety in patients with advanced solid tumors.

    PubMed

    Yoshino, Takayuki; Kojima, Takashi; Bando, Hideaki; Yamazaki, Tomoko; Naito, Yoichi; Mukai, Hirofumi; Fuse, Nozomu; Goto, Koichi; Ito, Yuko; Doi, Toshihiko; Ohtsu, Atsushi

    2016-05-01

    TAS-102, a novel oral antitumor agent, consists of trifluridine and tipiracil hydrochloride (molar ratio, 1:0.5). We investigated the effects of food on trifluridine and tipiracil hydrochloride. The efficacy and safety of TAS-102 were evaluated in patients with advanced solid tumors. We analyzed drug pharmacokinetics using a randomized, single-dose, two-treatment (fed versus fasting), two-period, two-sequence cross-over design, followed by repeated administration. Patients were given single doses of TAS-102 (35 mg/m(2) ) in the pharmacokinetic phase and received twice-daily doses of TAS-102 in 28-day cycles in the repeated administration phase for evaluating efficacy and safety. Food showed no effect on the area under the curve from 0 to 12 h or 0 h-infinity values of trifluridine following administration of TAS-102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased by approximately 40%. Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption and bioavailability of trifluridine and tipiracil hydrochloride, respectively. During the repeated administration, stable disease was observed in nine patients with rectal, small-cell lung, breast, thymic, duodenal, and prostate cancers. Major adverse events were neutropenia, leukopenia, anemia, and nausea. Postprandial administration was optimal for TAS-102 because trifluridine's area under the curve was not changed by food, indicating that its clinical efficacy would not be affected. Additionally, postprandial administration was reasonable because the maximum concentration of trifluridine decreased in neutrophils, which correlated with previous studies. These results suggest that TAS-102 would be an effective treatment for small-cell lung, thymic, and colorectal cancers. This trial is registered with the Japan Pharmaceutical Information Center (no. JapicCTI-111482). © 2016 The Authors. Cancer Science published by John Wiley & Sons

  19. Safety and Population Pharmacokinetic Analysis of Intravenous Acetaminophen in Neonates, Infants, Children, and Adolescents With Pain or Fever

    PubMed Central

    Zuppa, Athena F.; Hammer, Gregory B.; Barrett, Jeffrey S.; Kenney, Brian F.; Kassir, Nastya; Mouksassi, Samer; Royal, Mike A.

    2011-01-01

    OBJECTIVES The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. METHODS Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to <2 years), children (2 to <12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. RESULTS Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. CONCLUSIONS Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration. PMID:22768009

  20. Safety and population pharmacokinetic analysis of intravenous acetaminophen in neonates, infants, children, and adolescents with pain or Fever.

    PubMed

    Zuppa, Athena F; Hammer, Gregory B; Barrett, Jeffrey S; Kenney, Brian F; Kassir, Nastya; Mouksassi, Samer; Royal, Mike A

    2011-10-01

    The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to <2 years), children (2 to <12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration.

  1. Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration

    PubMed Central

    Peters-Strickland, Timothy; Nylander, Anna-Greta; Baker, Ross A.; Eramo, Anna; Jin, Na; Bricmont, Patricia; Repella, Jennifer; McQuade, Robert D.; Hertel, Peter; Larsen, Frank

    2017-01-01

    Abstract Background: Two open-label, randomized, parallel-arm studies compared pharmacokinetics, safety, and tolerability of aripiprazole once-monthly 400 mg following deltoid vs gluteal injection in patients with schizophrenia. Methods: In the single-dose study, 1 injection of aripiprazole once-monthly 400 mg in the deltoid (n=17) or gluteal (n=18) muscle (NCT01646827) was administered. In the multiple-dose study, the first aripiprazole once-monthly 400 mg injection was administered in either the deltoid (n=71) or gluteal (n=67) muscle followed by 4 once-monthly deltoid injections (NCT01909466). Results: After single-dose administration, aripiprazole exposure (area under the concentration-time curve) was similar between deltoid and gluteal administrations, whereas median time to maximum plasma concentration was shorter (7.1 [deltoid] vs 24.1 days [gluteal]) and maximum concentration was 31% higher after deltoid administration. In the multiple-dose study, median time to maximum plasma concentration for deltoid administration was shorter (3.95 vs 7.1 days), whereas aripiprazole mean trough concentrations, maximum concentration, and area under the concentration-time curve were comparable between deltoid and gluteal muscles (historical data comparison). Multiple-dose pharmacokinetic results for the major metabolite, dehydro-aripiprazole, followed a similar pattern to that of the parent drug for both deltoid and gluteal injection sites. Safety and tolerability profiles were similar after gluteal or deltoid injections. Based on observed data, minimum aripiprazole concentrations achieved by aripiprazole once-monthly 400 mg are comparable with those of oral aripiprazole 15 to 20 mg/d. Conclusions: The deltoid muscle is a safe alternative injection site for aripiprazole once-monthly 400 mg in patients with schizophrenia. PMID:28204607

  2. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults.

    PubMed

    Ledgerwood, J E; Coates, E E; Yamshchikov, G; Saunders, J G; Holman, L; Enama, M E; DeZure, A; Lynch, R M; Gordon, I; Plummer, S; Hendel, C S; Pegu, A; Conan-Cibotti, M; Sitar, S; Bailer, R T; Narpala, S; McDermott, A; Louder, M; O'Dell, S; Mohan, S; Pandey, J P; Schwartz, R M; Hu, Z; Koup, R A; Capparelli, E; Mascola, J R; Graham, B S

    2015-12-01

    VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing HIV-1 monoclonal antibody (mAb) isolated from the B cells of an HIV-infected patient. It is directed against the HIV-1 CD4 binding site and is capable of potently neutralizing the majority of diverse HIV-1 strains. This Phase I dose-escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose-limiting toxicities. Mean 28-day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5-40 mg/kg i.v. dose range (n = 18), the clearance was 0.016 l/h and terminal half-life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half-life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV-1 prevention efficacy studies.

  3. A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients.

    PubMed

    Kanai, Masashi; Otsuka, Yoshihiko; Otsuka, Kazunori; Sato, Maremi; Nishimura, Takafumi; Mori, Yukiko; Kawaguchi, Michiya; Hatano, Etsuro; Kodama, Yuzo; Matsumoto, Shigemi; Murakami, Yoshiki; Imaizumi, Atsushi; Chiba, Tsutomu; Nishihira, Jun; Shibata, Hiroyuki

    2013-06-01

    A growing number of preclinical studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clinical application. To overcome this problem, we developed a new form of curcumin (Theracurmin) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin in cancer patients. Pancreatic or biliary tract cancer patients who failed standard chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin containing 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin was orally administered every day with standard gemcitabine-based chemotherapy. In addition to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated. Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin administration were 324 ng/mL (range, 47-1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179-1,380 ng/mL) at Level 2. No unexpected adverse events were observed and 3 patients safely continued Theracurmin administration for >9 months. Repetitive systemic exposure to high concentrations of curcumin achieved by Theracurmin did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.

  4. Comparison of Pharmacokinetics and Safety of Voriconazole Intravenous-to-Oral Switch in Immunocompromised Adolescents and Healthy Adults ▿

    PubMed Central

    Driscoll, Timothy A.; Frangoul, Haydar; Nemecek, Eneida R.; Murphey, Donald K.; Yu, Lolie C.; Blumer, Jeffrey; Krance, Robert A.; Baruch, Alice; Liu, Ping

    2011-01-01

    The current voriconazole dosing recommendation in adolescents is based on limited efficacy and pharmacokinetic data. To confirm the appropriateness of dosing adolescents like adults, a pharmacokinetic study was conducted in 26 immunocompromised adolescents aged 12 to <17 years following intravenous (IV) voriconazole to oral switch regimens: 6 mg/kg IV every 12 h (q12h) on day 1 followed by 4 mg/kg IV q12h, then switched to 300 mg orally q12h. Area under the curve over a 12-hour dosing interval (AUC0–12) was calculated using a noncompartmental method and compared to the value for adults receiving the same dosing regimens. On average, the AUC0–12 in adolescents after the first loading dose on day 1 and at steady state during IV treatment were 9.14 and 22.4 μg·h/ml, respectively (approximately 34% and 36% lower, respectively, than values for adults). At steady state during oral treatment, adolescents also had lower average exposure than adults (16.7 versus 34.0 μg·h/ml). Larger intersubject variability was observed in adolescents than in adults. There was a slight trend for some young adolescents with low body weight to have lower voriconazole exposure. It is likely that these young adolescents may metabolize voriconazole more similarly to children than to adults. Overall, with the same dosing regimens, voriconazole exposures in the majority of adolescents were comparable to those in adults. The young adolescents with low body weight during the transitioning period from childhood to adolescence (e.g., 12 to 14 years old) may need to receive higher doses to match the adult exposures. Safety of voriconazole in adolescents was consistent with the known safety profile of voriconazole. PMID:21911570

  5. Dose comparison of conivaptan (Vaprisol®) in patients with euvolemic or hypervolemic hyponatremia – efficacy, safety, and pharmacokinetics

    PubMed Central

    Palmer, Biff F; Rock, Amy D; Woodward, Emily J

    2016-01-01

    Purpose This study aimed to evaluate the efficacy, safety, and pharmacokinetics of 20 and 40 mg/day conivaptan (Vaprisol®) in patients with hypervolemic or euvolemic hyponatremia. Methods Hyponatremic patients – serum sodium (sNa) ≤130 mEq/L – received either 20 or 40 mg/day of conivaptan for 4 days, following an initial 20 mg loading dose. Efficacy was evaluated by the magnitude and extent of change in sNa. Safety was evaluated by the incidence of adverse events, changes in vital signs and laboratory parameters, rate of sNa correction, and frequency of infusion-site reactions. Pharmacokinetic parameters were also measured. Results A total of 37 patients received 20 mg/day and 214 patients received 40 mg/day conivaptan. Baseline-adjusted sNa-area under the concentration–time curve increased by an average of 753.8±499.9 mEq·hr/L (20 mg/day) and 689.2±417.3 mEq·hr/L (40 mg/day) over the course of the 4-day treatment period. The majority of patients in both treatment groups achieved a 4 mEq/L increase in sNa over baseline in ~24 hours (82.5%). Average increase in sNa after 4 days was ~10 mEq/L, varying with dosage level and baseline volume status. Treatment success (normal sNa or increase of ≥6 mEq/L) was attained by 70.3% of patients in the 20 mg/day group and 72.0% in the 40 mg/day group. Conclusion Both 20 and 40 mg/day doses of conivaptan are efficacious in increasing sNa over 4 days of treatment with no observed increase in the frequency of adverse events or specific infusion-site reactions using the higher dose. The pharmacokinetic parameters of both doses were similar to what has been reported previously, exhibiting greater-than-dose-proportional plasma concentrations. PMID:26848258

  6. Intravenous topiramate: safety and pharmacokinetics following a single dose in patients with epilepsy or migraines taking oral topiramate.

    PubMed

    Clark, Anne M; Kriel, Robert L; Leppik, Ilo E; White, James R; Henry, Thomas R; Brundage, Richard C; Cloyd, James C

    2013-06-01

    Although topiramate is widely prescribed for epilepsy and migraine, there is no intravenous product. We have developed an injectable topiramate formulation in which the drug is solubilized in a cyclodextrin matrix, Captisol(®) (Ligand Pharmaceuticals, Inc., La Jolla, CA). Our long-term goal is to evaluate intravenous topiramate for the treatment of neonatal seizures. Prior to studies in newborns, we carried out an investigation of injectable topiramate's safety and pharmacokinetics in adult patients. Twenty adult volunteers with epilepsy or migraine on stable, on maintenance topiramate therapy were given 25 mg of a stable-labeled intravenous topiramate over 10 min, followed by their usual oral doses. Vital signs were taken, electrocardiography studies (ECGs) were recorded, and the infusion sites were periodically examined prior to and up to 24 h after dosing. Blood samples were collected prior to administration and serially for 96 h thereafter. Plasma concentrations of both stable-labeled and regular topiramate were measured using liquid chromatography-mass spectrometry (LC-MS). Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2 (Pharsight Corporation, Mountain View, CA, U.S.A.). Seven patients experienced one or more of the following minor adverse events including nausea and vomiting (1), tingling around the lips (1), paresthesia in the arms and legs (1), and a mild vasovagal response with intravenous catheter placement (1). Included in the adverse events were four patients with epilepsy who had seizures consistent with their histories. There were no changes in heart rate, blood pressure, or ECG results, and there were no infusion site reactions. Pharmacokinetic parameters (mean ± standard deviation [SD]) determined following the intravenous dose included absolute bioavailability: 110 ± 16%, distribution volume: 0.79 ± 0.22 L/kg, clearance: 2.03 ± 1.07 L/h, and elimination half-life: 27.6 ± 9.7 h. Distribution volume

  7. A pharmacokinetic and safety study of a fixed oral dose of enzastaurin HCl in native Chinese patients with refractory solid tumors and lymphoma

    PubMed Central

    Li, Su; Zhang, Weijing; Yang, Nong; Cui, Yimin; Huang, He; Cai, Ruiqing; Lin, Xiaoting; Fu, Xiaohong; Hong, Huangming; Lin, Tongyu

    2016-01-01

    Purpose This study was conducted to assess the pharmacokinetics and safety of enzastaurin in native Chinese patients with refractory solid tumors and lymphoma. Methods Eligible patients received 500 mg of enzastaurin orally once daily. The pharmacokinetics of enzastaurin and its metabolites were assessed on days 14 to 18. Patients were allowed to continue receiving the agent in a safety extension phase until disease progression or presentation with unacceptable toxicity. Results Twenty-five patients received at least 1 dose of enzastaurin, and twenty-one patients completed the pharmacokinetic phase. Fifteen patients entered the safety extension phase. Except for transient, asymptomatic grade 3 QT interval prolongation in one patient who had baseline grade 2 QT prolongation, other adverse events were of grade 1 to 2. The t1/2, Cav, ss, and AUCτ, ss for enzastaurin and its primary active metabolite LSN326020 were 14 and 42 h, 1,210 and 907 nmol/L, and 29,100 and 21,800 nmol•h/L, respectively. One patient with relapsed diffuse large B-cell lymphoma achieved a partial response that lasted for 8.1 months. Conclusions The pharmacokinetics of enzastaurin in Chinese cancer patients were consistent with those observed in previous studies abroad. Enzastaurin 500 mg daily was well tolerated by Chinese patients. We recommend 500 mg daily as the phase II dose in this population. Its efficacy in lymphoma deserves further investigation. Trial Registration ClinicalTrials.gov: NCT01432951 PMID:26942463

  8. A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload

    PubMed Central

    Rienhoff, Hugh Young; Viprakasit, Vip; Tay, Lay; Harmatz, Paul; Vichinsky, Elliott; Chirnomas, Deborah; Kwiatkowski, Janet L.; Tapper, Amy; Kramer, William; Porter, John B.; Neufeld, Ellis J.

    2011-01-01

    Background There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator. Design and Methods This phase 1b dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload, was conducted in 16 adult patients with iron overloaded consequent to transfusions. FBS0701 was given daily for 7 days at doses up to 32 mg/kg and was well tolerated at all dose levels. Results Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (Cmax) was reached within 60–90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t1/2) was approximately 19 hours. There were no serious adverse events associated with the drug. Conclusions On the basis of these safety and pharmacokinetic data, FBS0701 warrants further clinical evaluation in patients with transfusional iron overload. (Clinicaltrials.gov identifier: NCT01186419) PMID:21173101

  9. The effects of renal impairment on the pharmacokinetics, safety, and tolerability of naloxegol.

    PubMed

    Bui, Khanh; She, Fahua; Sostek, Mark

    2014-12-01

    The impact of renal impairment on the pharmacokinetics of a 25-mg oral dose of naloxegol was examined in patients with renal impairment classified as moderate, severe, or end-stage renal disease (ESRD) and compared with healthy subjects (n = 8/group). Geometric mean area under the plasma concentration-time curve (AUC) was increased in patients with moderate (1.7-fold) or severe (2.2-fold) impairment, and maximum plasma concentrations (Cmax ) were elevated in patients with moderate (1.1-fold) or severe (1.8-fold) impairment. These findings were driven by higher exposures in two patients in each of the moderate and severe impairment groups; exposures in all other patients were similar to the control group. Overall exposures in ESRD patients were similar and Cmax was 29% lower versus normal subjects. Renal impairment minimally affected other plasma pharmacokinetic parameters. As renal clearance was a minor component of total clearance, exposure to naloxegol was unaffected by the degree of renal impairment, with no correlation between either AUC or Cmax and estimated glomerular filtration rate (eGFR). Hemodialysis was an ineffective means to remove naloxegol. Naloxegol was generally well tolerated in all groups. Renal impairment could adversely affect clearance by hepatic and gut metabolism, resulting in the increased exposures observed in outliers of the moderate and severe renal impairment groups.

  10. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers.

    PubMed

    Spence, Rebecca; Mandagere, Arun; Dufton, Christopher; Venitz, Jürgen

    2008-12-01

    The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and ambrisentan, an ET(A)-selective, propanoic acid-based endothelin receptor antagonist (ERA), was studied in a 2-period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC(0-infinity)) and maximum plasma concentration (C(max)) determined over 24 hours for a 10-mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily. The AUC(0-infinity) and C(max) for sildenafil and N-desmethyl sildenafil (active metabolite) were determined over 24 hours for a 20-mg dose of sildenafil alone and again after 7 days of dosing with ambrisentan 10 mg once daily. There was no clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil or N-desmethyl sildenafil. Ambrisentan C(max) was unchanged (96.3% [90% confidence interval: 86.0%-107.8%]), with a minor increase in AUC(0-infinity) (108.5% [102.6%-111.7%]) with sildenafil coadministration. Sildenafil C(max) was increased slightly (113.4% [99.6%-129.1%]), and AUC(0-infinity) was unchanged (98.7% [91.2%-110.5%]) with ambrisentan coadministration. N-desmethyl sildenafil was unaltered. Dose adjustment of either drug is not necessary compared with administration alone.

  11. Clinical Trial with Sodium (99m)Tc-Pertechnetate Produced by a Medium-Energy Cyclotron: Biodistribution and Safety Assessment in Patients with Abnormal Thyroid Function.

    PubMed

    Selivanova, Svetlana V; Lavallée, Éric; Senta, Helena; Caouette, Lyne; McEwan, Alexander J B; Guérin, Brigitte; Lecomte, Roger; Turcotte, Éric

    2017-05-01

    A single-site prospective open-label clinical study with cyclotron-produced sodium (99m)Tc-pertechnetate ((99m)Tc-NaTcO4) was performed in patients with indications for a thyroid scan to demonstrate the clinical safety and diagnostic efficacy of the drug and to confirm its equivalence with conventional (99m)Tc-NaTcO4 eluted from a generator. Methods:(99m)Tc-NaTcO4 was produced from enriched (100)Mo (99.815%) with a cyclotron (24 MeV; 2 h of irradiation) or supplied by a commercial manufacturer (bulk vial eluted from a generator). Eleven patients received 325 ± 29 (mean ± SD) MBq of the cyclotron-produced (99m)Tc-NaTcO4, whereas the age- and sex-matched controls received a comparable amount of the generator-derived tracer. Whole-body and thyroid planar images were obtained for each participant. In addition to the standard-energy window (140.5 keV ± 7.5%), data were acquired in lower-energy (117 keV ± 10%) and higher-energy (170 keV ± 10%) windows. Vital signs and hematologic and biochemical parameters were monitored before and after tracer administration. Results: Cyclotron-produced (99m)Tc-NaTcO4 showed organ and whole-body distributions identical to those of conventional (99m)Tc-NaTcO4 and was well tolerated. All images led to a clear final diagnosis. The fact that the number of counts in the higher-energy window was significantly higher for cyclotron-produced (99m)Tc-NaTcO4 did not influence image quality in the standard-energy window. Image definition in the standard-energy window with cyclotron-produced (99m)Tc was equivalent to that with generator-eluted (99m)Tc and had no particular features allowing discrimination between the (99m)Tc production methods. Conclusion: The systemic distribution, clinical safety, and imaging efficacy of cyclotron-produced (99m)Tc-NaTcO4 in humans provide supporting evidence for the use of this tracer as an equivalent for generator-eluted (99m)Tc-NaTcO4 in routine clinical practice. © 2017 by the Society of Nuclear Medicine

  12. Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion

    PubMed Central

    2012-01-01

    Background CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time. Methods A phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab. Results No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies. Conclusions This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000). PMID:23171508

  13. Lymphatic Biodistribution of Polylactide Nanoparticles

    PubMed Central

    Chaney, Eric J.; Tang, Li; Tong, Rong; Cheng, Jianjun; Boppart, Stephen A.

    2013-01-01

    Tumor metastases occur through both the cardiovascular and lymphatic circulations. However, the majority of nanoparticle biodistribution studies have been focused on the cardiovascular circulation. In this study, we report the formulation of Cy5-labeled polylactide (Cy5-PLA) nanoparticles with controlled size and surface features and the subsequent evaluation of their lymphatic biodistribution. Cy5-PLA nanoparticles were formulated through Cy5/(BDI)ZnN(TMS)2-mediated [(BDI) = 2-((2,6-diisopropylphenyl) amido)-4-((2,6-diisopropylphenyl)-imino)-2-pentene] ring-opening polymerization of lactide followed by nanoprecipitation. Their lymphatic biodistribution was evaluated by using whole-body fluorescence imaging of nude mice and ex vivo fluorescence imaging of the resected organs. This technique has the potential for providing optical contrast and drug delivery through the lymphatic circulation for the treatment of metastatic cancer. PMID:20487681

  14. Improved Safety, Bioavailability and Pharmacokinetics of Zidovudine through Lactoferrin Nanoparticles during Oral Administration in Rats.

    PubMed

    Kumar, Prashant; Lakshmi, Yeruva Samrajya; C, Bhaskar; Golla, Kishore; Kondapi, Anand K

    2015-01-01

    Zidovudine (AZT) is one of the most referred antiretroviral drug. In spite of its higher bioavailability (50-75%) the most important reason of its cessation are bone marrow suppression, anemia, neutropenia and various organs related toxicities. This study aims at the improvement of oral delivery of AZT through its encapsulation in lactoferrin nanoparticles (AZT-lactonano). The nanoparticles (NPs) are of 50-60 nm in size and exhibit 67% encapsulation of the AZT. They are stable in simulated gastric and intestinal fluids. Anti-HIV-1 activity of AZT remains unaltered in nanoformulation in acute infection. The bioavailability and tissue distribution of AZT is higher in blood followed by liver and kidney. AZT-lactonano causes the improvement of pharmacokinetic profile as compared to soluble AZT; a more than 4 fold increase in AUC and AUMC in male and female rats. The serum Cmax for AZT-lactonano was increased by 30%. Similarly there was nearly 2-fold increase in Tmax and t1/2. Our in vitro study confirms that, the endosomal pH is ideal for drug release from NPs and shows constant release from up to 96h. Bone marrow micronucleus assay show that nanoformulation exhibits approximately 2fold lower toxicity than soluble form. Histopathological and biochemical analysis further confirms that less or no significant organ toxicities when nanoparticles were used. AZT-lactonano has shown its higher efficacy, low organs related toxicities, improved pharmacokinetics parameter while keeping the antiviral activity intact. Thus, the nanoformulation are safe for the target specific drug delivery.

  15. Analgesics in Pregnancy: An Update on Use, Safety and Pharmacokinetic Changes in Drug Disposition.

    PubMed

    Price, Hayley R; Collier, Abby C

    2017-08-25

    Although medications should only be prescribed in pregnancy if benefits to the mother outweigh the risk to the fetus, drug use in pregnancy especially prescribed and over-the-counter analgesics, is very common. The objective of this review is to present an update on known changes in analgesic disposition in pregnancy caused by pharmacokinetic mechanisms. Herein, we discuss a wide range of medical, biomedical and scientific literature that includes reports from the fields of dentistry, general medicine, obstetrics and gynecology, pharmacology and toxicology to provide an update on the use (including indications, contraindications and concerns) of major classes of analgesics during human pregnancy. Over 50% of analgesics are in pregnancy category C, and even more category D specifically in the third trimester. Changes in renal filtration, cardiac output, plasma protein concentration and plasma volume particularly affect analgesics and dose adjustments may be necessary to maintain therapeutic concentrations in pregnant woman, and/or to protect the developing fetus. Analgesics are one of the most frequently used drug classes in pregnancy. More than 60% of women self-report using analgesics while pregnant, both prescribed and by self-medication. For the majority of analgesics available (excepting acetaminophen and the NSAIDs, and to a lesser extent certain opioids), good prospective clinical trials documenting pharmacokinetic changes do not exist. More research is needed in both the scientific and clinical community to understand the risks and benefits of analgesic use in pregnancy, particularly as prevalence is rising. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Pharmacokinetics and safety of ceftiofur crystalline free acid in New Zealand White rabbits (Oryctolagus cuniculus).

    PubMed

    Gardhouse, Sara; Guzman, David Sanchez-Migallon; Cox, Sherry; Kass, Philip H; Drazenovich, Tracy L; Byrne, Barbara A; Hawkins, Michelle G

    2017-07-01

    OBJECTIVE To determine the pharmacokinetics and adverse effects following SC administration of ceftiofur crystalline free acid (CCFA) in New Zealand White rabbits. ANIMALS 6 adult sexually intact female New Zealand White rabbits. PROCEDURES Each rabbit was administered 40 mg of CCFA/kg SC. A blood sample was obtained immediately before (0 minutes), at 5 and 30 minutes after, and at 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 95, 120, 144, and 168 hours after administration, and plasma concentrations of ceftiofur free acid equivalents (CFAE) were measured. Pharmacokinetic parameters were calculated. For each rabbit, body weight, food consumption, fecal output, and injection site were monitored. Minimum inhibitory concentrations of ceftiofur for 293 bacterial isolates from rabbit clinical samples were determined. RESULTS Mean ± SD peak plasma concentration of CFAE and time to maximum plasma concentration were 33.13 ± 10.15 μg/mL and 1.75 ± 0.42 hours, respectively. The mean terminal half-life of CFAE was 42.6 ± 5.2 hours. Plasma CFAE concentration was > 4 μg/mL for approximately 24 hours and > 1 μg/mL for at least 72 hours after CCFA administration. An apparently nonpainful subcutaneous nodule developed at the injection site in 3 of 6 rabbits. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that CCFA (40 mg/kg) could be administered SC every 24 to 72 hours to New Zealand White rabbits to treat infections with ceftiofur-susceptible bacteria. Single-dose administration of CCFA resulted in minimal adverse effects. Additional studies are needed to evaluate the effects of repeated CCFA administration in New Zealand White rabbits.

  17. Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

    PubMed

    Han, Yi; Ayalasomayajula, Surya; Pan, Wei; Yang, Fan; Yuan, Yaozong; Langenickel, Thomas; Hinder, Markus; Kalluri, Sampath; Pal, Parasar; Sunkara, Gangadhar

    2017-02-01

    Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last), and maximum plasma concentration (C max) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

  18. Safety, Pharmacokinetics, Pharmacodynamics, and Plasma Lipoprotein Distribution of Eritoran (E5564) during Continuous Intravenous Infusion into Healthy Volunteers

    PubMed Central

    Rossignol, Daniel P.; Wasan, Kishor M.; Choo, Eugene; Yau, Edwin; Wong, Nancy; Rose, Jeffrey; Moran, Jeffrey; Lynn, Melvyn

    2004-01-01

    Eritoran, a structural analogue of the lipid A portion of lipopolysaccharide (LPS), is an antagonist of LPS in animal and human endotoxemia models. Previous studies have shown that low doses (350 to 3,500 μg) of eritoran have demonstrated a long pharmacokinetic half-life but a short pharmacodynamic half-life. The present study describes the safety, pharmacokinetics and pharmacodynamics, and lipid distribution profile of eritoran during and after a 72-h intravenous infusion of 500, 2,000, or 3,500 μg/h into healthy volunteers. Except for the occurrence of phlebitis, eritoran administration over 72 h was safe and well tolerated. Eritoran demonstrated a slow plasma clearance (0.679 to 0.930 ml/h/kg of body weight), a small volume of distribution (45.6 to 49.8 ml/kg), and a relatively long half-life (50.4 to 62.7 h). In plasma, the majority (∼55%) of eritoran was bound to high-density lipoproteins. During infusion and for up to 72 h thereafter, ex vivo response of blood to 1- or 10-ng/ml LPS was inhibited by ≥85%, even when the lowest dose of eritoran (500 μg/h) was infused. Inhibition of response was dependent on eritoran dose and the concentration of LPS used as an agonist. Finally, in vitro analysis with purified lipoprotein and protein fractions from plasma obtained from healthy volunteers indicated that eritoran is inactivated by high-density but not low-density lipoproteins, very-low-density lipoproteins, or albumin. From these results, we conclude that up to 252 mg of eritoran can be safely infused into normal volunteers over 72 h and even though it associates extensively with high-density lipoproteins, antagonistic activity is maintained, even after infusion ceases. PMID:15328078

  19. Pharmacokinetic and safety evaluation of the use of ciprofloxacin on an isoniazid-rifampicin regimen in rabbits.

    PubMed

    Padilha, Elias Carvalho; Pires, Rodrigo Vieira; Filho, Marco Antonio Ferraz Nogueira; de Pontes Machado, Diego Vinicius; Baldan, Helen Mariana; Davanço, Marcelo Gomes; Campos, Michel Leandro; Brunetti, Iguatemy Lourenço; Peccinini, Rosângela Gonçalves

    2012-12-01

    The combination of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR) is used in the treatment of tuberculosis. Although this treatment is effective in most clinical cases, the side-effects and the development of mycobacterium resistance have hindered its success. There is evidence that the combination of INH, RMP and ciprofloxacin (CIPRO) is useful in the treatment of tuberculosis. However, the influence of this drug combination on the hepatotoxicity of INH is unknown. In this study, the safety of combined INH, RMP and CIPRO was evaluated. Male albino rabbits (n = 20) were divided into four groups and subjected to multiple oral doses for 7 days according to the following treatments: water (group 1); 50 mg/kg INH (group 2); 50 mg/kg INH + 100 mg/kg RMP (group 3) and 50 mg/kg INH + 100 mg/kg RMP + 50 mg/kg CIPRO (group 4). Blood samples were taken before and after treatments for the determination of ALT, AST, ALP and bilirubin to assess hepatotoxicity. For pharmacokinetic analysis, serial blood samples were collected over 24 h on day 7 of treatment. Plasma concentrations of INH and acetylisoniazid (AcINH) were determined by HPLC. Biochemical parameters did not show any statistically significant differences between the groups that received the drug combinations. The pharmacokinetic profile of INH was also similar for both groups of combinations. These findings allow us to infer that the inclusion of CIPRO did not increase the risk of hepatotoxicity when compared with the classic combination of INH and RMP.

  20. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran.

    PubMed

    Glund, Stephan; Moschetti, Viktoria; Norris, Stephen; Stangier, Joachim; Schmohl, Michael; van Ryn, Joanne; Lang, Benjamin; Ramael, Steven; Reilly, Paul

    2015-05-01

    Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.

  1. Pharmacokinetics, Pharmacodynamics, Safety, and Clinical Activity of Multiple Doses of RCT-18 in Chinese Patients With Systemic Lupus Erythematosus.

    PubMed

    Zhao, Qian; Chen, Xia; Hou, Yong; Jiang, Ji; Zhong, Wen; Yao, Xuejing; Wang, Wenxiang; Li, Lin; Fang, Jianmin; Zhang, Fengchun; Hu, Pei

    2016-08-01

    RCT-18 is a novel recombinant fusion protein that blocks the activity of a B-lymphocyte stimulator and a proliferation-inducing ligand. This was a randomized, single-blind, and placebo-controlled phase 1 study in 12 patients with systemic lupus erythematosus. Eligible patients were randomized 3:1 to receive multiple subcutaneous doses of RCT-18 for 4 weeks (180 mg, once weekly) or placebo and monitored over an 84-day observation period for pharmacokinetics, pharmacodynamics, immunogenicity, safety, and clinical activity. After multiple-dose RCT-18, the maximal serum concentration (Cmax ) of total and free RCT-18 was reached within 1 to 2 days. Mean elimination half-life for total RCT-18 and free RCT-18 was 11.4 to 26.4 days and 2.4 to 26.5 days, respectively. Slight accumulation was found after multiple subcutaneous administrations. The average accumulation ratios of AUC and Cmax after the fourth administration of RCT-18 were 2.0 and 1.7 for total RCT-18, and 1.8 and 1.6 for free RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to Cmax of 14 to 46 days. Pharmacokinetic characteristics of RCT-18 in SLE patients were similar to those in patients with rheumatoid arthritis. No positive reaction was detected in the immunogenicity assessments. RCT-18 was biologically active, according to serum immunoglobulin and B-cell levels. Treatment-related IgM and IgA reduction was found during this study. CD19(+) , IgD(+) , and CD27(+) B-cell counts were increased after administration and decreased subsequently. SLE patients treated with RCT-18 were more prone to infections, including moderate and severe infections. Lower dosages of RCT-18 should be considered in further clinical development. © 2016, The American College of Clinical Pharmacology.

  2. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men

    PubMed Central

    Basaria, Shehzad; Collins, Lauren; Dillon, E. Lichar; Orwoll, Katie; Storer, Thomas W.; Miciek, Renee; Ulloor, Jagadish; Zhang, Anqi; Eder, Richard; Zientek, Heather; Gordon, Gilad; Kazmi, Syed; Sheffield-Moore, Melinda

    2013-01-01

    Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. Methods. In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should

  3. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men.

    PubMed

    Basaria, Shehzad; Collins, Lauren; Dillon, E Lichar; Orwoll, Katie; Storer, Thomas W; Miciek, Renee; Ulloor, Jagadish; Zhang, Anqi; Eder, Richard; Zientek, Heather; Gordon, Gilad; Kazmi, Syed; Sheffield-Moore, Melinda; Bhasin, Shalender

    2013-01-01

    Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. In this placebo-controlled study, 76 healthy men (21-50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone-binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function

  4. UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis.

    PubMed

    O'Brien, S H; Yee, D L; Lira, J; Goldenberg, N A; Young, G

    2015-09-01

    Direct thrombin inhibitors offer potential advantages over unfractionated heparin but have been poorly studied in children. To determine appropriate dosing of bivalirudin in children and adolescents and the relationship between activated partial thromboplastin time (APTT) and plasma bivalirudin concentration. The UNBLOCK (UtilizatioN of BivaLirudin On Clots in Kids) study was an open-label, single-arm, dose-finding, pharmacokinetic, safety and efficacy study of bivalirudin for the acute treatment of deep vein thrombosis (DVT) in children aged 6 months to 18 years. Drug initiation consisted of a bolus dose (0.125 mg kg(-1) ) followed by continuous infusion (0.125 mg kg h(-1) ). Dose adjustments were based on the APTT, targeting a range of 1.5-2.5 times each patient's baseline APTT. Safety was assessed by specific bleeding endpoints and efficacy by repeat imaging at 48-72 h and 25-35 days. Eighteen patients completed the study. Following the bolus dose and the initial infusion rate, most patients' APTT values were within the target range. The infusion rate bivalirudin correlated more closely with drug concentration than the APTT. At 48-72 h, nine (50%) patients had complete or partial thrombus resolution, increasing to 16 (89%) at 25-35 days. No major and one minor bleeding event occurred. Bivalirudin demonstrated reassuring safety and noteworthy efficacy in terms of early clot resolution in children and adolescents with DVT. Although a widely available and familiar monitoring tool, the APTT correlates poorly with plasma bivalirudin concentration, possibly limiting its utility in managing pediatric patients receiving bivalirudin for DVT. © 2015 International Society on Thrombosis and Haemostasis.

  5. Safety, Tolerability, and Pharmacokinetic Profile of the Novel Translocator Protein 18 kDa Antagonist ONO-2952 in Healthy Volunteers.

    PubMed

    Suto, Fumitaka; Wood, Andrew T; Kobayashi, Michiyoshi; Komaba, Junji; Duffy, Kevin; Bruce, Mark

    2015-09-01

    To investigate safety, tolerability, and pharmacokinetic properties of single and multiple doses of novel translocator protein 18 kDa antagonist ONO-2952 in healthy subjects. Double-blind, placebo-controlled single (SAD) and multiple (MAD) dose escalation studies were conducted. Healthy men and women aged 18 to 55 years inclusive and without history of psychiatric disorders were eligible. Forty-eight volunteers received single doses of ONO-2952 (3, 10, 30, 100, 200, or 400 mg) or placebo under fasted conditions (SAD study), and 36 received ONO-2952 (30, 60, or 100 mg/d) or placebo for 21 consecutive days under fed conditions (MAD study). ONO-2952 10 and 200 mg were administered under fasted and fed conditions in the SAD study to investigate the effect of food on the absorption of ONO-2952. Safety assessments included adverse events, vital signs, 12-lead ECGs, and clinical laboratory evaluations. Plasma and urine pharmacokinetic profiles of ONO-2952 were determined. Across both studies, mean age ranged from 29.8 to 39.8 years, most participants were white, and the proportion of female volunteers was 52%. No treatment or dose-related trends in adverse events were observed. The most frequent adverse events were headache and presyncope (n = 2 each [SAD study]) and constipation and headache (n = 3 each [MAD study]). All headache and constipation episodes were possibly related to the study drug. Plasma ONO-2952 concentrations peaked 2.5 to 3.5 hours (SAD study) and 3.0 to 4.0 hours (MAD study) postdose. ONO-2952 systemic exposure increased less than dose proportionally under fasted conditions. Fed conditions significantly increased exposure compared with fasted conditions: geometric mean ratios of Cmax (90% CIs) were 229% (176-299 [10 mg]) and 778% (623-971 [200 mg]), and AUClast were 159% (131-192 [10 mg]) and 382% (288-506 [200 mg]). In the MAD study, the systemic exposure of ONO-2952 increased in a slightly greater than dose-proportional manner. Geometric mean

  6. Preclinical Studies on the Pharmacokinetics, Safety and Toxicology of Oxfendazole: Toward First in Human Studies

    PubMed Central

    Codd, Ellen E.; Ng, Hanna H.; McFarlane, Claire; Riccio, Edward S.; Doppalapudi, Rupa; Mirsalis, Jon C.; Horton, R. John; Gonzalez, Armando E.; Garcia, H. Hugo; Gilman, Robert H.

    2015-01-01

    A two-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased WBC levels, a class effect of benzimidazole anthelminthics, returned to normal during the recovery period. The NOAEL was determined to be >5 but < 25 mg/kg/d and the MTD 100 mg/kg/d. The highest dose, 200 mg/kg/d resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after seven days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma or rat micronucleus assays, nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases. PMID:25701764

  7. Switching Opioid-Dependent Patients From Methadone to Morphine: Safety, Tolerability, and Methadone Pharmacokinetics.

    PubMed

    Glue, Paul; Cape, Gavin; Tunnicliff, Donna; Lockhart, Michelle; Lam, Fred; Gray, Andrew; Hung, Noelyn; Hung, C Tak; Harland, Sarah; Devane, Jane; Howes, John; Weis, Holger; Friedhoff, Lawrence

    2016-08-01

    The aim of this study was to switch patients established on methadone opioid substitution therapy (OST) to morphine over 1 week. Subjects established on daily methadone OST (mean dose 60 mg/day) were switched to morphine slow-release capsules, dosed at 4× the previous total daily methadone dose, for 6 days, then given morphine syrup dosed q3h. All 27 subjects enrolled in this study completed the switch from methadone to morphine. Opioid withdrawal symptoms (OWS) peaked within 12-24 hours of starting morphine, and 24/27 subjects required higher daily morphine doses (mean 5.2× multiple). Pharmacokinetic evaluation showed that 91% of methadone was cleared during this time, with a mean elimination half-life of 59 hours. The most frequent treatment-emergent non-OWS adverse events were headache, nausea, constipation, and neck pain. The method described here appears to be a safe and acceptable approach to switch subjects from methadone to morphine. © 2016, The American College of Clinical Pharmacology.

  8. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers.

    PubMed

    Dooley, K E; Bliven-Sizemore, E E; Weiner, M; Lu, Y; Nuermberger, E L; Hubbard, W C; Fuchs, E J; Melia, M T; Burman, W J; Dorman, S E

    2012-05-01

    Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AU C0–24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.

  9. Safety and Pharmacokinetics of Escalating Daily Doses of the Antituberculosis Drug Rifapentine in Healthy Volunteers

    PubMed Central

    Dooley, KE; Bliven-Sizemore, EE; Weiner, M; Lu, Y; Nuermberger, EL; Hubbard, WC; Fuchs, EJ; Melia, MT; Burman, WJ; Dorman, SE

    2013-01-01

    Rifapentine (RPT) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RIF). The maximal tolerated daily dose of RPT and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high as a prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RPT concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AUC0–24) and maximum concentration (Cmax) were similar in the 15- and 20-mg/kg cohorts. Although RPT pharmacokinetics (PK) appeared to be time-dependent, accumulation occurred with daily dosing. The mean AUC0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01). Changes in the oral clearance of MDZ did not vary by RPT dose. In conclusion, RPT was tolerated at doses as high as 20 mg/kg/day, its PK were less than dose-proportional, and its CYP3A induction was robust. PMID:22472995

  10. Effectiveness, safety, and pharmacokinetics of quetiapine in aggressive children with conduct disorder.

    PubMed

    Findling, Robert L; Reed, Michael D; O'Riordan, Mary Ann; Demeter, Christine A; Stansbrey, Robert J; McNamara, Nora K

    2006-07-01

    To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale (RAAPPS), Nisonger Child Behavior Rating Form (NCBRF), and the Conners Parent Rating Scale (CPRS-48). Blood sampling for PK analyses occurred at the end of weeks 2 and 8. Seventeen children (16 boys, mean age 8.9 years) were treated. The mean dose at week 8 was 4.4 mg/kg (SD = 1.1 mg/kg). Significant decreases in the baseline scores of the RAAPPS, and several subscales of the NCBRF and the CPRS were found by the end of the study (p <.05). No patients discontinued because of an adverse event. No patients experienced extrapyramidal side effects. Quetiapine disposition was linear over the dose range studied. The elimination half-life of the drug averaged 3.9 and 2.9 hours and total body clearance averaged 3.5 and 3.0 L/hr/kg after study weeks 2 and 8, respectively. These preliminary data suggest that aggressive children with CD may benefit from quetiapine. The PK of quetiapine supports twice-daily dosing in children with CD.

  11. Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection.

    PubMed

    Trachtman, H; Frymoyer, A; Lewandowski, A; Greenbaum, L A; Feig, D I; Gipson, D S; Warady, B A; Goebel, J W; Schwartz, G J; Lewis, K; Anand, R; Patel, U D

    2015-07-01

    Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options--including angiotensin-converting enzyme inhibitors--are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m(2)), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥ 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations. © 2015 American Society for Clinical Pharmacology and Therapeutics.

  12. Comparison of pharmacokinetics and safety of pegfilgrastim administered by two delivery methods: on-body injector and manual injection with a prefilled syringe.

    PubMed

    Yang, Bing-Bing; Morrow, Phuong Khanh; Wu, Xikun; Moxness, Michael; Padhi, Desmond

    2015-06-01

    For patients with clinically significant risk of febrile neutropenia, pegfilgrastim administration should occur the day after myelosuppressive chemotherapy; however, a variety of factors may preclude patients from returning to the clinic the next day for pegfilgrastim administration, necessitating other strategies. This study compared the pharmacokinetics and safety of pegfilgrastim administered via an on-body injector applied to the subject's skin versus manual injection using a prefilled syringe. Healthy subjects aged 18-50 years were randomized 1:1 to receive a single 6-mg subcutaneous pegfilgrastim dose from an on-body injector or a prefilled syringe. Blood for pharmacokinetic measurements was collected at baseline and prespecified time points after pegfilgrastim administration; safety was assessed throughout the 6-week study. Primary endpoints were maximum concentration (C max) and area under the concentration curve from time 0 to infinity (AUC0-inf). Secondary endpoints included safety, tolerability, and immunogenicity. Pegfilgrastim mean AUC0-inf values for the on-body injector (n = 125) and manual injection (n = 128) were 10,900 and 11,100 h ng/mL, respectively; mean C max values were 248 and 262 ng/mL, respectively. The least squares geometric mean ratios were 0.97 for C max and 1.00 for AUC0-inf; the corresponding 90 % CIs were within the prespecified range (0.80-1.25), indicating comparable pegfilgrastim pharmacokinetics between delivery methods. Treatment-emergent adverse events (AEs) were similar between groups (injector, 86 %; manual, 85 %). Injector- or syringe-related AEs were more prevalent with the injector (13 %; manual, 4 %); none were serious. No pegfilgrastim-neutralizing antibodies were detected. Pegfilgrastim pharmacokinetics and safety were comparable between the on-body injector and manual injection groups.

  13. Pharmacokinetics and safety of olopatadine hydrochloride 0.77% in healthy subjects with asymptomatic eyes: data from 2 independent clinical studies.

    PubMed

    Meier, Edward; Narvekar, Abhijit; Iyer, Ganesh R; DuBiner, Harvey B; Vutikullird, Apinya; Wirta, David; Sall, Kenneth

    2017-01-01

    To assess the pharmacokinetics and safety of hydrochloride ophthalmic solution 0.77% olopatadine from 2 independent (Phase I and Phase III, respectively) clinical studies in healthy subjects. The Phase I, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥18 years old (N=36) to assess the systemic pharmacokinetics of olopatadine 0.77% following single- and multiple-dose exposures. The Phase III, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥2 years old (N=499) to evaluate long-term ocular safety of olopatadine 0.77%. Subjects received olopatadine 0.77% or vehicle once daily bilaterally for 7 days in the pharmacokinetic study and 6 weeks in the safety study. In the pharmacokinetic study, olopatadine 0.77% was absorbed slowly and reached a peak plasma concentration (Cmax) of 1.65 ng/mL following single-dose and 1.45 ng/mL following multiple-dose exposures in 2 hours (time to reach maximum plasma concentration [Tmax]). After reaching peak concentrations, olopatadine showed a similar mono-exponential decay following single and multiple doses with mean elimination half-life ranging from 2.90 to 3.40 hours. No accumulation in olopatadine exposure (Cmax and area under the plasma concentration-time curve from 0 to 12 hours) was evident after multiple doses when compared to single dose. In the safety study, treatment-emergent adverse events were reported in 26.7% and 31.4% of subjects with olopatadine 0.77% and vehicle, respectively. Blurred vision was the most frequent ocular treatment-emergent adverse event in both treatment groups (olopatadine 0.77% vs vehicle, 4.8% vs 4.1%). No deaths or serious adverse events were reported during the study. Olopatadine 0.77% had minimal systemic exposure or accumulation in healthy subjects and was well tolerated in both adult and pediatric subjects.

  14. Safety and Biosimilarity of ior(®)LeukoCIM Compared to Neupogen(®) Based on Toxicity, Pharmacodynamic, and Pharmacokinetic Studies in the Sprague-Dawley Rat.

    PubMed

    Licollari, Albert; Riddle, Katherine; Taylor, Simon R; Ledon, Nuris; Bolger, Gordon T

    2017-02-24

    This study examined the safety, pharmacodynamic and pharmacokinetic similarity of the human recombinant filgrastim products ior(®)LeukoCIM and Neupogen(®) following a 28-day repeated subcutaneous dose administration in male and female Sprague-Dawley rats with a 14-day recovery period. Safety profiling was based on clinical observations, clinical pathology, and pathology findings for control rats dosed with vehicle and rats dosed either with 15, 75, and 150 μg/kg of ior(®)LeukoCIM or with 150 μg/kg of Neupogen(®). The major adverse treatment-related clinical finding was mild to severe swelling of the hock-joint (tarsal joint) and hind limb, alone or accompanied with lameness which was more prominent in males and which had a similar frequency of occurrence for both ior(®)LeukoCIM and Neupogen(®). All adverse findings were fully reversible. As expected, ior(®)LeukoCIM and Neupogen(®) both increased white blood cell and neutrophil levels in rats and to a similar extent for high-dose ior(®)LeukoCIM and Neupogen(®). The pharmacokinetics of filgrastim following dosing with ior(®)LeukoCIM were well behaved and comparable for high-dose ior(®)LeukoCIM and Neupogen(®). The results of this study imply that ior(®)LeukoCIM and Neupogen(®) had similar safety profiles, pharmacodynamic responses, and pharmacokinetic profiles that suggest they are biosimilar.

  15. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis

    PubMed Central

    Yoo, Dae Hyun; Suh, Chang-Hee; Shim, Seung Cheol; Jeka, Slawomir; Cons-Molina, Francisco Fidencio; Hrycaj, Pawel; Wiland, Piotr; Lee, Eun Young; Medina-Rodriguez, Francisco G; Shesternya, Pavel; Radominski, Sebastiao; Stanislav, Marina; Kovalenko, Volodymyr; Sheen, Dong Hyuk; Myasoutova, Leysan; Lim, Mie Jin; Choe, Jung-Yoon; Lee, Sang Joon; Lee, Sung Young; Kwon, Taek Sang; Park, Won

    2017-01-01

    Objective To demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or intolerances to antitumour necrosis factor agents. Methods In this randomised phase I trial, patients with active RA were randomly assigned (2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued methotrexate therapy). Primary endpoints were area under the serum concentration–time curve from time zero to last quantifiable concentration (AUC0–last) and maximum serum concentration after second infusion (Cmax). Additional pharmacokinetic parameters, efficacy, pharmacodynamics, immunogenicity and safety were also assessed. Data are reported up to week 24. Results 103 patients were assigned to CT-P10 and 51 to RTX. The 90% CIs for the ratio of geometric means (CT-P10/RTX) for both primary endpoints were within the bioequivalence range of 80%–125% (AUC0–last: 97.7% (90% CI 89.2% to 107.0%); Cmax: 97.6% (90% CI 92.0% to 103.5%)). Pharmacodynamics and efficacy were comparable between groups. Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles. Conclusions CT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety. Trial registration number NCT01534884. PMID:27624791

  16. A Pharmacokinetics, Efficacy, and Safety Study of Gadoterate Meglumine in Pediatric Subjects Aged Younger Than 2 Years.

    PubMed

    Scala, Mario; Koob, Meriam; de Buttet, Sophie; Bourrinet, Philippe; Felices, Mathieu; Jurkiewicz, Elzbieta

    2017-09-12

    The primary objective of this study was to investigate the pharmacokinetic profile of gadoterate meglumine in pediatric patients younger than 2 years; the secondary objectives were to document its efficacy and safety. This was a Phase IV open-label, prospective study conducted in 9 centers (4 countries). Forty-five patients younger than 2 years with normal estimated glomerular filtration rate and scheduled to undergo routine gadolinium-enhanced magnetic resonance imaging (MRI) of any organ were included and received a single intravenous injection of gadoterate meglumine (0.1 mmol/kg). To perform the population pharmacokinetics analysis, 3 blood samples per subject were drawn during 3 time windows at time points allocated by randomization. Gadoterate meglumine concentrations were best fitted using a 2-compartmental model with linear elimination from central compartment. The median total clearance adjusted to body weight was estimated at 0.06 L/h per kg and increased with estimated glomerular filtration rate according to a power model. The median volume of distribution at steady state (Vss) adjusted to body weight was estimated at 0.047 L/kg. Estimated median terminal half-life (t1/2β) was 1.35 h, and the median systemic exposure (area under the curve) was 1591 μmol h/L. Efficacy was assessed by comparing precontrast +postcontrast images to precontrast images in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues. A total of 28 lesions were identified and analyzed in 15 subjects with precontrast images versus 30 lesions in 16 subjects with precontrast + postcontrast images. Lesion visualization was improved with a mean (SD) increase in scores at subject level of 0.7 (1.0) for lesion border delineation, 0.9 (1.6) for internal morphology, and 3.1 (3.2) for contrast enhancement. Twenty-six adverse events occurred postinjection in 13 subjects (28.9%), including 3 serious reported in 1 subject (2.2%). One subject (2

  17. Efficacy, safety, pharmacokinetics and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: A phase II study

    PubMed Central

    Zhu, Andrew X.; Ancukiewicz, Marek; Supko, Jeffrey G.; Sahani, Dushyant V.; Blaszkowsky, Lawrence S.; Meyerhardt, Jeffrey A.; Abrams, Thomas A.; McCleary, Nadine Jackson; Bhargava, Pankaj; Muzikansky, Alona; Sheehan, Susan; Regan, Eileen; Vasudev, Eamala; Knowles, Michelle; Fuchs, Charles S.; Ryan, David P.; Jain, Rakesh K.; Duda, Dan G.

    2013-01-01

    Purpose We performed a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK) and biomarkers for cediranib. Results Cediranib treatment resulted in an estimated 3-month-PFS rate of 77% [60%, 99%]. Median PFS was 5.3 [3.5,9.7] months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 [7.5–13.6] months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%) and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-γ. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-α, CAIX and CD34+CD133+CD45dim circulating progenitor cells and on-treatment levels of sVEGFR2. Conclusions Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not appear to affect the steady-state PK of cediranib. Exploratory studies suggested pro-angiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC. PMID:23362324

  18. Pharmacokinetics and safety of posaconazole delayed-release tablets for invasive fungal infections.

    PubMed

    Wiederhold, Nathan P

    2016-01-01

    Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various pathogenic fungi, including yeast and moulds. Clinical studies have demonstrated that this agent is efficacious as prophylaxis against invasive fungal infections in patients at high risk, and may also be useful as salvage therapy against invasive aspergillosis and mucormycosis. However, the bioavailability of posaconazole following administration by oral suspension, which was the only formulation clinically available for many years, is highly variable and negatively influenced by several factors. Because of this, many patients had subtherapeutic or undetectable posaconazole levels when the oral suspension was used. To overcome this limitation, a delayed-release tablet was developed and is now available for clinical use. Hot-melt extrusion technology is used to combine a pH-sensitive polymer with posaconazole to produce a formulation that releases the drug in the elevated pH of the intestine where absorption occurs rather than in the low-pH environment of the stomach. This results in enhanced bioavailability and increased posaconazole exposure. Studies in healthy volunteers have demonstrated significantly higher and more consistent exposures with the tablet formulation compared to the oral suspension. In addition, pharmacokinetic parameters following administration of the tablets were not significantly affected by medications that raise gastric pH or increase gastric motility, and the tablets could also be administered without regard to food. Similar results have also been found in patients at high risk for invasive fungal infections who have received posaconazole tablets. The tablet formulation also appears to be well tolerated to date, although data regarding clinical efficacy are needed.

  19. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis.

    PubMed

    Parasrampuria, Dolly A; Marbury, Thomas; Matsushima, Nobujo; Chen, Shuquan; Wickremasingha, Prachi K; He, Ling; Dishy, Victor; Brown, Karen S

    2015-04-01

    Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oral dose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC0-∞; 676.2 ng·h/ml) as compared with that observed in subjects off-dialysis (691.7 ng·h/ml). Mean maximum observed plasma concentration (Cmax) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.

  20. Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment

    PubMed Central

    Fordyce, Marshall; Garner, William; Vimal, Mona; Ling, Kah Hiing J.; Kearney, Brian P.; Ramanathan, Srinivasan

    2016-01-01

    Tenofovir alafenamide (TAF) is an oral prodrug of tenofovir (TFV) that has greater stability in plasma than TFV disoproxil fumarate (TDF) and circulates as intact TAF, resulting in the direct and higher lymphatic loading of and exposure to TFV diphosphate, the active moiety. Unlike TFV, TAF is minimally eliminated in urine. The pharmacokinetics (PK) of TAF and TFV in HIV-uninfected subjects with severe renal impairment and matched healthy controls were evaluated. Subjects with severe renal impairment (RI; estimated glomerular filtration rate [eGFR], 15 to 29 ml/min) and controls (eGFR, ≥90 ml/min) matched for age, gender, and body mass index received a single dose of TAF at 25 mg. Blood and urine samples for TAF and TFV PK determinations were collected over 7 days postdosing, and subjects were followed up at 14 days. A total of 14 renally impaired subjects and 13 control subjects enrolled and completed the study. The TAF maximum observed concentration in plasma (Cmax) and the area under the concentration-versus-time curve (AUC) extrapolated to infinite time (AUCinf) were 79% and 92% higher, respectively, in subjects with severe RI than the controls, primarily due to higher absorption. The TFV Cmax and AUCinf were 2.8-fold and 5.7-fold higher, respectively, in subjects with severe RI than the controls. In subjects with severe RI, TAF at 25 mg provided a TFV AUC 10 to 40% lower than that from historical TDF-based TFV exposures in subjects with normal renal function. There were no discontinuations due to adverse events. In subjects with severe RI receiving TAF at 25 mg, TAF exposures were higher than those for the controls; these differences are unlikely to be clinically meaningful. TFV exposures were higher than those for the controls but lower than the exposures in nonrenally impaired subjects on TDF-based regimens. PMID:27216057

  1. Pharmacokinetics and safety of posaconazole delayed-release tablets for invasive fungal infections

    PubMed Central

    Wiederhold, Nathan P

    2016-01-01

    Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various pathogenic fungi, including yeast and moulds. Clinical studies have demonstrated that this agent is efficacious as prophylaxis against invasive fungal infections in patients at high risk, and may also be useful as salvage therapy against invasive aspergillosis and mucormycosis. However, the bioavailability of posaconazole following administration by oral suspension, which was the only formulation clinically available for many years, is highly variable and negatively influenced by several factors. Because of this, many patients had subtherapeutic or undetectable posaconazole levels when the oral suspension was used. To overcome this limitation, a delayed-release tablet was developed and is now available for clinical use. Hot-melt extrusion technology is used to combine a pH-sensitive polymer with posaconazole to produce a formulation that releases the drug in the elevated pH of the intestine where absorption occurs rather than in the low-pH environment of the stomach. This results in enhanced bioavailability and increased posaconazole exposure. Studies in healthy volunteers have demonstrated significantly higher and more consistent exposures with the tablet formulation compared to the oral suspension. In addition, pharmacokinetic parameters following administration of the tablets were not significantly affected by medications that raise gastric pH or increase gastric motility, and the tablets could also be administered without regard to food. Similar results have also been found in patients at high risk for invasive fungal infections who have received posaconazole tablets. The tablet formulation also appears to be well tolerated to date, although data regarding clinical efficacy are needed. PMID:26730212

  2. Self-micellizing solid dispersion of cyclosporine A for pulmonary delivery: Physicochemical, pharmacokinetic and safety assessments.

    PubMed

    Suzuki, Hiroki; Ueno, Kodai; Mizumoto, Takahiro; Seto, Yoshiki; Sato, Hideyuki; Onoue, Satomi

    2017-01-01

    The present study aimed to develop an inhalable self-micellizing solid dispersion of cyclosporine A (SMSD/CsA) for the direct delivery to the respiratory system with improved therapeutic efficacy and minimized systemic exposure. SMSD/CsA was obtained by wet-milling, and then jet-milled SMSD/CsA was blended with lactose carrier, producing a respirable powder of SMSD/CsA (SMSD/CsA-RP). The physicochemical, pharmacological, and pharmacokinetic properties of SMSD/CsA-RP were characterized, and the hepatotoxic and nephrotoxic potentials were investigated by biomarker analysis. Cascade impactor analysis demonstrated that SMSD/CsA-RP had high in vitro inhalation performance, with a fine particle fraction of 36%. In simulated lung fluid, the SMSD/CsA exhibited better dissolution behavior than amorphous CsA. Pretreatment with SMSD/CsA-RP resulted in significant suppression of antigen-evoked inflammatory events in rats. After intratracheal administration of SMSD/CsA-RP at a pharmacologically effective dose (100μg-CsA/rat), the AUC0-24 value was <1% of that after oral administration of Neoral(®) at a toxic dose (10mg-CsA/kg). Compared with oral Neoral(®), insufflated SMSD/CsA-RP showed 99% reductions of CsA concentrations in both liver and kidney. No significant increases of biomarker levels in plasma were observed even after repeated intratracheal administration of SMSD/CsA-RP for 7days. From these findings, SMSD/CsA-RP might be a favorable dosage form for effective and safe inhalation therapy of CsA. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. A safety and pharmacokinetic dosing study of glucagon-like peptide 2 in infants with intestinal failure.

    PubMed

    Sigalet, David L; Brindle, Mary E; Boctor, Dana; Dicken, Bryan; Lam, Viona; Lu, Lily Sia; de Heuvel, Elaine; Hartmann, Bolette; Holst, Jens J

    2017-05-01

    Glucagon-like peptide 2 (GLP-2) analogues are approved for adults with intestinal failure (IF), but no studies have included infants. This study examined the pharmacokinetics (PK), safety, and nutritional effects of GLP-2 in infants with IF. With parental consent (Health Canada Protocol:150,979), parenteral nutrition (PN)-dependent infants were treated with 5-20-μg/kg/day GLP-2 for 3days (phase 1), and if tolerated continued for 42days (phase 2). Nutritional therapy was by primary caregivers, and follow-up was to one year. Six patients were enrolled, age 5.4±3.2months, bowel length: 27±12% of predicted, PN dependent (67±18% of calories). GLP-2 did not affect vital signs, nor were there significant adverse events during the trial. Dosing 5μg/kg/day gave GLP-2 levels of 52-57pmol/L, with no change in half-life or endogenous GLP-2 levels. Enteral feeds, weight, Z scores, stooling frequency, and citrulline levels improved numerically. The trial was discontinued early because of a drop in potency. GLP-2 was well tolerated in infants, and pK was similar to children with no changes in endogenous GLP-2 release. The findings suggest that GLP-2 ligands may be safely used in infants and may have beneficial effects on nutritional status. Further study is required. 2b Prospective Interventional Study. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. AGT-181: expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys.

    PubMed

    Boado, Ruben J; Hui, Eric K-W; Lu, Jeff Zhiqiang; Pardridge, William M

    2009-10-26

    Enzyme replacement therapy is not effective for the brain, owing to the lack of transport of the enzyme across the blood-brain barrier (BBB). Recombinant proteins such as the lysosomal enzyme, iduronidase, can penetrate the human BBB, following the re-engineering of the protein as an IgG fusion protein, where the IgG moiety targets an endogenous BBB transport system. The IgG acts as a molecular Trojan horse to ferry the fused protein into brain. AGT-181 is a genetically engineered fusion protein of human iduronidase and a chimeric monoclonal antibody against the human insulin receptor. Adult Rhesus monkeys were administered repeat intravenous doses of AGT-181 ranging from 0.2 to 20 mg/kg. Chronic AGT-181 dosing resulted in no toxicity at any dose, no changes in organ histology, no change in plasma or cerebrospinal fluid glucose, and no significant immune response. AGT-181 was rapidly removed from plasma, based on measurements of either plasma immunoreactive AGT-181 or plasma iduronidase enzyme activity. Plasma pharmacokinetics analysis showed a high systemic volume of distribution, and a clearance rate comparable to a small molecule. The safety pharmacology studies provide the basis for future drug development of AGT-181 as a new therapeutic approach to treatment of the brain in Hurler's syndrome.

  5. The Effect of Food and Formulation on the Pharmacokinetics, Safety, and Tolerability of GSK1322322 in Healthy Volunteers

    PubMed Central

    Naderer, Odin; Jones, Lori S; Zhu, John; Coffin, Mark D; Kurtinecz, Milena; Dumont, Etienne

    2015-01-01

    GSK1322322 is the first in a new class of antibiotics that inhibit peptide deformylase, necessary for bacterial protein maturation. Previously, low absolute bioavailability was observed for the 1500-mg oral tablet formulation, resulting in a less than dose-proportional increase from the 1000-mg dose. Furthermore, high variability of pharmacokinetic (PK) parameters within cohorts was suggested to be associated with differences in body weight. This open-label, randomized, 4-period, crossover, single-dose phase I study in healthy individuals compared the PK, safety, and tolerability of free base oral tablets under fasted or fed conditions with intravenous and oral mesylate salt solution of GSK1322322 under fasted conditions. Absolute bioavailability of GSK1322322 1500-mg free base tablets under fasted conditions, fed conditions, and oral mesylate salt solution was 57%, 77%, and 92%, respectively. Moderate-fat/calorie food intake increased area under the concentration–time curve (AUC0−∞) by 36%, maintained maximum observed concentration (Cmax), and delayed time to Cmax. It appeared that AUC0−∞ decreased with body weight, whereas clearance increased. GSK1322322 administration resulted in only mild-to-moderate adverse events. These results support future clinical investigations of the free base oral tablet formulation of GSK1322322 1500 mg after intake of a moderate-fat/calorie meal, including further investigation of a potential weight-based dosage change. PMID:26097792

  6. Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial

    PubMed Central

    Noguchi-Shinohara, Moeko; Ono, Kenjiro; Hamaguchi, Tsuyoshi; Iwasa, Kazuo; Nagai, Toshitada; Kobayashi, Shoko; Nakamura, Hiroyuki; Yamada, Masahito

    2015-01-01

    The aim of this study was to evaluate the safety, tolerability and pharmacokinetics of single dose of Melissa officinalis extract which contained rosmarinic acid, including food-effects in healthy individuals. A total of eleven healthy individuals were randomly assigned to treatment arms in the two studies [Study 1 (fasted state) and Study 2 (fed state)]. Rosmarinic acid in serum was measured by a coulometric detection method using High-Performance Liquid Chromatography electrochemical detector. The serum concentration of total rosmarinic acid peaked at 1 hour after administration of Melissa officinalis extract containing 500mg rosmarinic acid in fasted state, with a maximum serum concentration 162.20 nmol/ L. The area under the curve for intact rosmarinic acid was calculated from the serum concentration-time profile to be 832.13 nmol • hour/ L. Food intake increases area under the curve and delayed time at which the maximum serum concentration. Rosmarinic acid supplementation did not affect liver, kidney, or blood cell function parameters. No adverse event was reported by any of the participants due to the study treatment. Single dose of Melissa officinalis extract containing 500 mg rosmarinic acid appears to be safe and tolerable in healthy individuals. Food intake increased the exposure of rosmarinic acid and delayed absorption of rosmarinic acid in healthy individuals. Trial Registration Trial Registration: UMIN-CTR UMIN000004997 PMID:25978046

  7. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ-secretase modulator, E2212, in healthy human subjects.

    PubMed

    Yu, Yanke; Logovinsky, Veronika; Schuck, Edgar; Kaplow, June; Chang, Min-Kun; Miyagawa, Takehiko; Wong, Nancy; Ferry, Jim

    2014-05-01

    E2212, a novel γ-secretase modulator, is under development for the treatment of Alzheimer's disease. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses (10-250 mg, double-blind, placebo-controlled, randomized) of E2212 were evaluated. In this phase I clinical trial, E2212 was found to be well tolerated in single doses. Maximum tolerated dose was not achieved up to 250 mg. Most AEs were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant findings on physical and ophthalmologic examinations as well as vital signs, laboratory, ECG and C-SSRS assessments. E2212 was rapidly absorbed, with median tmax values ranging from 0.5 to 1.0 h. E2212 exhibited biphasic disposition with the terminal t1/2 of 12.5-19.0 h. Renal excretion was the minor pathway for E2212 elimination. Increased PD response (reduction in plasma concentrations of Aβ(x-42)) was observed with increasing doses. The maximum PD response was observed in the highest dose 250 mg cohort, with ΔAUAC(0-24 h) of 44.1% and Amax of 53.6%. These results support further clinical development of E2212. © 2014, The American College of Clinical Pharmacology.

  8. Intra-articular administration of lidocaine in anaesthetized dogs: pharmacokinetic profile and safety on cardiovascular and nervous systems.

    PubMed

    Di Salvo, A; Bufalari, A; De Monte, V; Cagnardi, P; Marenzoni, M L; Catanzaro, A; Vigorito, V; Della Rocca, G

    2015-08-01

    The intra-articular administration of lidocaine is a frequent practice in human orthopaedic surgical procedures, but an eventual absorption of the drug into the bloodstream can lead to toxicity, mainly concerning the central nervous system and the cardiovascular systems. The purpose of this study was to determine the pharmacokinetic profile and the safety, in terms of cardiovascular and CNS toxicity, of lidocaine after intra-articular administration to anesthetized dogs undergoing arthroscopy. Lidocaine 2% was administered to eight dogs before surgery in differing amounts, depending on the volume of the joints involved, and blood samples were taken at predetermined time points. The maximum serum concentration of lidocaine ranged from 0.50 to 3.01 μg/mL (mean ± SD: 2.18 ± 0.91 μg/mL), and the time to reach it was 28.75 ± 15.74 min. No signs of cardiac toxicity were detected during the entire procedure, and possible signs of CNS toxicity were masked by the anaesthesia. However, concentrations reported in literature as responsible for neurotoxicity in dog were achieved in three of eight investigated subjects. Pending further studies, veterinarians should consider the possibility of side effects occurring following the intra-articular administration of local anaesthetics.

  9. Pharmacodynamics, pharmacokinetics, and safety of AM211: a novel and potent antagonist of the prostaglandin D2 receptor type 2.

    PubMed

    Bain, G; King, C D; Brittain, J; Hartung, J P; Dearmond, I; Stearns, B; Truong, Y P; Hutchinson, J H; Evans, J F; Holme, K

    2012-10-01

    The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater-than-dose-proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half-life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single- and multiple-dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.

  10. Phase I Safety and Pharmacokinetics Study of Micronized Atovaquone in Human Immunodeficiency Virus-Infected Infants and Children

    PubMed Central

    Hughes, Walter; Dorenbaum, Alejandro; Yogev, Ram; Beauchamp, Belinda; Xu, Jing; McNamara, James; Moye, John; Purdue, Lynette; van Dyke, Russell; Rogers, Michael; Sadler, Brian; Group, The Pediatric Aids Clinical Trials

    1998-01-01

    A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 μg/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 μg/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day. PMID:9624466

  11. Adult and paediatric poor metabolisers of desloratadine: an assessment of pharmacokinetics and safety.

    PubMed

    Prenner, Bruce; Kim, Kenneth; Gupta, Samir; Khalilieh, Sauzanne; Kantesaria, Bhavna; Manitpisitkul, Prasarn; Lorber, Richard; Wang, Zaiqi; Lutsky, Barry

    2006-03-01

    Antihistamines are widely used to treat allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) in adults and children. Desloratadine is a once-daily oral antihistamine with a favourable sedation profile that is approved for the treatment of AR and CIU. Phenotypic polymorphism in the metabolism of desloratadine has been observed, such that some individuals have a decreased ability to form 3-hydroxydesloratadine, the major metabolite of desloratadine; such individuals are termed 'poor metabolisers of desloratadine'. This review describes the prevalence of poor metabolisers of desloratadine, quantifies the exposure to desloratadine in poor metabolisers and demonstrates that the increased exposure in poor metabolisers is independent of age when administered at age-appropriate doses. Furthermore, this review demonstrates that the increased exposure to desloratadine in poor metabolisers is not associated with any changes in the safety and tolerability profile of desloratadine, including cardiovascular safety.

  12. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

    SciTech Connect

    Trifilieff, Alexandre; Ethell, Brian T.; Sykes, David A.; Watson, Kenny J.; Collingwood, Steve; Charlton, Steven J.; Kent, Toby C.

    2015-08-15

    Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED{sub 50} values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M{sub 2} muscarinic receptor occupancy, which predicted significantly higher M{sub 2} receptor blockade at ED{sub 50} doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED{sub 50} doses for bronchoprotection we model systemic M{sub 2} receptor occupancy. • Glycopyrrolate demonstrates lower M

  13. Safety and Pharmacokinetics of Once-Daily Dapsone Gel, 7.5% in Patients With Moderate Acne Vulgaris.

    PubMed

    Jarratt, Michael T; Jones, Terry M; Chang-Lin, Joan-En; Tong, Warren; Berk, David R; Lin, Vince; Kaoukhov, Alexandre

    2016-10-01

    Reducing the dosing frequency of topical acne treatments to once daily may improve adherence. Evaluate pharmacokinetics (PK), safety, and tolerability of 3 formulations of once-daily dapsone gel, 7.5% and of twice-daily dapsone gel, 5% over 28 days in patients with moderate acne vulgaris. This phase 1, multicenter, parallel-group study randomized males and females aged 16 to 35 years to 1 of 3 dapsone gel, 7.5% formulations (DAP-11078, DAP-11079, or DAP-11080 double-blind; applied once daily) or to dapsone gel, 5% (investigator-blinded only, applied twice-daily). Blood samples were collected for PK assessments of dapsone and its metabolites, N-acetyl dapsone (NAD) and dapsone hydroxylamine (DHA), before the morning dose on days 1, 7, 14, 18, 21, 26, 27, and 28, and at several follow-up time points (days 29-32). Safety profile assessments included adverse events (AEs), physical examinations, laboratory tests, and local tolerability assessments. Steady-state dapsone, NAD, and DHA concentrations were reached within 7 days of the first dose in all treatment groups. Daily systemic exposures of the 3 dapsone gel, 7.5% formulations were approximately 25% to 40% lower than that for dapsone gel, 5%, and these differences were statistically significant. Among the 3 dapsone gel, 7.5% formulations, the highest daily exposure of dapsone (per the AUC) was observed with DAP-11080, with respective Cmax and AUC0-24 being approximately 28.6% and 28.7% lower relative to dapsone gel, 5%. Most AEs were mild to moderate in intensity. The safety profiles for all 3 formulations of once-daily dapsone, 7.5% gel and twice-daily dapsone gel, 5% were similar following 28 days of topical administration. All 4 dapsone formulations were well tolerated. This study demonstrated lower systemic exposure with all 3 once-daily dapsone gel, 7.5% formulations than with twice-daily dapsone gel, 5%. All 4 formulations were well tolerated and demonstrated similar safety profiles.

    J Drugs

  14. Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizures: a phase 1, randomized controlled study.

    PubMed

    Mann, Donald; Liu, Jing; Chew, Marci L; Bockbrader, Howard; Alvey, Christine W; Zegarac, Elizabeth; Pellock, John; Pitman, Verne W

    2014-12-01

    To evaluate the safety, tolerability, and pharmacokinetics (PK) of pregabalin as adjunctive therapy in children with refractory partial seizures. This was a phase 1, randomized, placebo-controlled, parallel-group, escalating-dose, multiple-dose study comprising a 7-day, double-blind treatment period and a single-blind, single dose of pregabalin administered to all children on day 8. Children in four age cohorts (1-23 months, 2-6, 7-11, and 12-16 years) received one of four doses of pregabalin (2.5, 5, 10, or 15 mg/kg/day) or placebo. Safety and tolerability were assessed throughout the study. Steady-state and single-dose PK parameters on day 8 were analyzed using standard noncompartmental procedures. Sixty-five children received at least one dose of treatment. Four pregabalin-treated children discontinued treatment, three of whom received 15 mg/kg/day. Two children experienced serious adverse events, one of whom received pregabalin 15 mg/kg/day. During double-blind treatment, the most common adverse events reported in the pregabalin-treated population were somnolence (27.1%) and dizziness (12.5%). Steady-state pregabalin peak and total exposure in each age cohort appeared to increase linearly with dose. Apparent oral clearance (CL/F) was directly related to creatinine clearance, consistent with adults. CL/F normalized for body weight was 43% higher in patients weighing <30 kg. Steady-state and single-dose PK were consistent. Pregabalin at doses up to 10 mg/kg/day in children aged 1 month to 16 years, and at doses up to 15 mg/kg/day in those aged <6 years, demonstrated acceptable safety and tolerability. For children weighing <30 kg, a dose increase of 40% (mg/kg dosing) is required to achieve comparable exposure with adults or children weighing ≥30 kg. These data will inform dose selection in phase 3 trials of the efficacy and safety of adjunctive pregabalin in children with refractory partial seizures. Wiley Periodicals, Inc. © 2014 International League Against

  15. Pharmacokinetics, safety and efficacy of a recombinant factor IX product, trenonacog alfa in previously treated haemophilia B patients.

    PubMed

    Collins, P W; Quon, D V K; Makris, M; Chowdary, P; Kempton, C L; Apte, S J; Ramanan, M V; Hay, C R M; Drobic, B; Hua, Y; Babinchak, T J; Gomperts, E D

    2017-08-17

    Trenonacog alfa (IB1001) is a recombinant factor IX (rFIX) manufactured in Chinese hamster ovary (CHO) cells. IB1001 was evaluated in a multicentre clinical trial with haemophilia B patients. The aim was to establish IB1001 pharmacokinetic non-inferiority to comparator rFIX, safety and efficacy in previously treated patients (PTPs) with haemophilia B. Subjects were severe or moderately severe haemophilia B adult and adolescent PTPs with no history of FIX inhibitors. IB1001 PK non-inferiority to comparator rFIX was demonstrated through ratio of AUC0-∞ in 32 subjects. IB1001 was well tolerated in all 76 treated subjects; the most common adverse drug reaction was headache (2.6% of subjects) and there were no reports of FIX inhibitors. Transient non-inhibitory binding FIX antibodies and anti-CHO cell protein antibodies developed in 21% and 29% of subjects respectively; no safety concerns were associated with development of these antibodies. Prophylaxis (mean duration ± SD: 17.9 ± 9.6 months, mean dose: 55.5 ± 12.9 IU/kg, median 1.0 infusion per week) was effective in preventing bleeds (median annual bleed rate: 1.52, interquartile range: 0.0-3.46). One or two IB1001 infusions resolved 84% of the bleeds, while for 84% of treatments haemostatic efficacy of IB1001 was rated excellent or good. IB1001 haemostatic efficacy for all 19 major surgeries was rated adequate or better than adequate. IB1001 is safe and efficacious for treatment of bleeds, routine prophylaxis and perioperative management in haemophilia B patients. © 2017 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

  16. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model.

    PubMed

    Trifilieff, Alexandre; Ethell, Brian T; Sykes, David A; Watson, Kenny J; Collingwood, Steve; Charlton, Steven J; Kent, Toby C

    2015-08-15

    Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1h; >200 fold at 6h) than with tiotropium (1.5 and 4.2 fold at 1h; 4.6 and 5.5 fold at 6h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M2 muscarinic receptor occupancy, which predicted significantly higher M2 receptor blockade at ED50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium.

  17. Safety, tolerability and pharmacokinetics of 2-pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD.

    PubMed

    Moorthy, Ganesh; Sallee, Floyd; Gabbita, Prasad; Zemlan, Frank; Sallans, Larry; Desai, Pankaj B

    2015-10-01

    Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with the betahistine dose (R2 0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for the power model were 0.8684 (Cmax) and 1.007 (AUC0-4). A population pharmacokinetic model with first-order absorption of betahistine and metabolism to 2-PAA, followed by a first-order elimination of 2-PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested.

  18. Dose modifications in Asian cancer patients with hepatic dysfunction receiving weekly docetaxel: A prospective pharmacokinetic and safety study.

    PubMed

    Syn, Nicholas Li-Xun; Wang, Lingzhi; Wong, Andrea Li-Ann; Soe, Mu-Yar; Chuah, Benjamin; Chan, Daniel; Tan, Sing-Huang; Soo, Ross Andrew; Lee, Soo-Chin; Goh, Boon-Cher; Yong, Wei-Peng

    2016-02-01

    Hepatic dysfunction may modify the safety profile and pharmacokinetics of docetaxel in cancer patients, but no validated guideline exists to guide dose modification necessitated by this uncommon comorbidity. We carried out the first prospective study of a personalized dosage regimen for cancer patients with liver dysfunction treated with docetaxel. Weekly dosages were stratified by hepatic dysfunction classification as such: Category 1, normal; Category 2, mild--alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase ≤5× upper limit of normal (ULN), and total bilirubin within normal range; and Category 3, moderate--any alkaline phosphatase, and aspartate aminotransferase or alanine aminotransferase ≤5-10× ULN, and/or total bilirubin ≤1-1.5× ULN. Category 1, 2 and 3 patients received starting dosages of 40, 30, and 20 mg/m(2) docetaxel, respectively. Pharmacokinetics were evaluated on day 1 and 8 of the first treatment cycle, and entered into a multilevel model to delineate interindividual and interoccasion variability. Adverse event evaluation was carried out weekly for two treatment cycles. We found that docetaxel clearance was significantly different between patient categories (P < 0.001). Median clearance was 22.8, 16.4, and 11.3 L/h/m(2) in Categories 1, 2, and 3, respectively, representing 28% and 50% reduced clearance in mild and moderate liver dysfunction patients, respectively. However, docetaxel exposure (area under the concentration-time curve) and docetaxel-induced neutropenia (nadir and the maximum percentage decrease in neutrophil count) were not significantly different between categories. Median area under the concentration-time curve was 1.74, 1.83, and 1.77 mg·h/L in Categories 1, 2, and 3, respectively. The most common Grade 3/4 toxicity was neutropenia (30.0%). An unplanned comparison with the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group grouping systems suggests that the proposed

  19. Preclinical pharmacokinetic, biodistribution, toxicology, and dosimetry studies of 111In-DTPA-human epidermal growth factor: an auger electron-emitting radiotherapeutic agent for epidermal growth factor receptor-positive breast cancer.

    PubMed

    Reilly, Raymond M; Chen, Paul; Wang, Judy; Scollard, Deborah; Cameron, Ross; Vallis, Katherine A

    2006-06-01

    Our objective was to evaluate the pharmacokinetics, normal tissue distribution, radiation dosimetry, and toxicology of human epidermal growth factor (hEGF) labeled with (111)In ((111)In-diethylenetriaminepentaacetic acid [DTPA]-hEGF) in mice and rabbits. (111)In-DTPA-hEGF (3.6 MBq; 1.3 or 13 microg) was administered intravenously to BALB/c mice. The blood concentration-time data were fitted to a 3-compartment model. Acute toxicity was studied with female BALB/c mice at 42 times the maximum planned human dose (MBq/kg) or with New Zealand White rabbits at 1 times the maximum planned human dose (MBq/kg) for a phase I clinical trial. Toxicity was evaluated by monitoring body weight, by determination of hematology and clinical biochemistry parameters, and by morphologic examination of tissues. Radiation dosimetry projections in humans were estimated on the basis of the residence times in mice by use of the OLINDA version 1.0 computer program. The largest amounts of radioactivity were taken up by the liver (41.3 +/- 7.8 [mean +/- SD] percentage injected dose [%ID] at 1 h after injection and decreasing to 4.9 +/- 0.3 %ID at 72 h after injection) and kidneys (18.6 +/- 0.8 %ID at 1 h and decreasing to 4.5 +/- 0.2 %ID at 72 h after injection). (111)In-DTPA-hEGF was cleared rapidly from the blood, with a half-life at alpha-phase of 2.7-6.2 min and a half-life at beta-phase of 24.0-36.3 min. The half-life of the long terminal phase could not be accurately determined. The volume of distribution of the central compartment was 340-375 mL/kg, and the volume of distribution at steady state was 430-685 mL/kg. There was no significant difference in the ratio of body weight at 15 d to pretreatment weight for mice administered (111)In-DTPA-hEGF (1.02 +/- 0.01) and mice administered unlabeled DTPA-hEGF (1.01 +/- 0.01). Erythrocyte, leukocyte, and platelet counts and serum alanine aminotransferase and creatinine levels remained in the normal ranges. No morphologic changes were observed

  20. [Review of pharmacokinetic monitoring of 5-Fluorouracil as a tool to increase efficacy and safety].

    PubMed

    Matus-Santos, Juan Antonio; Aguilar-Ponce, José Luis; Lara-Medina, Fernando Ulises; Herrera-Gómez, Ángel; Meneses-García, Abelardo; López-Gamboa, Mireya

    2016-01-01

    Recent progress in medical knowledge has indicated that both clinical and biological markers will determine the response to different medical treatments: age, gender and genetics will determine the success of treatment. Genetic variability in this respect is fundamental and determines efficiency and safety of drugs, as well as susceptibility and illness' development. Fortunately, personalized medicine now offers individually tailored treatment strategies for each patient's needs. This is of outmost importance in oncology, since treatment is per se toxic and the commonly found low serum drug concentrations result in low treatment efficacy. Personalized medicine will allow a better approach to this, until now, a poorly managed disease. In this review we intent to raise awareness of personalized medicine and of clinical pharmacologic monitoring, with the aim to achieve adequate levels of efficacy and safety in the use of the cytotoxic drug 5-Fluorouracil (5-FU). Additionally, the importance of pharmacogenomics for the use of 5-FU is discussed. We designed this discussion towards medical practitioners challenged with treatment decisions every day, together with their patients.

  1. Pharmacokinetics, safety, and tolerability of phentermine in healthy participants receiving taranabant, a novel cannabinoid-1 receptor (CB1R) inverse agonist.

    PubMed

    Addy, Carol; Jumes, Patricia; Rosko, Kimberly; Li, Susie; Li, Hankun; Maes, Andrea; Johnson-Levonas, Amy O; Chodakewitz, Jeffrey; Stoch, S Aubrey; Wagner, John A

    2009-10-01

    This study assessed the potential pharmacokinetic interaction and safety/tolerability of taranabant and phentermine coadministration. This was a randomized, double-blind, 3-panel, fixed-sequence study in healthy participants. Panels A, B, and C evaluated the safety/tolerability of phentermine 15 mg coadministered with taranabant 0.5, 1, and 2 mg for 7 days (panel A) and 28 days (panels B and C). In panels A and C, phentermine 15 mg was administered both with (7 days, panel A; 28 days, panel C) and without (7 days) taranabant 0.5 mg or 2 mg to evaluate pharmacokinetics. The primary endpoint was phentermine AUC(0-24 h) in panels A and C. Secondary endpoints were changes from baseline in blood pressure and heart rate for all panels. The geometric mean ratios and 90% confidence intervals for phentermine AUC(0-24 h) in the presence/absence of taranabant 0.5 mg and 2 mg were 1.08 (0.99, 1.17) and 1.04 (0.98, 1.10), respectively. No significant differences in blood pressure and heart rate were observed with any treatment versus placebo. Coadministration of taranabant 0.5 mg, 1 mg, and 2 mg with phentermine was well tolerated with no pharmacokinetic interaction and did not result in meaningful changes in blood pressure or heart rate versus placebo.

  2. Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV‐1106, a Long‐Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects

    PubMed Central

    Barkay, Hadas; Rasamoelisolo, Michele; Butler, Kathleen; Yamada, Kazumasa; Bassan, Merav; Yoon, Esther; Spiegelstein, Ofer

    2016-01-01

    Abstract TV‐1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long‐acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV‐1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV‐1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV‐1106 demonstrated relatively slow absorption (median tmax, 10–30 hours) and a mean elimination half‐life of 26–36 hours. Apparent clearance and volume of distribution decreased with increasing TV‐1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin‐like growth factor‐1 (IGF‐1) and IGF binding protein‐3 (IGFBP‐3) increased in a dose‐related manner, with maximum responses observed at 33–96 and 42–109 hours, respectively. IGF‐1 and IGFBP‐3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV‐1106, and 336 hours following 50 and 100 mg of TV‐1106. TV‐1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV‐1106 between Japanese and caucasian populations. The data also demonstrate long‐acting growth hormone properties of TV‐1106 and support its potential for once‐weekly dosing. PMID:27489211

  3. Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model

    NASA Astrophysics Data System (ADS)

    Cekanova, Maria; Uddin, Md. Jashim; Legendre, Alfred M.; Galyon, Gina; Bartges, Joseph W.; Callens, Amanda; Martin-Jimenez, Tomas; Marnett, Lawrence J.

    2012-11-01

    We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1 mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1 mg/kg showed a peak of fluorocoxib A (92±28 ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.

  4. Single, Escalating Dose Pharmacokinetics, Safety and Food Effects of a New Oral Androgen Dimethandrolone Undecanoate in Man: A prototype oral male hormonal contraceptive

    PubMed Central

    Swerdloff, Ronald S.; Nya-Ngatchou, Jean Jacques; Liu, Peter Y.; Amory, John K.; Leung, Andrew; Hull, Laura; Blithe, Diana L.; Woo, Jason; Bremner, William J.; Wang, Christina

    2014-01-01

    The novel androgen, dimethandrolone (DMA) has both androgenic and progestational activities, properties that may maximize gonadotropin suppression. We assessed the pharmacokinetics of dimethandrolone undecanoate (DMAU), an orally bioavailable, longer-acting ester of DMA, for male contraceptive development. Our objective was to examine the safety and pharmacokinetics of single, escalating doses of DMAU (powder in capsule formulation) administered orally with or without food in healthy men. We conducted a randomized, double-blind Phase 1 study. For each dose of DMAU (25 to 800 mg), ten male volunteers received DMAU and two received placebo at two academic medical centers. DMAU was administered both fasting and after a high fat meal (200–800 mg doses). Serial serum samples were collected over 24h following each dose. DMAU was well tolerated without significant effects on vital signs, safety laboratory tests or electrocardiograms. When administered while fasting, serum DMA (active compound) was detectable in only 4/10 participants after the 800mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200mg DMAU and showed a dose-incremental increase up to 800mg, with peak levels 4 to 8h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12h after DMAU administration with food at doses above 200mg. This first-in-man study demonstrated that a single, oral dose of DMAU up to 800 mg is safe. A high-fat meal markedly improved DMAU/DMA pharmacokinetics. PMID:24789057

  5. Efficacy, safety and pharmacokinetics of indacaterol in Caucasian and Japanese patients with chronic obstructive pulmonary disease: a comparison of data from two randomized, placebo-controlled studies.

    PubMed

    Hosoe, Motoi; Woessner, Ralph; Matsushima, Soichiro; Lawrence, David; Kramer, Benjamin

    2011-01-01

    Indacaterol is a novel, inhaled, once-daily, ultra-long-acting β2-adrenoceptor agonist that has been approved in the EU for the treatment of chronic obstructive pulmonary disease (COPD). Ethnic differences may influence the pharmacokinetics and pharmacodynamics of a drug, and it is therefore important to compare these parameters in different populations. To compare the efficacy, safety and pharmacokinetics of indacaterol between Caucasian and Japanese patients with COPD. Data from two randomized, double-blind, single-dose crossover, placebo-controlled studies in Caucasian and Japanese patients with moderate-to-severe COPD were compared. The two studies were similar in terms of study design, study population (inclusion/exclusion criteria), parameters examined and the indacaterol doses (150, 300 or 600 μg) tested. Efficacy (primary endpoint: 24-hour post-dose [trough] forced expiratory volume in 1 second [FEV1]), pharmacokinetics, and safety were assessed for 24 hours post-dose in each treatment period. Fifty-one Caucasian (86.3% male; mean age 61.8 years) patients were randomized into the first study and 50 Japanese (92.0% male; mean age 67.2 years) patients were randomized into the second study; ≥90% of patients completed the studies. In both studies, 24-hour post-dose trough FEV1 was significantly higher for all indacaterol doses versus placebo (p<0.001), with clinically relevant differences of 140 and 130 mL for the lowest (150 μg) dose in the Caucasian and Japanese studies, respectively. In both studies, single doses of indacaterol provided improvements in FEV1 that were sustained for 24 hours (p<0.001 vs placebo at all time points). In both populations, the average maximum serum concentration (Cmax) of indacaterol was observed at the first sampling time point and pharmacokinetic profiles were similar between populations. The increase in exposure (Cmax and area under the serum concentration-time curve from time zero to 24 hours) with increasing

  6. Evaluation of Herbal Medicines: Value Addition to Traditional Medicines Through Metabolism, Pharmacokinetic and Safety Studies.

    PubMed

    Thelingwani, Roslyn; Masimirembwa, Collen

    2014-01-01

    The safety and efficacy of herbal medicines remain major issues of concern especially in the developing world where the use is high. The World Health Organisation estimates up to 80% of the population in Africa relies on herbal medicines for treatment of many diseases. Minimum safety evaluations need to be done for both the herbal and conventional drugs, in particular when there is a high likelihood of co-administration. This is particularly important in Africa where there is increased access to antiretrovirals in the treatment of HIV/AIDS, which are being used in a population background characterized by rampant use of herbal medicines. Many techniques used in the discovery and evaluation of conventional drugs can be adapted to herbal medicines. Such evaluations will add value to herbal medicines as doctors and patients will be better informed on which drugs and herbal medicines to take or not take together. This can also lead to the adoption of guidelines by regulatory agents such as the European Medicines Agency (EMA), Food and Drug Administration (FDA) and governmental agencies controlling the use of medicines. Of current interest is the evaluation of drug-herb interactions (DHI) involving the absorption, distribution, metabolism and excretion (ADME) of medicines where there is a promising possibility to adopt the current FDA and EMA guidelines on the evaluation of herbal medicines for drug-drug interactions (DDI). In this review we demonstrate progress made so far in DHI and point to possible future developments that will contribute to the safe use of herbal medicines.

  7. Pharmacokinetics and Safety of Triple Therapy with Vonoprazan, Amoxicillin, and Clarithromycin or Metronidazole: A Phase 1, Open-Label, Randomized, Crossover Study.

    PubMed

    Sakurai, Yuuichi; Shiino, Madoka; Okamoto, Hiroyuki; Nishimura, Akira; Nakamura, Koki; Hasegawa, Setsuo

    2016-09-01

    Vonoprazan (TAK-438) is a novel potassium-competitive acid blocker that inhibits gastric H(+), K(+)-ATPase. The objectives of this study were to evaluate the influence of triple therapy with vonoprazan-amoxicillin-clarithromycin or vonoprazan-amoxicillin-metronidazole on the pharmacokinetics of each component of the triple therapies (primary) and to evaluate the safety and tolerability of vonoprazan-based triple therapies (secondary) in healthy adults. In this single-center, phase 1, open-label, randomized, four-way crossover study, Helicobacter pylori-negative, healthy Japanese male subjects were randomly assigned to 1 of 4 treatment sequences in two cohorts (12 subjects per cohort). Each treatment sequence comprised four treatment periods separated by a washout period of 7 or 14 days. Pharmacokinetic parameters for vonoprazan, amoxicillin, clarithromycin and metronidazole in single therapy or triple therapies were assessed. All adverse events were recorded. Compared with single therapy, triple therapy with vonoprazan-amoxicillin-clarithromycin increased the area under the plasma concentration-time curve from time 0-12 h (AUC0-12) and maximum plasma concentration (C max) of plasma vonoprazan free base by 1.846- and 1.868-fold, respectively, and increased the AUC0-12 and C max of plasma clarithromycin by 1.450- and 1.635-fold, respectively. Triple therapy with vonoprazan-amoxicillin-metronidazole had no influence on the pharmacokinetics of vonoprazan or metronidazole. The pharmacokinetics of amoxicillin was not influenced by vonoprazan-based triple therapies. Seven adverse events were reported. Two subjects discontinued because of an adverse event (rash, liver function test abnormal); both events were considered to be study drug-related. In healthy Japanese male subjects, triple therapy with vonoprazan-amoxicillin-clarithromycin increased vonoprazan and clarithromycin exposure. The safety and tolerability profile of triple therapy with vonoprazan

  8. Relative bioavailability, food effect, and safety of the single-dose pharmacokinetics of omecamtiv mecarbil following administration of different modified-release formulations in healthy subjects

    PubMed Central

    Palaparthy, Rameshraja; Banfield, Christopher; Alvarez, Paco; Yan, Lucy; Smith, Brian; Johnson, Jessica; Monsalvo, Maria Laura; Malik, Fady

    2016-01-01

    Objective: Omecamtiv mecarbil is a novel small molecule that directly activates cardiac myosin and increases cardiac contractility without increasing cardiac myocyte intracellular calcium. This study evaluated the relative bioavailability, food effect, and safety of several modified-release (MR) formulations of omecamtiv mecarbil. Methods: This was a phase 1, randomized, open-label, 4-way crossover, incomplete block-design study evaluating 5 MR formulations of omecamtiv mecarbil vs. an immediate-release (IR) formulation. Materials: Healthy subjects were randomized to 1 of 30 possible sequences: within each sequence, subjects were assigned to receive a single 25-mg dose of 2 of the 6 possible formulations in the fasting and/or fed states. Results: 65 subjects were screened and enrolled; 5 were replacement subjects. Pharmacokinetic and safety data were analyzed from 62 and 63 subjects in the fasting and fed states, respectively. Compared with the IR formulation, median tmax was longer (0.5 vs. 2 – 10 hours), and mean Cmax was lower for all 5 MR formulations (262 vs. 34 – 78 ng/mL); t1/2,z was similar (18 – 21 hours). The relative bioavailability was high (> 75%) for three MR formulations but lower (< 65%) for the other two. Overall, the effect of food on omecamtiv mecarbil pharmacokinetics was minimal for four of the MR formulations. The pharmacokinetics of the inactive metabolites M3 and M4 were similar across all formulations. Conclusions: The relative bioavailability of omecamtiv mecarbil was high (> 75%) for 3 of the five MR formulations. Food had a marginal, nonclinically meaningful effect on the pharmacokinetics of the MR formulations of omecamtiv mecarbil. PMID:26709596

  9. Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell®)

    PubMed Central

    Dautzenberg, Bertrand; Nides, Mitchell; Kienzler, Jean-Luc; Callens, Anne

    2007-01-01

    Background The use of nicotine replacement therapy (NRT) can almost double the chances of success for smokers to quit. Nevertheless, there is still a considerable number of cessation attempts that are made without any treatment. This novel oral formulation, (lozenge containing nicotine bitartrate dihydrate) has been developed to enlarge the offer for efficient smoking cessation drug therapies, assuming that increasing treatment options will bring more smokers to find the support they personally need to stop smoking. Methods Three pharmacokinetic (PK), one safety and two efficacy studies were carried out with Nicotinell lozenges. PK trials were: (1) a single-dose, three-way crossover study comparing 1 and 2 mg lozenges with 2 mg nicotine gum; (2) a multiple-dose, two-way crossover study comparing 1 mg lozenge with 2 mg gum; (3) a multiple-dose, three-way crossover study comparing 1 and 2 mg lozenges with 4 mg gum. Safety trial: (4) a single dose study to assess the safety of swallowing up to 12 lozenges containing 1 mg nicotine. Efficacy trials: two efficacy studies in (5) France and (6) the USA, including more than 900 smokers followed-up for up to one year, conducted with the 1 mg lozenge. Results The results of the individual PK trials showed that the 1 mg Nicotinell lozenge is bioequivalent to 2 mg polacrilex gum, as demonstrated by similar blood PK parameters (tmax, Cmax, AUC). The 2 mg lozenge was found to deliver quantities of nicotine that were intermediate between those delivered by 2 and 4 mg polacrilex gum. The short-term efficacy of the 1 mg lozenge in comparison with placebo was also demonstrated with significantly more subjects continuously abstinent from smoking with active lozenges on week 6 in two different populations: moderate to heavy smokers (FTND between 4 and 7) OR = 1.72 [95% CI: 1.05–2.80]; heavy to very heavy smokers (FTND 6 and over) OR = 2.87 [95% CI: 1.18–6.97]. Nicotinell lozenges were found to be safe with mainly mild and

  10. Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism.

    PubMed

    Shimatsu, Akira; Teramoto, Akira; Hizuka, Naomi; Kitai, Kazuo; Ramis, Joaquim; Chihara, Kazuo

    2013-01-01

    The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

  11. Single-dose pharmacokinetics and safety of azilsartan medoxomil in children and adolescents with hypertension as compared to healthy adults.

    PubMed

    Webb, Nicholas J A; Wells, Thomas; Tsai, Max; Zhao, Zhen; Juhasz, Attila; Dudkowski, Caroline

    2016-04-01

    This open-label, multicenter, single-dose study characterized the pharmacokinetics and short-term safety of azilsartan medoxomil (AZL-M) in hypertensive pediatric subjects (12-16 years [cohort 1a; n = 9]; 6-11 years [cohort 2; n = 8]; 4-5 years [cohort 3; n = 3]). Model-based simulations were performed to guide dosing, especially in 1-5-year olds, who were difficult to enroll. AZL-M was dosed according to body weight (20-60-mg tablet, cohorts 1a and 2; 0.66 mg/kg granule suspension, cohort 3). In cohort 1, gender-matched healthy adults (cohort 1b; n = 9) received AZL-M 80 mg. Exposure to AZL (active moiety of AZL-M), measured by dose-/body weight-normalized C max and AUC0-∞, was ∼15-30 % lower in pediatric subjects versus adults. In simulations, exposure with 0.66 mg/kg AZL-M in pediatric subjects weighing 8-25 kg approximated to AZL-M 40 mg (typical starting dose) in adults. The simulations suggest that 25-50-kg subjects require half the adult dose (10-40 mg), whereas 50-100-kg subjects can use the same dosing as adults. Adverse events were mild in intensity, apart from one moderate event (migraine). This dosing strategy should be safe in pediatric patients, as AZL exposure would not exceed that seen in adults with the highest approved AZL-M dose (80 mg).

  12. Pharmacokinetics and preliminary safety study of pod-intravaginal rings delivering antiretroviral combinations for HIV prophylaxis in a macaque model.

    PubMed

    Moss, John A; Srinivasan, Priya; Smith, Thomas J; Butkyavichene, Irina; Lopez, Gilbert; Brooks, Amanda A; Martin, Amy; Dinh, Chuong T; Smith, James M; Baum, Marc M

    2014-09-01

    Preexposure prophylaxis using oral regimens involving the HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) demonstrated efficacy in three clinical trials. Adherence was determined to be a key parameter for success. Incorporation of the TDF-FTC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with those of oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described; this constitutes the first report of an IVR delivering TDF and FTC, as well as a triple-combination IVR delivering TDF, FTC, and the entry inhibitor maraviroc (MVC). The pharmacokinetics and preliminary local safety of the two combination pod-IVRs were evaluated in the pig-tailed macaque model. The devices exhibited sustained release at controlled rates over the 28-day study period. Median steady-state drug levels in vaginal tissues in the TDF-FTC group were 30 μg g(-1) (tenofovir [TFV], in vivo hydrolysis product of TDF) and 500 μg g(-1) (FTC) and in the TDF-FTC-MVC group were 10 μg g(-1) (TFV), 150 μg g(-1) (FTC), and 20 μg g(-1) (MVC). No adverse events were observed, and there were no toxicological findings. Mild-to-moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and the absence of the IVRs. The IVRs did not disturb the vaginal microbiota, and levels of proinflammatory cytokines remained stable throughout the study. Pod-IVR candidates based on the TDF-FTC combination have potential for the prevention of vaginal HIV acquisition and merit clinical investigation.

  13. Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects.

    PubMed

    Abbas, Richat; Chalon, Stephan; Leister, Cathie; El Gaaloul, Myriam; Sonnichsen, Daryl

    2013-01-01

    Bosutinib, a dual Src/Abl kinase inhibitor in development for treatment of chronic myeloid leukemia, is primarily metabolized by the CYP3A4 hepatic enzyme. This study evaluated the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects. Hepatically impaired patients were aged 18-65 years and of Child-Pugh classes A, B, or C; healthy subjects were matched by age, sex, body mass index, and smoking habits. A single oral dose of bosutinib 200 mg was administered on day 1 within 5 min after completion of breakfast. Compared with healthy subjects (n = 9), maximal plasma concentration (C(max)) and area under the curve increased 2.42-fold and 2.25-fold in Child-Pugh A (n = 6), 1.99-fold and 2.0-fold in Child-Pugh B (n = 6), and 1.52-fold and 1.91-fold in Child-Pugh C patients (n = 6). Time to C(max) decreased from 4 h in healthy subjects to 2.5, 2.0, and 1.5 h in Child-Pugh A, B, and C patients, respectively; the elimination half-life increased from 55 h in healthy subjects to 86, 113, and 111 h in Child-Pugh A, B, and C patients. Bosutinib oral clearance was lower in hepatically impaired patients compared with healthy subjects. Frequently reported adverse events included prolonged QTc interval (37.0%, n = 10), nausea (11.1%, n = 3), and vomiting (7.4%, n = 2). A single oral dose of bosutinib 200 mg showed acceptable tolerability in healthy subjects and in patients with mild, moderate, or severe chronic hepatic impairment.

  14. Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

    PubMed Central

    Moss, John A.; Srinivasan, Priya; Smith, Thomas J.; Butkyavichene, Irina; Lopez, Gilbert; Brooks, Amanda A.; Martin, Amy; Dinh, Chuong T.; Smith, James M.

    2014-01-01

    Preexposure prophylaxis using oral regimens involving the HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) demonstrated efficacy in three clinical trials. Adherence was determined to be a key parameter for success. Incorporation of the TDF-FTC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with those of oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described; this constitutes the first report of an IVR delivering TDF and FTC, as well as a triple-combination IVR delivering TDF, FTC, and the entry inhibitor maraviroc (MVC). The pharmacokinetics and preliminary local safety of the two combination pod-IVRs were evaluated in the pig-tailed macaque model. The devices exhibited sustained release at controlled rates over the 28-day study period. Median steady-state drug levels in vaginal tissues in the TDF-FTC group were 30 μg g−1 (tenofovir [TFV], in vivo hydrolysis product of TDF) and 500 μg g−1 (FTC) and in the TDF-FTC-MVC group were 10 μg g−1 (TFV), 150 μg g−1 (FTC), and 20 μg g−1 (MVC). No adverse events were observed, and there were no toxicological findings. Mild-to-moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and the absence of the IVRs. The IVRs did not disturb the vaginal microbiota, and levels of proinflammatory cytokines remained stable throughout the study. Pod-IVR candidates based on the TDF-FTC combination have potential for the prevention of vaginal HIV acquisition and merit clinical investigation. PMID:24936594

  15. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

    PubMed Central

    Khwaja, Omar S.; Ho, Eugenia; Barnes, Katherine V.; O’Leary, Heather M.; Pereira, Luis M.; Finkelstein, Yaron; Nelson, Charles A.; Vogel-Farley, Vanessa; DeGregorio, Geneva; Holm, Ingrid A.; Khatwa, Umakanth; Kapur, Kush; Alexander, Mark E.; Finnegan, Deirdre M.; Cantwell, Nicole G.; Walco, Alexandra C.; Rappaport, Leonard; Gregas, Matt; Fichorova, Raina N.; Shannon, Michael W.; Sur, Mriganka; Kaufmann, Walter E.

    2014-01-01

    Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities. PMID:24623853

  16. A Phase 1 Randomized Placebo-Controlled Safety and Pharmacokinetic Trial of a Tenofovir Disoproxil Fumarate Vaginal Ring

    PubMed Central

    Keller, Marla J.; Mesquita, Pedro M.; Marzinke, Mark A.; Teller, Ryan; Espinoza, Lilia; Atrio, Jessica M.; Lo, Yungtai; Frank, Bruce; Srinivasan, Sujatha; Fredricks, David N.; Rabe, Lorna; Anderson, Peter L.; Hendrix, Craig W.; Kiser, Patrick F.; Herold, Betsy C.

    2015-01-01

    Background Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), may be ideal for topical HIV preexposure prophylaxis because it has higher tissue and cell permeability than TFV, is not adversely impacted by seminal proteins, and its active metabolite, TFV-diphosphate (TFV-DP), has a long intracellular half-life. We engineered a TDF eluting polyurethane reservoir intravaginal ring (IVR) to provide near constant mucosal antiretroviral concentrations. Methods A first-in-human randomized placebo-controlled trial was conducted to assess the safety and pharmacokinetics of the TDF IVR in healthy, sexually abstinent women (15 TDF and 15 placebo). Drug concentrations were measured in cervicovaginal fluid (CVF) obtained by swab, cervical tissue, plasma, and dried blood spots (DBS) over 14 days of continuous ring use. Results There were 43 total, 23 reproductive tract, and 8 product-related Grade 1 adverse events. Steady state CVF TFV concentrations were achieved proximal (vagina, ectocervix) and distal (introitus) to the TDF IVR one day after ring insertion. Median tissue TFV-DP concentrations 14 days after TDF IVR placement were 120 fmol/mg (interquartile range 90, 550). CVF collected from the cervix one week and two weeks after TDF IVR insertion provided significant protection against ex vivo HIV challenge. Eleven of 14 (78%) participants had detectable TFV-DP DBS concentrations 14 days after TDF IVR placement, suggesting that DBS may provide a surrogate marker of adherence in future clinical trials. Conclusions A TDF IVR is safe, well tolerated, and results in mucosal TFV concentrations that exceed those associated with HIV protection. The findings support further clinical evaluation of this TDF IVR. PMID:26605514

  17. Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: a Double-Blind Randomized Trial

    PubMed Central

    Chen, Beatrice A.; Panther, Lori; Marzinke, Mark A.; Hendrix, Craig W.; Hoesley, Craig J.; van der Straten, Ariane; Husnik, Marla J.; Soto-Torres, Lydia; Nel, Annalene; Johnson, Sherri; Richardson-Harman, Nicola; Rabe, Lorna K.; Dezzutti, Charlene S.

    2015-01-01

    Background Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery. Methods MTN-013/IPM 026, a multi-site, double-blind, randomized, placebo-controlled trial in 48 HIV-negative U.S. women, evaluated vaginal rings containing dapivirine (25 mg) and maraviroc (100 mg), dapivirine-only, maraviroc-only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics. Results There was no difference in related genitourinary adverse events between treatment arms compared to placebo. Dapivirine and maraviroc concentrations rose higher initially before falling more rapidly with the combination ring compared to relatively stable concentrations with the single drug rings. Dapivirine concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. Maraviroc was consistently detected only in CVF. Dapivirine and maraviroc CVF and dapivirine tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and dapivirine levels. Conclusions In this first study of a combination microbicide vaginal ring, all four rings were safe and well tolerated. Tissue dapivirine concentrations were 1,000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. Dapivirine, but not maraviroc, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Since maraviroc concentrations were consistently detectable only in CVF and not in plasma, improved drug release of maraviroc rings is needed. PMID:26034880

  18. Phase I Combination of Sorafenib and Erlotinib Therapy in Solid Tumors: Safety, Pharmacokinetic and Pharmacodynamic Evaluation from an Expansion Cohort

    PubMed Central

    Quintela-Fandino, Miguel; Le Tourneau, Christophe; Duran, Ignacio; Chen, Eric X.; Wang, Lisa; Tsao, Ming; Bandarchi-Chamkhaleh, Bizhan; Pham, Nhu-Ann; Do, Trevor; MacLean, Martha; Nayyar, Rakesh; Tusche, Michael W.; Metser, Ur; Wright, John J.; Mak, Tak W.; Siu, Lillian L.

    2010-01-01

    The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic (PK) and pharmacodynamic (PD) markers with clinical outcome. In addition, a novel PD marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a one-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. EGFR expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pre-treatment, prior to erlotinib dosing and during the administration of both drugs. In addition, PET-CT scans and PK assessments were performed. Eleven patients received a total of 57 cycles (median: 5, range: 1–10). Only 4 patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of 4 or more cycles. PK analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in 7 patients. Other PD markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib. PMID:20197396

  19. Pharmacokinetics, thrombogenicity and safety of a double viral inactivated factor IX concentrate compared with a prothrombin complex concentrate.

    PubMed

    Ruiz-Sáez, A; Hong, A; Arguello, A; Echenagucia, M; Boadas, A; Fabbrizzi, F; Minichilli, F; Bosch, N B

    2005-11-01

    Therapeutic options for developing countries have to assure an optimum safety and efficacy and low-cost antihaemophilic concentrates. A single blind randomized crossover study was carried out in 12 previously treated HB patients, comparing the pharmacokinetics (PK), thrombogenicity (TG) and safety of two plasma-derived double-inactivated (solvent/detergent heating at 100 degrees C, 30 min) factor IX (FIX) concentrates, UMAN COMPLEX DI (product A) [plasma-derived prothrombin concentrates (PCC)] and a high purity FIX concentrate AIMAFIX DI (product B, HPFIX). In a non-bleeding state, they received one single intravenous dose 50 IU FIX kg(-1) of PCC or HPFIX, and after a wash-out period of 14 days, the other product. We evaluated acute tolerance and determined PK parameters based on FIX levels measured over a 50 h postinfusion period. We studied fibrinogen, platelets, antithrombin, F1 + 2, TAT, D-dimer, over a 360 min postinfusion period. Ten cases remained in on-demand treatment for 6 months, five with PCC and five with HPFIX. PK and anti-FIX inhibitors were repeated at 3 and 6 months. No inhibitors were detected. PK values (PCC vs. HPFIX): clearence (CL; mL h(-1) kg(-1)) 5.2 +/- 1.4 vs. 6.5 +/- 1.4; the volume of distribution at steady state (mL kg(-1)) 154.9 +/- 54.9 vs. 197.5 +/- 72.5; mean residence time (h) 29.7 +/- 8.1 vs. 30.7 +/- 9.2; T(1/2) (h) 22.3 +/- 7 vs. 23.5 +/- 12.3; incremental recovery (IR; U dL(-1) U(-1) kg(-1)) 0.96 +/- 0.17 vs. 0.76 +/- 0.13. HPFIX showed significant lower IR and higher CL. There were no differences in PK at 3 and 6 months. In TG, significant increments in TAT and F1 + 2 at 30 min and 6 h were found with PCC. Product B PK results agrees with reported results for other HPFIX preparations. Use of PCC product A has to consider its thrombogenic activity.

  20. Pharmacokinetics and Safety of Caspofungin in Neonates and Infants Less than 3 Months of Age▿

    PubMed Central

    Sáez-Llorens, Xavier; Macias, Mercedes; Maiya, Padmanabha; Pineros, Juan; Jafri, Hasan S.; Chatterjee, Archana; Ruiz, Gloria; Raghavan, Janaki; Bradshaw, Susan K.; Kartsonis, Nicholas A.; Sun, Peng; Strohmaier, Kim M.; Fallon, Marissa; Bi, Sheng; Stone, Julie A.; Chow, Joseph W.

    2009-01-01

    Candida infections represent a major threat in neonatal intensive care units. This is the first prospective study to obtain caspofungin plasma levels and safety data for neonates and very young infants. Patients of <3 months of age receiving intravenous amphotericin B for documented or highly suspected candidiasis were enrolled in a single-dose (n = 6) or subsequent multiple-dose (n = 12) panel; all received caspofungin at 25 mg/m2 once daily as a 1-hour infusion. Caspofungin plasma levels were measured by high-performance liquid chromatography and compared to historical data from adults. Patient chronological ages ranged from 1 to 11 weeks, and weights ranged from 0.68 to 3.8 kg. Gestational ages ranged from 24 to 41 weeks. Geometric mean (GM) peak (C1 h) and trough (C24 h) caspofungin levels were 8.2 and 1.8 μg/ml, respectively, on day 1, and 11.1 and 2.4 μg/ml, respectively, on day 4. GM ratios for C1 h and C24 h for neonates/infants relative to adults receiving caspofungin at 50 mg/day were 1.07 and 1.36, respectively, on day 1, and 1.18 and 1.21, respectively, on day 4. Clinical and laboratory adverse events occurred in 17 (94%) and 8 (44%) patients, respectively. Five patients (28%) had serious adverse events, none of which were considered drug related. Caspofungin at 25 mg/m2 once daily was well tolerated in this group of neonates/infants of <3 months of age and appears to provide relatively similar plasma exposure to that obtained in adults receiving 50 mg/day. However, the small number of patients studied precludes any definitive recommendations about caspofungin dosing for this group comprising a broad range of ages and weights. PMID:19075070

  1. Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties

    PubMed Central

    Girolami, Federica; Persiani, Stefano

    2012-01-01

    Glucosamine is an amino monosaccharide and a natural constituent of glycosaminoglycans in articular cartilage. When administered exogenously, it is used for the treatment of osteoarthritis as a prescription drug or a dietary supplement. The latter use is mainly supported by its perception as a cartilage building block, but it actually exerts specific pharmacologic effects, mainly decreasing interleukin 1-induced gene expression by inhibiting the cytokine intracellular signaling cascade in general and nuclear factor-kappa B (NF-kB) activation in particular. As a whole, the use of glucosamine in the management of osteoarthritis is supported by the clinical trials performed with the original prescription product, that is, crystalline glucosamine sulfate. This is the stabilized form of glucosamine sulfate, while other formulations or different glucosamine salts (e.g. hydrochloride) have never been shown to be effective. In particular, long-term pivotal trials of crystalline glucosamine sulfate 1500 mg once daily have shown significant and clinically relevant improvement of pain and function limitation (symptom-modifying effect) in knee osteoarthritis. Continuous administration for up to 3 years resulted in significant reduction in the progression of joint structure changes compared with placebo as assessed by measuring radiologic joint space narrowing (structure-modifying effect). The two effects combined may suggest a disease-modifying effect that was postulated based on an observed decrease in the risk of undergoing total joint replacement in the follow up of patients receiving the product for at least 12 months in the pivotal trials. The safety of the drug was good in clinical trials and in the postmarketing surveillance. Crystalline glucosamine sulfate 1500 mg once daily is therefore recommended in the majority of clinical practice guidelines and was found to be cost effective in pharmacoeconomic analyses. Compared with other glucosamine formulations, salts, or

  2. A randomized, double-blind, placebo-controlled study to investigate the safety, tolerability, and pharmacokinetics of single enantiomer (+)-mefloquine compared with racemic mefloquine in healthy persons.

    PubMed

    Tansley, Robert; Lotharius, Julie; Priestley, Anthony; Bull, Fiona; Duparc, Stephan; Möhrle, Jörg

    2010-12-01

    Racemic mefloquine is a highly effective antimalarial whose clinical utility has been compromised by its association with neuropsychiatric and gastrointestinal side effects. It is hypothesized that the cause of the side effects may reside in the (-) enantiomer. We sought to compare the safety, tolerability and pharmacokinetic profile of (+)-mefloquine with racemic mefloquine in a randomized, ascending-dose, double-blind, active and placebo-controlled, parallel cohort study in healthy male and female adult volunteers. Although differing in its manifestations, both study drugs displayed a substantially worse tolerability profile compared with placebo. The systemic clearance was slower for (-)-mefloquine than (+)-mefloquine. Thus, (+)-mefloquine has a different safety and tolerability profile compared with racemic mefloquine but its global safety profile is not superior and replacement of the currently used antimalarial drug with (+)-mefloquine is not warranted.

  3. The metabolism and pharmacokinetics of phospho-sulindac (OXT-328) and the effect of difluoromethylornithine

    PubMed Central

    Xie, G; Nie, T; Mackenzie, GG; Sun, Y; Huang, L; Ouyang, N; Alston, N; Zhu, C; Murray, OT; Constantinides, PP; Kopelovich, L; Rigas, B

    2012-01-01

    BACKGROUND AND PURPOSE Phospho-sulindac (PS; OXT-328) prevents colon cancer in mice, especially when combined with difluoromethylornithine (DFMO). Here, we explored its metabolism and pharmacokinetics. EXPERIMENTAL APPROACH PS metabolism was studied in cultured cells, liver microsomes and cytosol, intestinal microsomes and in mice. Pharmacokinetics and biodistribution of PS were studied in mice. KEY RESULTS PS undergoes reduction and oxidation yielding PS sulphide and PS sulphone; is hydrolysed releasing sulindac, which generates sulindac sulphide (SSide) and sulindac sulphone (SSone), all of which are glucuronidated. Liver and intestinal microsomes metabolized PS extensively but cultured cells converted only 10% of it to PS sulphide and PS sulphone. In mice, oral PS is rapidly absorbed, metabolized and distributed to the blood and other tissues. PS survives only partially intact in blood; of its three major metabolites (sulindac, SSide and SSone), sulindac has the highest Cmax and SSone the highest t1/2; their AUC0–24h are similar. Compared with conventional sulindac, PS generated more SSone but less SSide, which may contribute to the safety of PS. In the gastroduodenal wall of mice, 71% of PS was intact; sulindac, SSide and SSone together accounted for <30% of the total. This finding may explain the lack of gastrointestinal toxicity by PS. DFMO had no effect on PS metabolism but significantly reduced drug level in mouse plasma and other tissues. CONCLUSIONS AND IMPLICATIONS Our findings establish the metabolism of PS define its pharmacokinetics and biodistribution, describe its interactions with DFMO and largely explain its gastrointestinal safety. PMID:21955327

  4. The metabolism and pharmacokinetics of phospho-sulindac (OXT-328) and the effect of difluoromethylornithine.

    PubMed

    Xie, G; Nie, T; Mackenzie, G G; Sun, Y; Huang, L; Ouyang, N; Alston, N; Zhu, C; Murray, O T; Constantinides, P P; Kopelovich, L; Rigas, B

    2012-04-01

    Phospho-sulindac (PS; OXT-328) prevents colon cancer in mice, especially when combined with difluoromethylornithine (DFMO). Here, we explored its metabolism and pharmacokinetics. PS metabolism was studied in cultured cells, liver microsomes and cytosol, intestinal microsomes and in mice. Pharmacokinetics and biodistribution of PS were studied in mice. PS undergoes reduction and oxidation yielding PS sulphide and PS sulphone; is hydrolysed releasing sulindac, which generates sulindac sulphide (SSide) and sulindac sulphone (SSone), all of which are glucuronidated. Liver and intestinal microsomes metabolized PS extensively but cultured cells converted only 10% of it to PS sulphide and PS sulphone. In mice, oral PS is rapidly absorbed, metabolized and distributed to the blood and other tissues. PS survives only partially intact in blood; of its three major metabolites (sulindac, SSide and SSone), sulindac has the highest C(max) and SSone the highest t(1/2) ; their AUC(0-24h) are similar. Compared with conventional sulindac, PS generated more SSone but less SSide, which may contribute to the safety of PS. In the gastroduodenal wall of mice, 71% of PS was intact; sulindac, SSide and SSone together accounted for <30% of the total. This finding may explain the lack of gastrointestinal toxicity by PS. DFMO had no effect on PS metabolism but significantly reduced drug level in mouse plasma and other tissues. Our findings establish the metabolism of PS define its pharmacokinetics and biodistribution, describe its interactions with DFMO and largely explain its gastrointestinal safety. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  5. A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers.

    PubMed

    Chilengi, Roma; Juma, Rashid; Abdallah, Ahmed M; Bashraheil, Mahfudh; Lodenyo, Hudson; Nyakundi, Priscilla; Anabwani, Evelyn; Salim, Amina; Mwambingu, Gabriel; Wenwa, Ednah; Jemutai, Julie; Kipkeu, Chemtai; Oyoo, George O; Muchohi, Simon N; Kokwaro, Gilbert; Niehues, Tim; Lang, Trudie; Nzila, Alexis

    2011-03-16

    Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C(max)) was 160-200 nM and after 6 hours, the effective concentration (C(eff)) was <150 nM. Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable C(eff) of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

  6. Grepafloxacin: an overview of antibacterial activity, pharmacokinetics, clinical efficacy and safety.

    PubMed

    Geddes, A M

    1999-04-01

    chronic bronchitis (ABECB), 7-10 days treatment with o.d. grepafloxacin 400 mg or 600 mg has been shown to be equivalent to that with either t.i.d. amoxycillin 500 mg, or b.i.d. ciprofloxacin 500 mg. In patients with a documented bacterial pathogen, microbiological success with both grepafloxacin dosage regimens was superior to amoxycillin 500 mg t.i.d. In addition, short course treatment of ABECB with 400 mg of grepafloxacin given o.d. for five days has been shown to be as effective, clinically and microbiologically as a ten-day course of the same dose. The safety profile of grepafloxacin has been well-characterised from data from over 12,000 patients treated in Phase II/III and post-marketing studies, and over 400,000 patients treated worldwide in routine clinical practice. The most commonly reported adverse events are gastrointestinal, mainly nausea and unpleasant taste. The potential for photosensitivity and central nervous system effects is low, and there have been no reports of convulsions. No unique or unexpected.

  7. Pharmacokinetics, Safety, and 48-Week Efficacy of Oral Raltegravir in HIV-1–Infected Children Aged 2 Through 18 Years

    PubMed Central

    Nachman, Sharon; Zheng, Nan; Acosta, Edward P.; Teppler, Hedy; Homony, Brenda; Graham, Bobbie; Fenton, Terence; Xu, Xia; Wenning, Larissa; Spector, Stephen A.; Frenkel, Lisa M.; Alvero, Carmelita; Worrell, Carol; Handelsman, Edward; Wiznia, Andrew; Moultrie, Harry; Kindra, Gurpreet; Sanders, Margaret Ann; Williams, Ruth; Jensen, Jennifer; Acevedo, Midnela; Fabregas, Lizbeth; Jurgrau, Andrea; Foca, Marc; Higgins, Alice; Deville, Jaime G.; Nielsen-Saines, Karin; Carter, Michele F.; Swetnam, John; Wilson, Joan; Donnelly, Margaret; Akleh, Siham; Rigaud, Mona; Kaul, Aditya; Patel, Nehali; Gaur, Aditya; Utech, L. Jill; Cardoso, Edmundo; Moreira, Ana Maria; Santos, Breno; Bobat, Raziya; Mngqibisa, Rosie; Burey, Marlene; Abadi, Jacob; Rosenberg, Michael; Luzuriaga, Katherine; Picard, Donna; Pagano-Therrien, Jessica; Dittmer, Sylvia; Ndiweni, Hilda Ntatule; Patel, Amisha; DelRey, Michelle; McMullen-Jackson, Chivon; Paul, Mary E.; Melvin, Ann; Venema-Weiss, Corry; Lane, Jenna; Beneri, Christy; Ferraro, Denise; Infanzon, Erin; McAuley, James B; Aziz, Mariam; McNichols, Maureen; Pelton, Stephen; McLaud, Deb; Clarke, Diana; Zeichner, Steven; Akar, Arezou; Thompson, Deidre; Douglas, Steven D.; Rutstein, Richard M.; Vincent, Carol A.; Vachon, Mary Elizabeth; Cavallo, Martha; Purswani, Murli Udharam; Masheto, Gaerolwe; Ogwu, Anthony; Kakhu, Tebogo; Viani, Rolando M.; Darcey, Anita,; Norris, Kimberly; Burchett, Sandra K.; Kneut, Catherine; Karthas, Nancy; Casey, Denise; Emmanuel, Patricia; Lujan-Zilbermann, Jorge; Rana, Sohail; Houston, Patricia; Mengistab, Mulu; Rathore, Mobeen; Mirza, Ayesha; Gayton, Tabetha; Barr, Emily; Dunn, Jennifer; Hahn, Kerry; Eysallenne, Zulma; Howard, F. Sholar; Graham, Kathleen; Negra, Marinella Della; Queiroz, Wladimir; Lian, Yu Ching; Wara, Diane; Ruel, Ted; VanDyke, Russell; Reilly, Patricia; Bradford, Sheila; van Rensburg, Anita Janse; Dobbels, Els; Bester, Marietjie; Bamji, Mahrukh; Paul, Santa; Sarza, Mirala; Kovacs, Andrea; Homans, James; Spencer, LaShonda; Hofer, Cristna; Abreu, Thalita; Oliveira, Ricardo; Joao, Esau C.; Pinto, Jorge; Ferreira, Flavia; Kakehasi, Fabiana; Cervi, Maria Celia; Isaac, Marcia De Lima; Losso, Marcelo H.; Stankievich, Erica; Foradori, Irene; Tucker, Diane; Church, Joseph; Belzer, Marvin; Hopkins, Johns; Ellen, Jonathan; Agwu, Allison; Laurel, Borkovic

    2014-01-01

    Background. IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)–infected youth. Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction between baseline and week 24. Results. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/µL (4.6%). Conclusions. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses. Clinical Trials Registration NCT00485264. PMID:24145879

  8. Safety, efficacy and pharmacokinetics of humanized anti-CD52 monoclonal antibody alemtuzumab in Japanese patients with relapsed or refractory B-cell chronic lymphocytic leukemia.

    PubMed

    Ishizawa, Kenichi; Fukuhara, Noriko; Nakaseko, Chiaki; Chiba, Shigeru; Ogura, Michinori; Okamoto, Akihiko; Sunaga, Yoshinori; Tobinai, Kensei

    2017-01-01

    To evaluate the safety, efficacy and pharmacokinetics of alemtuzumab in Japanese patients, we conducted a phase I study in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. Six patients received alemtuzumab by intravenous infusion every other day three times a week for 12 weeks. The dose was gradually escalated on daily basis (3, 10 and then 30 mg) until the patient tolerated. The primary objective was to evaluate the safety of alemtuzumab in Japanese patients and the secondary objectives were to evaluate the overall response rate and the pharmacokinetics. The major treatment-emergent adverse events were anemia, neutropenia (6/6 patients each) and thrombocytopenia (5/6 patients) in hematologic adverse events, and nausea, vomiting, decreased appetite, cytomegalovirus test positive and pyrexia (4/6 patients) in non-hematologic adverse events. As serious adverse events, cytomegalovirus infection, pulmonary tuberculosis and diffuse large B-cell lymphoma were reported in 1/6 patient each. The overall response rate was 33% (95% confidence interval: 4-78) (1/6 patient each achieved complete response and partial response, respectively) and 3/6 patients had stable disease and 1/6 patient had progressive disease. The median time to response was 2.9 months. After last intravenous dosing (Week 12) of alemtuzumab 30 mg every other day three times a week, Cmax, tmax, AUC0-τ and t1/2 were higher and CL and Vss were lower than the values observed after the first dose. The efficacy, safety and pharmacokinetics results observed with alemtuzumab in Japanese patients were generally similar to those reported in overseas clinical studies. Alemtuzumab at 30 mg by intravenous infusion every other day three times a week for 12 weeks should be safe and effective similarly in Japanese B-cell chronic lymphocytic leukemia patients. NCT00923182. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Quantitative cumulative biodistribution of antibodies in mice

    PubMed Central

    Yip, Victor; Palma, Enzo; Tesar, Devin B; Mundo, Eduardo E; Bumbaca, Daniela; Torres, Elizabeth K; Reyes, Noe A; Shen, Ben Q; Fielder, Paul J; Prabhu, Saileta; Khawli, Leslie A; Boswell, C Andrew

    2014-01-01

    The neonatal Fc receptor (FcRn) plays an important and well-known role in antibody recycling in endothelial and hematopoietic cells and thus it influences the systemic pharmacokinetics (PK) of immunoglobulin G (IgG). However, considerably less is known about FcRn’s role in the metabolism of IgG within individual tissues after intravenous administration. To elucidate the organ distribution and gain insight into the metabolism of humanized IgG1 antibodies with different binding affinities FcRn, comparative biodistribution studies in normal CD-1 mice were conducted. Here, we generated variants of herpes simplex virus glycoprotein D-specific antibody (humanized anti-gD) with increased and decreased FcRn binding affinity by genetic engineering without affecting antigen specificity. These antibodies were expressed in Chinese hamster ovary cell lines, purified and paired radiolabeled with iodine-125 and indium-111. Equal amounts of I-125-labeled and In-111-labeled antibodies were mixed and intravenously administered into mice at 5 mg/kg. This approach allowed us to measure both the real-time IgG uptake (I-125) and cumulative uptake of IgG and catabolites (In-111) in individual tissues up to 1 week post-injection. The PK and distribution of the wild-type IgG and the variant with enhanced binding for FcRn were largely similar to each other, but vastly different for the rapidly cleared low-FcRn-binding variant. Uptake in individual tissues varied across time, FcRn binding affinity, and radiolabeling method. The liver and spleen emerged as the most concentrated sites of IgG catabolism in the absence of FcRn protection. These data provide an increased understanding of FcRn’s role in antibody PK and catabolism at the tissue level. PMID:24572100

  10. Pharmacokinetics and safety of olopatadine hydrochloride 0.77% in healthy subjects with asymptomatic eyes: data from 2 independent clinical studies

    PubMed Central

    Meier, Edward; Narvekar, Abhijit; Iyer, Ganesh R; DuBiner, Harvey B; Vutikullird, Apinya; Wirta, David; Sall, Kenneth

    2017-01-01

    Purpose To assess the pharmacokinetics and safety of hydrochloride ophthalmic solution 0.77% olopatadine from 2 independent (Phase I and Phase III, respectively) clinical studies in healthy subjects. Materials and methods The Phase I, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥18 years old (N=36) to assess the systemic pharmacokinetics of olopatadine 0.77% following single- and multiple-dose exposures. The Phase III, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥2 years old (N=499) to evaluate long-term ocular safety of olopatadine 0.77%. Subjects received olopatadine 0.77% or vehicle once daily bilaterally for 7 days in the pharmacokinetic study and 6 weeks in the safety study. Results In the pharmacokinetic study, olopatadine 0.77% was absorbed slowly and reached a peak plasma concentration (Cmax) of 1.65 ng/mL following single-dose and 1.45 ng/mL following multiple-dose exposures in 2 hours (time to reach maximum plasma concentration [Tmax]). After reaching peak concentrations, olopatadine showed a similar mono-exponential decay following single and multiple doses with mean elimination half-life ranging from 2.90 to 3.40 hours. No accumulation in olopatadine exposure (Cmax and area under the plasma concentration–time curve from 0 to 12 hours) was evident after multiple doses when compared to single dose. In the safety study, treatment-emergent adverse events were reported in 26.7% and 31.4% of subjects with olopatadine 0.77% and vehicle, respectively. Blurred vision was the most frequent ocular treatment-emergent adverse event in both treatment groups (olopatadine 0.77% vs vehicle, 4.8% vs 4.1%). No deaths or serious adverse events were reported during the study. Conclusion Olopatadine 0.77% had minimal systemic exposure or accumulation in healthy subjects and was well tolerated in both adult and pediatric subjects. PMID:28435218

  11. Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers.

    PubMed

    Frey, Reiner; Mück, Wolfgang; Unger, Sigrun; Artmeier-Brandt, Ulrike; Weimann, Gerrit; Wensing, Georg

    2008-08-01

    The aim of the study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of BAY 63-2521, a new drug in development for pulmonary hypertension. Fifty-eight healthy male volunteers received a single oral dose of BAY 63-2521 (0.25-5 mg) or placebo. No serious adverse events were reported; there were no life-threatening events. Heart rate over 1 minute, an indicator of the effect of a vasodilating agent on the cardiovascular system in healthy subjects, was increased dose dependently versus placebo at BAY 63-2521 doses of 1 to 5 mg (P < .01). Mean arterial and diastolic pressures were decreased versus placebo at doses of 1 mg (P < .05) and 5 mg (P < .01). Systolic pressure was not significantly affected. BAY 63-2521 was readily absorbed and exhibited dose-proportional pharmacokinetics. The pharmacodynamic and pharmacokinetic properties of BAY 63-2521 suggest that it can offer a unique mode of action in the treatment of pulmonary hypertension.

  12. Non-clinical safety and pharmacokinetic evaluations of propylene glycol aerosol in Sprague-Dawley rats and Beagle dogs.

    PubMed

    Werley, Michael S; McDonald, Paddy; Lilly, Patrick; Kirkpatrick, Daniel; Wallery, Jeffrey; Byron, Peter; Venitz, Jürgen

    2011-09-05

    Aerosolized propylene glycol (PG) was generated as log-normally distributed particulate clouds in different concentrations using a novel capillary aerosol generator (CAG) and evaluated in a battery of non-clinical studies intended to assess its potential inhalation and systemic toxicity in 2 species before ICH-compliant "first-time-in-man" studies. Exposures were nose-only in rats, and via face mask with oropharyngeal tube in dogs. The CAG-generated PG aerosol had a mass median aerodynamic diameter (MMAD) of 2.29μm, with a 1.56 geometric standard deviation (GSD) in the rat studies, and a MMAD of 1.34μm (1.45 GSD) in the dog studies, consistent with expected particle size exposures in man. International Congress on Harmonization (ICH) Guidelines were followed, which recommend preliminary non-clinical safety studies using the vehicle and device (CAG-PG) prior to the first human exposure including safety pharmacology, pharmacokinetic (PK) studies, single dose toxicity studies, and repeated dose toxicity studies in two species. In the rat, the only biologically relevant findings included clinical signs of ocular and nasal irritation indicated by minor bleeding around the eyes and nose, and minimal laryngeal squamous metaplasia. This finding is commonly observed in inhalation studies in the rat, and likely related to the unique sensitivity of the tissue, as well as the circuitous airflow pathway through the larynx which increases particle deposition. In the female Beagle dog, treatment-related decreases in hemoglobin, red blood cells and hematocrit were observed in the two highest exposure groups, equivalent to approximately 18 and 60mg/kg/day. In male dogs from the high dose group, similar small decreases, albeit, non-statistically significant decreases were observed in these hematological markers as well. PK studies in rats and dogs showed that the absorption of PG following pulmonary inhalation exposure occurs rapidly, and equilibrium between lung tissue and plasma

  13. Safety, Tolerability, and Pharmacokinetic Characteristics of a Novel Nonopioid Analgesic, VVZ-149 Injections in Healthy Volunteers: A First-in-Class, First-in-Human Study.

    PubMed

    Oh, Jaeseong; Lee, SeungHwan; Kim, Anhye; Yoon, Jangsoo; Jang, Kyungho; Lee, Doo H; Cho, Sunyoung; Lee, Sang Rim; Yu, Kyung-Sang; Chung, Jae-Yong

    2017-08-16

    VVZ-149, a dual antagonist of GlyT2 and 5HT2 A receptors, is an investigational analgesic with a novel mechanism of action that is currently under early-stage clinical development as an injectable agent for the treatment of postoperative pain. Here, the safety, tolerability, and pharmacokinetics of VVZ-149 injections in healthy male volunteers were explored in a randomized, double-blind, single- and multiple-ascending-dose (SAD and MAD, respectively), placebo-controlled clinical study. Subjects randomly received a 4-hour intravenous infusion of 0.25-8 mg/kg VVZ-149 or placebo in the SAD study (n = 46) or a 4-hour intravenous infusion of 4-7 mg/kg VVZ-149 or placebo twice daily for 3 days in the MAD study (n = 20). Serial blood and urine samples were collected for the pharmacokinetic analysis of VVZ-149 and its active metabolite (VVZ-368). Noncompartmental and compartmental pharmacokinetic analyses were performed. Various dosing scenarios were simulated to identify the adequate dosing regimen for the subsequent trials. Plasma exposure to VVZ-149 and VVZ-368 showed a dose-proportional increase. VVZ-149 did not accumulate in the plasma, whereas the plasma concentration of VVZ-368 increased by 1.23- to 2.49-fold after the fifth and sixth doses, respectively, in the MAD trial. Among the simulated dosing regimens, a loading dose followed by a maintenance dose was found to be an optimal dosing regimen, yielding the effective concentration estimated from animal studies in rat models of neuropathic or inflammatory pain. Single- or multiple-dose administration of VVZ-149 was generally well tolerated. These results showed that 0.5-8 mg/kg VVZ-149 exhibited linear pharmacokinetic characteristics and can be safely administered in further clinical studies. © 2017, The American College of Clinical Pharmacology.

  14. Safety and pharmacokinetics of hyperimmune anti-human immunodeficiency virus (HIV) immunoglobulin administered to HIV-infected pregnant women and their newborns. Pediatric AIDS Clinical Trials Group Protocol 185 Pharmacokinetic Study Group.

    PubMed

    Lambert, J S; Mofenson, L M; Fletcher, C V; Moye, J; Stiehm, E R; Meyer, W A; Nemo, G J; Mathieson, B J; Hirsch, G; Sapan, C V; Cummins, L M; Jimenez, E; O'Neill, E; Kovacs, A; Stek, A

    1997-02-01

    The pharmacokinetics and safety of hyperimmune anti-human immunodeficiency virus (HIV) intravenous immunoglobulin (HIVIG) were evaluated in the first 28 maternal-infant pairs enrolled in a randomized, intravenous immunoglobulin (IVIG)-controlled trial of HIVIG maternal-infant HIV transmission prophylaxis. Using 200 mg/kg, mean half-life and volume of distribution (Vd) in women were 15 days and 72 mL/kg, respectively, after one and 32 days and 154 mL/kg after three monthly infusions, with stable 4 mL/kg/day clearance. Transplacental passage occurred. Newborn single-dose half-life, Vd, and clearance were 30 days, 143 mL/kg, and 4 mL/kg/day, respectively. HIVIG rapidly cleared maternal serum immune complex-dissociated p24 antigen, and plasma HIV-1 RNA levels were stable. Mild to moderate adverse clinical effects occurred in 2 of 103 maternal and 2 of 25 infant infusions. No adverse hematologic, blood chemistry, or immunologic effects were seen. HIVIG is well-tolerated in HIV-infected pregnant women and their newborns, clears antigenemia, crosses the placenta, and exhibits pharmacokinetics similar to those of other immunoglobulin preparations.

  15. A Randomized Phase 1 Dose Escalation Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Trabodenoson in Healthy Adult Volunteers

    PubMed Central

    Laties, Alan; Rich, Cadmus C.; Stoltz, Randall; Humbert, Vernon; Brickman, Chaim; McVicar, William

    2016-01-01

    Abstract Purpose: To investigate the safety, tolerability, and pharmacokinetics of trabodenoson, a highly selective adenosine mimetic targeting the adenosine A1 receptor. Methods: In Part 1, 60 healthy adult volunteers were randomized to 14 days of twice-daily topical monocular application of placebo or trabodenoson (200, 400, 800, 1,600, 2,400, or 3,200 μg). In Part 2, 10 subjects were randomized to placebo or 8 escalating doses of bilateral trabodenoson (total daily doses: 1,800–6,400 μg). Results: The incidence of treatment-related adverse events in Part 1 was similar in the trabodenoson (27.8%) and placebo (25.0%) groups. Most were mild in intensity. The most common adverse events (AEs) for trabodenoson and placebo were headache (25.0% vs. 33%, respectively) and eye pain (11.1% vs. 4.2%, respectively). Ocular AEs were infrequent (16.7% and 17.9%, respectively), were self-limited, lasted <24 h, and were typically mild in intensity. The most common ocular AE was eye pain (9.5% and 3.6%, respectively), with a single observation of ocular hyperemia (200 μg trabodenoson). Trabodenoson was rapidly absorbed [median time to maximum concentration (tmax): ∼0.08 to 0.27 h] and eliminated (t½: 0.48–2.0 h), with no evidence of drug accumulation. Systemic exposure to topical trabodenoson was dose related but not dose proportional, with a plateau effect at doses ≥2,400 mg per eye. No clinically significant treatment-related systemic AEs were observed, and increasing systemic exposure had no effect on heart rate or blood pressure. Conclusions: Ocular doses of trabodenoson up to 3,200 μg per eye were safe and well tolerated in the eye and resulted in no detectable systemic effects in healthy adult volunteers. PMID:27046445

  16. Safety, pharmacokinetics and pharmacological effects of the selective androgen receptor modulator, GSK2881078, in healthy men and postmenopausal women.

    PubMed

    Clark, Richard V; Walker, Ann C; Andrews, Susan; Turnbull, Philip; Wald, Jeffrey A; Magee, Mindy H

    2017-10-01

    Selective androgen receptor modulators (SARMs) induce anabolic effects on muscle without the adverse effects of androgenic steroids. In this first-in-human study, we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of the SARM GSK2881078. In Part A, healthy young men (n = 10) received a single dose of study drug (0 mg, 0.05 mg, 0.1 mg, 0.2 mg GSK2881078 or matching-placebo). In Part B, repeat-dose cohorts in men (n = 65) were 0.05 mg, 0.2 mg then 0.08 mg, 0.24 mg, 0.48 mg, 0.75 mg, or placebo; in women (n = 24) they were 0.24 mg, 0.35 mg, or placebo (7 days for 0.5 mg, 14 days for other doses). PK analysis showed dose-proportional increases in exposure and a long >100-h half-life. No significant effects on vital signs, electrocardiograms, cardiac telemetry or standard clinical laboratory studies were observed. A dose-response effect was observed on lowering both high-density lipoprotein and sex hormone-binding globulin. In females at 0.35 mg, differences from placebo were -0.518 (95% confidence interval: -0.703, -0.334) mmol l(-1) and -39.1 (-48.5, -29.7) nmol l(-1) , respectively. Women showed greater sensitivity to these parameters at lower doses than men. Drug-related adverse events (AEs) were mild. One woman developed a drug rash and was withdrawn. Two men had elevated creatine phosphokinase after physical exertion during follow-up. A serious AE occurred in a subject on placebo. These data demonstrate pharmacodynamic effects with acceptable tolerability and support further clinical evaluation of this SARM. © 2017 The British Pharmacological Society.

  17. Safety, Pharmacokinetics, Pharmacodynamics, and Activity of Navitoclax, a Targeted High Affinity Inhibitor of BCL-2, in Lymphoid Malignancies

    PubMed Central

    Wilson, Wyndham H.; O’Connor, Owen A.; Czuczman, Myron S.; LaCasce, Ann S.; Gerecitano, John F.; Leonard, John P.; Tulpule, Anil; Dunleavy, Kieron; Xiong, Hao; Chiu, Yi-Lin; Cui, Yue; Busman, Todd; Elmore, Steven W.; Rosenberg, Saul H.; Krivoshik, Andrew P.; Enschede, Sari H.; Humerickhouse, Rod A.

    2010-01-01

    SUMMARY Background BCL-2 family proteins play a central role in regulating clonal selection and survival of lymphocytes and are frequently over expressed in lymphomas. Navitoclax (ABT-263) is a targeted high-affinity small molecule that occupies the BH3 binding groove of BCL-2 and BCL-XL and inhibits their anti-apoptotic activity. Experimentally, navitoclax kills cells in a BAX/BAK-dependent manner and results in regression of lymphoid tumors in xenograft models. Methods This is a phase I dose-escalation study of navitoclax in patients with relapsed or refractory lymphoid malignancies. Study endpoints included safety, maximum tolerated dose (MTD), pharmacokinetic profile and clinical activity. In addition, mechanism-based pharmacodynamic effects on platelets and lymphocytes were assessed. Navitoclax was orally administered and assessed on an intermittent schedule of once daily for 14 days followed by 7 days off (14/21 days) or on a continuous once daily schedule (21/21 days). This trial is registered with ClinicalTrials.gov, number NCT00406809. Findings Fifty-five patients were enrolled, (median age 59 years, IQR 51–67), of whom two did not complete the first cycle and were not evaluable for assessment of dose-limiting toxicity (DLT). Common toxicities included grade 1/2 diarrhea and fatigue in 31 and 21 patients, respectively. Thrombocytopenia and neutropenia were the serious common toxicities with grade 3/4 observed in 29 and 17 patients, respectively. On the intermittent schedule (14/21), 5 DLT’s were observed; two due to hospitalizations for bronchitis and pleural effusion, and one each due to grade 3 transaminase elevation, grade 4 thrombocytopenia and grade 3 cardiac arrhythmia. Navitoclax caused a rapid and dose-dependent decline in peripheral platelets following initial drug exposure, followed by a rebound. To reduce the platelet nadir associated with intermittent dosing, a lead-in dose followed by continuous dosing (21/21 schedule) was examined. Three

  18. Daptomycin versus Vancomycin in a Methicillin-Resistant Staphylococcus aureus Endophthalmitis Rabbit Model: Bactericidal Effect, Safety, and Ocular Pharmacokinetics

    PubMed Central

    Saleh, Maher; Marcellin, Luc; Subilia, Audrey; Bourcier, Tristan; Prévost, Gilles; Jehl, François

    2012-01-01

    Staphylococcus aureus is a frequent cause of acute endophthalmitis, and infection with this virulent bacterium is often associated with a poor visual outcome. In this study, we investigated the bactericidal efficacy and the safety of intravitreal daptomycin (DAP), a lipopeptide antibiotic with broad-spectrum activity against Gram-positive bacteria, compared with those of intravitreal vancomycin (VAN) in a methicillin-resistant S. aureus endophthalmitis rabbit model. The pharmacokinetics and pharmacodynamics of daptomycin in the infected eyes were also studied. Rabbits were randomly divided into three treatment groups (n = 8) and one untreated group (n = 4), to compare the effect of single intravitreal injections of 0.2 mg and 1 mg of daptomycin (DAP 0.2 and DAP 1 groups, respectively) with that of 1 mg of intravitreal vancomycin (VAN 1 group). Vitreal aspirates were regularly collected and grading of ocular inflammation was regularly performed until euthanasia on day 7. In the DAP 0.2 group, 62.5% of the eyes were sterilized and the mean bacterial count presented a reduction of 1 log unit. In the DAP 1 and VAN 1 groups, the infection was eradicated (100% and 87.5% of eyes sterilized, respectively), with a 4-log-unit reduction of the mean bacterial count. The bactericidal efficacy in the DAP 1 group was not inferior to that in the VAN 1 group and was superior to that of the other regimens in limiting the ocular inflammation and preserving the architecture of the ocular structures (P < 0.05). The elimination half-life (t1/2β) of daptomycin was independent of the administered dose (38.8 ± 16.5 h and 40.9 ± 6.7 h, respectively, for the DAP 0.2 and DAP 1 groups) and was significantly longer than the t1/2β of vancomycin (20.5 ± 2.0 h for the VAN 1 group) (P < 0.05). This antibiotic could therefore be considered for the treatment of intraocular infections caused by Gram-positive bacteria. PMID:22371888

  19. Pharmacokinetic and Safety Evaluation of BILR 355, a Second-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers▿

    PubMed Central

    Huang, Fenglei; Koenen-Bergmann, Michael; MacGregor, Thomas R.; Ring, Arne; Hattox, Susan; Robinson, Patrick

    2008-01-01

    BILR 355 is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) under clinical development for the treatment of human immunodeficiency virus infection, particularly in those who harbor virus resistant to the currently available NNRTIs. Two single-center, double-blinded, placebo-controlled, parallel dose-escalation studies were conducted to evaluate the pharmacokinetics and safety of oral BILR 355 administration alone and after coadministration with ritonavir (RTV) at 100 mg. Following a single dose of BILR 355 in oral solution, the mean half life (t1/2) was 2 to 4 h, with peak concentrations occurring at 0.5 to 1 h postadministration. The mean apparent clearance (CL/F) ranged from 79.2 to 246 liters/h for administered doses of 12.5 mg to 100 mg. This observed nonlinearity in CL/F resulted from the increased bioavailability attributed to a saturated absorption and/or elimination process at higher doses. In contrast, after the coadministration of single doses of 5 mg to 87.5 mg of BILR 355 with RTV, the mean CL/F ranged from 5.88 to 8.47 liters/h. Over the dose range (5 to 87.5 mg) studied, systemic BILR 355 exposures were approximately proportional to the doses administered when they were coadministered with RTV. With RTV coadministration, the mean t1/2 increased to 10 to 16 h, and the mean time of the maximum concentration in plasma lengthened to 1.5 to 5 h. Compared to the values for BILR 355 given alone, the mean area under the concentration-time curve from time zero to infinity, the maximum concentration in plasma, and the t1/2 of BILR 355 achieved after coadministration with RTV increased 15- to 30-fold, 2- to 5-fold, and 3- to 5-fold, respectively. In both studies, BILR 355 appeared to be safe and well tolerated in healthy volunteers when the outcomes in the treated volunteers were compared with those in the placebo group. PMID:18824608

  20. Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects.

    PubMed

    Bruderer, Shirin; Hurst, Noémie; Kaufmann, Priska; Dingemanse, Jasper

    2014-01-01

    The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 µg; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 µg between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. Dose levels of selexipag up to 1,600 μg were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curve and the maximum plasma concentration, the pharmacokinetics of selexipag and ACT-333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct of future clinical trials. © 2014 S. Karger AG, Basel.

  1. Pharmacokinetics, safety, and efficacy of APF530 (extended-release granisetron) in patients receiving moderately or highly emetogenic chemotherapy: results of two Phase II trials.

    PubMed

    Gabrail, Nashat; Yanagihara, Ronald; Spaczyński, Marek; Cooper, William; O'Boyle, Erin; Smith, Carrie; Boccia, Ralph

    2015-01-01

    Despite advances with new therapies, a significant proportion of patients (>30%) suffer delayed-onset chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 pharmacokinetics, safety, and efficacy were studied in two open-label, single-dose Phase II trials (C2005-01 and C2007-01, respectively) in patients receiving moderately emetogenic chemotherapy or highly emetogenic chemotherapy. In C2005-01, 45 patients received APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively). In C2007-01, 35 patients were randomized to APF530 250 or 500 mg SC. Injections were given 30 to 60 minutes before single-day moderately emetogenic chemotherapy or highly emetogenic chemotherapy. Plasma granisetron was measured from predose to 168 hours after study drug administration. Safety and efficacy were also evaluated. APF530 pharmacokinetics were dose proportional, with slow absorption and elimination of granisetron after a single SC dose. Median time to maximum plasma concentration and half-life were similar for APF530 250 and 500 mg in both trials, with no differences between the groups receiving moderately and highly emetogenic chemotherapy. Exposure to granisetron was maintained at a therapeutic level over the delayed-onset phase, at least 168 hours. Adverse events in both trials were as expected for granisetron; injection site reactions (eg, erythema and induration) were predominantly mild and seen in ≤20% of patients. Complete responses (no emesis, with no rescue medication) were obtained in the acute, delayed, and overall phases in ≥80% and ≥75% of patients in both trials with the 250 and 500 mg doses, respectively. After a single injection of APF530, there were dose-proportional pharmacokinetics and sustained concentrations of granisetron over 168 hours. The 250 and 500 mg doses were well tolerated and maintained therapeutic granisetron

  2. Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV-1106, a Long-Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects.

    PubMed

    Cohen-Barak, Orit; Barkay, Hadas; Rasamoelisolo, Michele; Butler, Kathleen; Yamada, Kazumasa; Bassan, Merav; Yoon, Esther; Spiegelstein, Ofer

    2017-07-01

    TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV-1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV-1106 demonstrated relatively slow absorption (median tmax , 10-30 hours) and a mean elimination half-life of 26-36 hours. Apparent clearance and volume of distribution decreased with increasing TV-1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) increased in a dose-related manner, with maximum responses observed at 33-96 and 42-109 hours, respectively. IGF-1 and IGFBP-3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV-1106, and 336 hours following 50 and 100 mg of TV-1106. TV-1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV-1106 between Japanese and caucasian populations. The data also demonstrate long-acting growth hormone properties of TV-1106 and support its potential for once-weekly dosing. © 2016, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

  3. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients

    PubMed Central

    Negrier, Claude; Klamroth, Robert; Tiede, Andreas; Pabinger-Fasching, Ingrid; Voigt, Christine; Jacobs, Iris; Morfini, Massimo

    2012-01-01

    A recombinant fusion protein linking coagulation factor IX (FIX) with human albumin (rIX-FP) has been developed to facilitate hemophilia B treatment by less frequent FIX dosing. This first-in-human dose-escalation trial in 25 previously treated subjects with hemophilia B (FIX ≤ 2 IU/dL) examined the safety and pharmacokinetics of 25, 50, and 75 IU/kg rIX-FP. Patients in the 50-IU/kg cohort underwent a comparative pharmacokinetics assessment with their previous FIX product (plasma-derived or recombinant). No allergic reactions or inhibitors were observed. Four mild, possibly treatment-related adverse events were reported. In the 50-IU/kg cohort (13 subjects), the mean half-life of rIX-FP was 92 hours, more than 5 times longer than the subjects' previous FIX product. After 25 or 50 IU/kg rIX-FP administration, the baseline-corrected mean FIX activity remained elevated at day 7 (7.4 IU/dL and 13.4 IU/dL, respectively) and day 14 (2.5 IU/dL and 5.5 IU/dL, respectively). The incremental recovery of rIX-FP was higher than both recombinant and plasma-derived FIX (1.4 vs 0.95 and 1.1 IU/dL per IU/kg, respectively). These results demonstrated both the safety and improved pharmacokinetics of rIX-FP, thus indicating this new product with extended half-life as possibly able to control and prevent bleeding with less frequent injection. The trial was registered at www.clinicaltrials.gov as no. NCT01233440. PMID:22859609

  4. A Pharmacokinetic and Safety Study of Trebananib, a Fc-Fusion Peptibody, in Patients with Advanced Solid Tumors and Varying Degrees of Renal Dysfunction.

    PubMed

    Wu, Benjamin; Lewis, Lionel D; Harvey, R Donald; Rasmussen, Erik; Gamelin, Erick; Sun, Yu-Nien; Friberg, Gregory; Koyner, Jay L; Dowlati, Afshin; Maitland, Michael L

    2017-01-11

    Clearance of trebananib (AMG 386), a 64 kD anti-angiogenic peptibody, has been associated with estimated glomerular filtration rate (eGFR). We prospectively evaluated trebananib pharmacokinetics and safety/tolerability in advanced solid tumor patients with varying degrees of renal function. Patients were assigned to normal renal function, mild, moderate, or severe renal dysfunction cohorts based on eGFR, received trebananib 15 mg/kg IV weekly, and underwent week 1 and week 5 pharmacokinetic and weekly safety assessments. For 28 patients, trebananib clearance decreased from normal renal function (1.52 mL/hr/kg), to mild (1.20 mL/hr/kg), moderate (0.79 mL/hr/kg), and severe (0.53 mL/hr/kg) renal dysfunction (P ≤ 0.001). Treatment-related adverse events showed no association with clearance. Trebananib clearance was proportional to eGFR and unrelated to pretreatment protein excretion. These data confirm a role for renal clearance of a recombinant peptibody with molecular weight < 69 kD and support a longer dosing interval for patients with severe renal dysfunction. This article is protected by copyright. All rights reserved.

  5. Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users.

    PubMed

    Harris, Stephen C; Perrino, Peter J; Smith, Ira; Shram, Megan J; Colucci, Salvatore V; Bartlett, Cynthia; Sellers, Edward M

    2014-04-01

    The objective of this study was to evaluate abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered, crushed reformulated OxyContin® (oxycodone HCl controlled-release) tablets (ORF), relative to crushed original OxyContin® (OC), oxycodone powder (Oxy API), and OC placebo. This randomized, double-blind, positive- and placebo-controlled crossover study enrolled healthy, adult, nonphysically dependent recreational opioid users with recent history of intranasal drug abuse (N = 27). Active treatments contained oxycodone (30 mg). Pharmacokinetics, pharmacodynamics (e.g., Overall Drug Liking [ODL], Take Drug Again [TDA], and High Visual Analog Scales [VAS]; Subjective Drug Value [SDV]; pupillometry; intranasal irritation), and safety (e.g., adverse events, vital signs, laboratory tests) were assessed to 24 hours postdose. Crushed ORF administration yielded reduced oxycodone Cmax and increased Tmax versus crushed OC and Oxy API. Peak effects for pharmacodynamic measures were delayed with ORF (1-2 hours) versus OC and Oxy API (0.5-1 hour). ODL, TDA, High VAS, and SDV Emax values were significantly lower (P ≤ .05) and some intranasal irritation ratings were greater for ORF versus OC and Oxy API. No significant or unexpected safety findings were observed. Compared with OC and Oxy API, intranasally administered ORF was associated with lower and delayed peak plasma concentrations, decreased drug-liking, and decreased intranasal tolerability. This suggests that ORF has a decreased potential for intranasal oxycodone abuse. There were no significant or unexpected safety findings. As is true for all abuse potential studies, epidemiological or other appropriate post-marketing studies are required to assess the impact of the reduction in intranasal oxycodone abuse potential observed in the present study on real-world patterns of ORF misuse, abuse, and diversion.

  6. First-in-Human Trial of MIV-150 and Zinc Acetate Coformulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence, and Pharmacodynamics

    PubMed Central

    Hoesley, Craig J.; Plagianos, Marlena; Hoskin, Elena; Zhang, Shimin; Teleshova, Natalia; Alami, Mohcine; Novak, Lea; Kleinbeck, Kyle R.; Katzen, Lauren L.; Zydowsky, Thomas M.; Fernández-Romero, José A.; Creasy, George W.

    2016-01-01

    Objective: To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored. Design: A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days. Methods: Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose–response inhibition analysis. Results: Participants (n = 20) ranged from 19–44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti–herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity. Conclusions: PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti–human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted

  7. No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study

    PubMed Central

    2011-01-01

    Background Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in chronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves lung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction effects between inhaled formoterol and oral roflumilast. Methods This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In Regimen A, healthy men were treated with roflumilast (500 μg tablet once daily; Day 2-18) and concomitant formoterol (24 μg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 μg twice daily; Day 2-18) and concomitant roflumilast (500 μg once daily; Day 9-18). Steady-state plasma pharmacokinetics of roflumilast, roflumilast N-oxide and/or formoterol (Cmax and AUC0-τ) as well as pharmacodynamics - blood pressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood eosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8 (Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast plus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling days and Day 19. Adverse events were monitored throughout the study. Results Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic interactions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular parameters as measured by ZCG, and these parameters were not affected during concomitant administration. Formoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval, without changes in the heart rate-corrected QTc interval. There were small effects on the other

  8. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals.

    PubMed

    Chow, H-H Sherry; Cai, Yan; Hakim, Iman A; Crowell, James A; Shahi, Farah; Brooks, Chris A; Dorr, Robert T; Hara, Yukihiko; Alberts, David S

    2003-08-15

    Green tea and green tea polyphenols have been shown to possess cancer preventive activities in preclinical model systems. In preparation for future green tea intervention trials, we have conducted a clinical study to determine the safety and pharmacokinetics of green tea polyphenols after 4 weeks of daily p.o. administration of epigallocatechin gallate (EGCG) or Polyphenon E (a defined, decaffeinated green tea polyphenol mixture). In an exploratory fashion, we have also determined the effect of chronic green tea polyphenol administration on UV-induced erythema response. Healthy participants with Fitzpatric skin type II or III underwent a 2-week run-in period and were randomly assigned to receive one of the five treatments for 4 weeks: 800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG as Polyphenon E once/day, 400 mg EGCG as Polyphenon E twice/day, or a placebo once/day (8 subjects/group). Samples were collected and measurements performed before and after the 4-week treatment period for determination of safety, pharmacokinetics, and biological activity of green tea polyphenol treatment. Adverse events reported during the 4-week treatment period include excess gas, upset stomach, nausea, heartburn, stomach ache, abdominal pain, dizziness, headache, and muscle pain. All of the reported events were rated as mild events. For most events, the incidence reported in the polyphenol-treated groups was not more than that reported in the placebo group. No significant changes were observed in blood counts and blood chemistry profiles after repeated administration of green tea polyphenol products. There was a >60% increase in the area under the plasma EGCG concentration-time curve after 4 weeks of green tea polyphenol treatment at a dosing schedule of 800 mg once daily. No significant changes were observed in the pharmacokinetics of EGCG after repeated green tea polyphenol treatment at a regimen of 400 mg twice daily. The pharmacokinetics of the conjugated metabolites of

  9. A Phase I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients.

    PubMed

    Gutman, Dikla; Hellriegel, Edward; Aycardi, Ernesto; Bigal, Marcelo E; Kunta, Jeevan; Chitra, Rohini; Kansagra, Sujay; Kidron, Orna Srur; Knebel, Helena; Linder, Steven; Ma, Yuju; Pierce, Mark; Winner, Paul K; Spiegelstein, Ofer

    2016-09-01

    To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger

  10. Safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects: two randomized studies.

    PubMed

    Cahn, Anthony; Tal-Singer, Ruth; Pouliquen, Isabelle J; Mehta, Rashmi; Preece, Andrew; Hardes, Kelly; Crater, Glenn; Deans, Amanda

    2013-07-01

    Chronic obstructive pulmonary disease (COPD) has a significant negative impact on quality of life and increases the risk of premature death. Umeclidinium is a long-acting muscarinic receptor antagonist in development for the treatment of COPD with the aim to broaden treatment options for clinicians and patients by providing improved symptom control. To characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects. Two randomized, placebo-controlled, ascending-dose studies were conducted in healthy ipratropium bromide-responsive subjects. In the single-dose study, subjects (n = 20) received umeclidinium (10-350 μg), tiotropium bromide 18 μg and placebo in a crossover dosing schedule. In this study, lung function was assessed for 24 h by measuring specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV1). In the repeat-dose study, subjects (n = 36) received umeclidinium (250-1,000 μg) and placebo for 14 days in a parallel-group schedule. Adverse events (AEs) were reported in five subjects (single-dose study) and 23 subjects (repeat-dose study); none were serious. In both studies, no abnormalities in 12-lead electrocardiogram parameters, 24-h Holter monitoring or lead II monitoring were reported as AEs. Umeclidinium was rapidly absorbed following single-dose administration [time to reach the maximum plasma concentration (tmax) 5-15 min] and repeat-dose administration (tmax 5-7 min). Following repeat dosing, the geometric mean plasma elimination half-life was approximately 27 h and statistically significant accumulation was observed for the area under the plasma concentration-time curve, maximum plasma concentration and cumulative amount of unchanged drug excreted into the urine at 24 h (range 1.5- to 4.5-fold). Umeclidinium at doses of 100 μg and above, and tiotropium bromide demonstrated statistically significant bronchodilatory effects

  11. Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment.

    PubMed

    Panhuizen, I F; Gold, S J A; Buerkle, C; Snoeck, M M J; Harper, N J N; Kaspers, M J G H; van den Heuvel, M W; Hollmann, M W

    2015-05-01

    This study evaluated efficacy and safety of sugammadex 4 mg kg(-1) for deep neuromuscular blockade (NMB) reversal in patients with severe renal impairment (creatinine clearance [CLCR] <30 ml min(-1)) vs those with normal renal function (CLCR ≥80 ml min(-1)). Sugammadex 4 mg kg(-1) was administered at 1-2 post-tetanic counts for reversal of rocuronium NMB. Primary efficacy variable was time from sugammadex to recovery to train-of-four (T4/T1) ratio 0.9. Equivalence between groups was demonstrated if two-sided 95% CI for difference in recovery times was within -1 to +1 min interval. Pharmacokinetics of rocuronium and overall safety were assessed. The intent-to-treat group comprised 67 patients (renal n=35; control n=32). Median (95% CI) time from sugammadex to recovery to T4/T1 ratio 0.9 was 3.1 (2.4-4.6) and 1.9 (1.6-2.8) min for renal patients vs controls. Estimated median (95% CI) difference between groups was 1.3 (0.6-2.4) min; thus equivalence bounds were not met. One control patient experienced acceleromyography-determined NMB recurrence, possibly as a result of premature sugammadex (4 mg kg(-1)) administration, with no clinical evidence of NMB recurrence observed. Rocuronium, encapsulated by Sugammadex, was detectable in plasma at day 7 in 6 patients. Bioanalytical data for sugammadex were collected but could not be used for pharmacokinetics. Sugammadex 4 mg kg(-1) provided rapid reversal of deep rocuronium-induced NMB in renal and control patients. However, considering the prolonged sugammadex-rocuronium complex exposure in patients with severe renal impairment, current safety experience is insufficient to support recommended use of sugammadex in this population. NCT00702715. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies.

    PubMed

    Andrade, E L; Bento, A F; Cavalli, J; Oliveira, S K; Schwanke, R C; Siqueira, J M; Freitas, C S; Marcon, R; Calixto, J B

    2016-12-12

    The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

  13. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

    PubMed Central

    Andrade, E.L.; Bento, A.F.; Cavalli, J.; Oliveira, S.K.; Schwanke, R.C.; Siqueira, J.M.; Freitas, C.S.; Marcon, R.; Calixto, J.B.

    2016-01-01

    The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose. PMID:27982281

  14. First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288.

    PubMed

    Gee, Kelvin W; Olincy, Ann; Kanner, Richard; Johnson, Lynn; Hogenkamp, Derk; Harris, Josette; Tran, Minhtam; Edmonds, Stephen A; Sauer, William; Yoshimura, Ryan; Johnstone, Timothy; Freedman, Robert

    2017-04-01

    Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects. Single-dose oral administration in ascending doses was conducted in a double-blind, placebo-controlled Phase I trial in non-smokers. The trial found indication of positive but non-significant effects on neurocognition at 10 and 30 mg, two doses that produced overlapping peak levels. There was also some evidence for effects on inhibition of the P50 auditory evoked potential to repeated stimuli, a biomarker that responds to alpha7-nicotinic receptor activation. The pharmacokinetic characteristics were consistent between subjects, and there were no safety concerns. The effects and safety profile were also assessed at 3 mg in a cohort of smokers, in whom concurrent nicotine administration did not alter either effects or safety. The trial demonstrates that a type I PAM can be safely administered to humans and that it has potential positive neurocognitive effects in central nervous system (CNS) disorders.

  15. Efficacy, plasma pharmacokinetics, and safety of icofungipen, an inhibitor of Candida isoleucyl-tRNA synthetase, in treatment of experimental disseminated candidiasis in persistently neutropenic rabbits.

    PubMed

    Petraitiene, Ruta; Petraitis, Vidmantas; Kelaher, Amy M; Sarafandi, Alia A; Mickiene, Diana; Groll, Andreas H; Sein, Tin; Bacher, John; Walsh, Thomas J

    2005-05-01

    Icofungipen (formerly PLD-118) is a synthetic derivative of the naturally occurring beta-amino acid cispentacin that blocks isoleucyl-tRNA synthetase, resulting in the inhibition of protein synthesis and growth of fungal cells. We investigated the efficacy, plasma pharmacokinetics, and safety of icofungipen in escalating dosages for the treatment of experimental subacute disseminated candidiasis in persistently neutropenic rabbits. Icofungipen was administered for 10 days starting 24 h after the intravenous inoculation of 10(3) Candida albicans blastoconidia. Study groups consisted of rabbits treated with icofungipen at 4 (ICO-4), 10 (ICO-10), and 25 (ICO-25) mg/kg of body weight/day in two divided dosages, rabbits treated with fluconazole at 10 mg/kg/day, rabbits treated with amphotericin B at 1 mg/kg/day, and untreated controls. Levels of icofungipen in plasma were derivatized by phthaldialdehyde and quantified by high-performance liquid chromatography with fluorescence detection. Rabbits treated with ICO-10 (P < 0.01) and ICO-25 (P < 0.001) showed significant dosage-dependent tissue clearance of C. albicans from the liver, spleen, kidney, brain, vitreous, vena cava, and lung in comparison to untreated controls. ICO-25 cleared C. albicans from all tissues and had activity comparable to that of amphotericin B versus untreated controls (P < 0.001). Pharmacokinetics of icofungipen in plasma approximated a dose-dependent relationship of the maximum concentration of drug in serum and the area under the concentration-time curve. There was no significant elevation of the levels of hepatic transaminases, alkaline phosphatase, bilirubin, urea nitrogen, or creatinine in icofungipen-treated rabbits. Icofungipen followed dose-dependent pharmacokinetics and was effective in the treatment of experimental disseminated candidiasis, including central nervous system infection, in persistently neutropenic rabbits.

  16. Safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate active ulcerative colitis: results of a randomized, double-blind study.

    PubMed

    Quiros, J Antonio; Heyman, Melvin B; Pohl, John F; Attard, Thomas M; Pieniaszek, Henry J; Bortey, Enoch; Walker, Kelli; Forbes, William P

    2009-11-01

    : A multicenter, double-blind study was conducted to evaluate the safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate ulcerative colitis (UC). : Sixty-eight patients, 5 to 17 years of age, with mild-to-moderate active UC based on the modified Sutherland UC activity index (MUCAI) were randomized to receive oral balsalazide 2.25 or 6.75 g/day for 8 weeks. The primary endpoint was clinical improvement (reduction of the MUCAI score by > or =3 points from baseline). Clinical remission (MUCAI score of 0 or 1 for stool frequency) and histological improvement after 8 weeks were also assessed. Pharmacokinetic parameters for balsalazide, 5-aminosalicylic acid, and N-acetyl-5-aminosalicylic acid were determined at 2 weeks. Adverse events and laboratory changes were monitored throughout the study. : Clinical improvement was achieved by 45% and 37% of patients and clinical remission by 12% and 9% of patients receiving 6.75 and 2.25 g/day, respectively. Improvement in histologic grade was achieved by 8 of 16 (50%) and 3 of 10 (30%) patients receiving 6.75 and 2.25 g/day, respectively. No significant differences were seen in efficacy. Pharmacokinetics in 12 patients were characterized by large interpatient variability and low systemic exposure. Adverse events were similar between the treatment groups, the most common being headache and abdominal pain. No clinically significant changes were observed in laboratory values, including those indicative of hepatic or renal toxicity. : Balsalazide is well tolerated and improves the signs and symptoms of mild-to-moderate active UC in pediatric patients 5 to 17 years of age.

  17. Safety, Efficacy, and Pharmacokinetics of Balsalazide in Pediatric Patients with Mild-to-Moderate Active Ulcerative Colitis: Results of a Randomized, Double-Blind Study

    PubMed Central

    Quiros, J. Antonio; Heyman, Melvin B.; Pohl, John F.; Attard, Thomas M.; Pieniaszek, Henry J.; Bortey, Enoch; Walker, Kelli; Forbes, William P.

    2012-01-01

    Objectives A multicenter, double-blind study was conducted to evaluate the safety, efficacy and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate UC. Methods Sixty-eight patients, 5 to 17 years of age, with mild-to-moderate active UC based on the modified Sutherland UC activity index (MUCAI), were randomized to receive oral balsalazide 2.25 or 6.75 g/day for 8 weeks. The primary endpoint was clinical improvement (reduction of the MUCAI score by ≥3 points from baseline). Clinical remission (MUCAI score of 0 or 1 for stool frequency) and histological improvement after 8 weeks were also assessed. Pharmacokinetic parameters for balsalazide, 5-aminosalicylic acid, and N-acetyl-5-aminosalicylic acid were determined at 2 weeks. Adverse events and laboratory changes were monitored throughout the study. Results Clinical improvement was achieved by 45% and 37% of patients and clinical remission by 12% and 9% of patients receiving 6.75 and 2.25 g/day, respectively. Improvement in histologic grade was achieved by 8 of 16 (50%) and 3 of 10 (30%) patients receiving 6.75 and 2.25 g/day, respectively. No significant differences were seen in efficacy. Pharmacokinetics in 12 patients were characterized by large inter-subject variability and low systemic exposure. Adverse events were similar between the treatment groups, the most common being headache and abdominal pain. No clinically significant changes were observed in laboratory values, including those indicative of hepatic or renal toxicity. Conclusions Balsalazide is well-tolerated and improves the signs and symptoms of mild-to-moderate active UC in pediatric patients 5 to 17 years of age. PMID:19633577

  18. Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus.

    PubMed

    Scheen, André J

    2014-09-01

    Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

  19. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study.

    PubMed

    Eisenberg, Elon; Ogintz, Miri; Almog, Shlomo

    2014-09-01

    Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a "main stream" pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC₀→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs.

  20. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

    PubMed Central

    Wacheck, Volker; Lahn, Michael; Dickinson, Gemma; Füreder, Wolfgang; Meyer, Renata; Herndlhofer, Susanne; Füreder, Thorsten; Dorfner, Georg; Pillay, Sada; André, Valérie; Burkholder, Timothy P; Akunda, Jacqueline K; Flye-Blakemore, Leann; Van Bockstaele, Dirk; Schlenk, Richard F; Sperr, Wolfgang R; Valent, Peter

    2011-01-01

    Background: Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML. Methods: In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug–drug interactions (DDI) were assessed. Results: Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients. Conclusion: No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile. PMID:21625399

  1. Pharmacokinetics and Safety of DW1029M, a Botanical Drug for the Treatment of Diabetic Nephropathy, Following Single Doses in Healthy Subjects.

    PubMed

    Kim, Yunjeong; Jeon, Ji-Young; Kim, Eun-Young; Lim, Cheol-Hee; Jang, Hwan Bong; Kim, Min-Gul

    2017-09-01

    DW1029M is a botanical extract of Morus albalinne root bark and Puerariae radix that is used for the treatment of diabetic nephropathy. This study evaluated the safety and pharmacokinetics of DW1029M following its administration in healthy Korean subjects. We conducted a randomized, open-label, single-dose, crossover phase 1 clinical study. During each period, subjects received 300, 600, or 1200 mg oral doses of DW1029M. Plasma concentrations of puerarin, daidzin, and daidzein were analyzed using a liquid chromatography-tandem mass spectrometry. Six healthy male subjects completed the study. The maximum concentration of the drug in the plasma (Cmax ) and area under the plasma drug concentration-time curve to the last measurable concentration (AUClast ) for puerarin, daidzin, and daidzein were assessed after oral administration of DW1029M. No serious adverse events or clinically or statistically significant adverse events associated with any of the drug levels were observed. The results of the measurement of vital signs, electrocardiogram, laboratory tests, and physical examinations indicated that no clinically significant changes occurred during this study. The DW1029M tablet was safe and well tolerated over a single dose range of 300-1200 mg. This pharmacokinetic study of a botanical drug may aid in the development of DW1029M. © 2017, The American College of Clinical Pharmacology.

  2. Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC).

    PubMed

    Meulenbeld, Hielke J; de Bono, Johann S; Tagawa, Scott T; Whang, Young E; Li, Xiaoyun; Heath, Karl H; Zandvliet, Anthe S; Ebbinghaus, Scot W; Hudes, Gary R; de Wit, Ronald

    2013-10-01

    Recent data indicate that there is a significant cross-talk between the PI3K/Akt/mTOR and androgen receptor signaling pathways. We evaluated safety and tolerability as well as potential drug-drug interaction of ridaforolimus, a mammalian target of rapamycin (mTOR) inhibitor, when combined with the androgen receptor inhibitor bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer. Patients were treated with the combination of ridaforolimus 30 mg/day for 5 consecutive days each week and bicalutamide 50 mg/day. Ridaforolimus pharmacokinetics was assessed with and without bicalutamide. Twelve patients were enrolled including 1 screen failure. Dose reductions were required in 7 patients. Three of the 11 patients experienced a dose-limited toxicity, 1 with Grade 3 hyperglycemia and 2 with Grade 2 stomatitis leading to <75 % of planned ridaforolimus dose during the first 35 days of study treatment. The pharmacokinetic results showed no differences in exposures to ridaforolimus with and without concomitant bicalutamide administration. Although there was no evidence of a clinically relevant pharmacological drug-drug interaction, the occurrence of dose-limiting toxicities in 3 of 11 evaluable patients at a reduced dose of ridaforolimus of 30 mg/day suggests that this combination may not be well suited for asymptomatic or minimally symptomatic prostate cancer patients.

  3. Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects.

    PubMed

    Akahori, Mizuki; Ayalasomayajula, Surya; Langenickel, Thomas; Pal, Parasar; Zhou, Wei; Sunkara, Gangadhar

    2017-06-01

    LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failure patients with reduced ejection fraction and approved in the US, Europe, and many other countries. This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receiving LCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.

  4. Altered biodistribution of radiopharmaceuticals: role of radiochemical/pharmaceutical purity, physiological, and pharmacologic factors.

    PubMed

    Vallabhajosula, Shankar; Killeen, Ronan P; Osborne, Joseph R

    2010-07-01

    One of the most common problems associated with radiopharmaceuticals is an unanticipated or altered biodistribution, which can have a significant clinical impact on safety, scan interpretation, and diagnostic imaging accuracy. In their most extreme manifestations, unanticipated imaging results may even compromise the utility and or accuracy of nuclear medicine studies. We present here an overall summary of altered biodistribution of radiopharmaceuticals with a special emphasis on the molecular mechanisms involved. Important factors affecting the biodistribution of radiopharmaceuticals can be described in 5 major categories and include (1) radiopharmaceutical preparation and formulation problems; (2) problems caused by radiopharmaceutical administration techniques and procedures; (3) by changes in biochemical and pathophysiology; (4) previous medical procedures, such as surgery, radiation therapy and dialysis; and finally (5) by drug interactions. The altered biodistribution of (99m)Tc radiopharmaceuticals are generally associated with increased amounts of (99m)Tc radiochemical impurities, such as free (99m)TcO(4)(-) and particulate impurities, such as (99m)Tc colloids or (99m)Tc-reduced hydrolyzed species. Faulty injection, such as dose infiltration or contamination with antiseptics and aluminum during dose administration, may cause significant artifacts. The patient's own medical problems, such as abnormalities in the regulation of hormone levels; failure in the function of excretory organs and systems, such as hepatobiliary and genitourinary systems; and even simple conditions, such as excessive talking may contribute to altered biodistribution of radiopharmaceuticals. Previous medical procedures (chemotherapy, radiation therapy, dialysis) and drug interaction are the some of the nontechnical factors responsible for unanticipated biodistribution of radiotracers. This review provides a comprehensive summary of various factors and specific examples to illustrate

  5. Long-term pharmacokinetic efficacy and safety of low-dose ritonavir as a booster and atazanavir pharmaceutical formulation based on solid dispersion system in rats.

    PubMed

    Fukushima, Keizo; Haraya, Kenta; Terasaka, Shuichi; Ito, Yukako; Sugioka, Nobuyuki; Takada, Kanji

    2008-06-01

    Atazanavir (ATV) is clinically coadministered with low-dose ritonavir (RTV), which boosts the oral bioavailability (BA) of ATV by inhibiting cytochrome P450 (CYP) 3A, and P-glycoprotein (Pgp) via the same metabolic pathway; however, it is well known that in the chronic phase, the inhibition effect of RTV on Pgp and CYP3A becomes an induction effect. In this study, we investigated the long-term efficacy and safety of RTV-boosted ATV in rats with a clinical relevant dosage of ATV and RTV, 7 mg/kg and 2 mg/kg, respectively, and drew a direct comparison with RTV-boosted ATV and the previously reported ATV pharmaceutical formulation based on a solid dispersion system (ATV-SLS SD+G). Rats received RTV-boosted ATV or ATV-SLS SD+G for 14 d in the pharmacokinetic study. In addition, after 14-d repeated administration of each formulation, cyclosporine A (CyA) was administered to rats and Western blot analysis of Pgp and CYP3A was performed to investigate the impact on pharmacokinetic interaction of each ATV formulation. After repeated administration of both formulations, there was no significant difference between ATV pharmacokinetic parameters on day 1 and 14; therefore, it was considered that the long-term efficacy of both ATV formulations was maintained. However, after treatment with RTV-boosted ATV, the Cmax and AUC0-infinity of the following CyA significantly decreased to 49% and 47% in comparison to the control, respectively, and the Pgp expression in the small intestine by Western blot analysis was approximately 2-fold higher than the control, whereas after treatment with ATV pharmaceutical formulation, neither significant alteration of CyA nor notable change in the expression of intestinal Pgp and hepatic CYP3A was observed. Therefore, it was considered that the BA of CyA after treatment with RTV-boosted ATV would decrease by the induction effect of RTV in chronic phase as described above. The results of this study revealed that the chronic use of low-dose RTV as a

  6. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects.

    PubMed

    Sidharta, Patricia N; van Giersbergen, Paul L M; Dingemanse, Jasper

    2013-11-01

    This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new endothelin receptor antagonist (ERA) with sustained receptor binding and enhanced tissue penetration properties compared to other ERAs. Healthy male subjects (n = 32) received once daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. Administration of macitentan was safe and well tolerated. Macitentan had no effect on bile salts, suggesting an improved liver safety profile. The multiple-dose pharmacokinetics of macitentan were dose-proportional and were characterized by a median tmax and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48 hours and accumulated approximately 8.5-fold. Compared to placebo, administration of macitentan caused a dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A small dose-dependent increase in the 6β-hydroxycortisol/cortisol urinary excretion ratio was observed, although there were no statistically significant differences between treatments including placebo. Effects of macitentan on cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET-1-dependent pathologies. © 2013, The American College of Clinical Pharmacology.

  7. Safety, pharmacokinetic and dosimetry evaluation of the proposed thrombus imaging agent 99mTc-DI-DD-3B6/22-80B3 Fab'.

    PubMed

    Macfarlane, David J; Smart, Richard C; Tsui, Wendy W; Gerometta, Michael; Eisenberg, Paul R; Scott, Andrew M

    2006-06-01

    (99m)Tc-DI-DD-3B6/22-80B3 (Thromboview, hereafter abbreviated to (99m)Tc-DI-80B3 Fab') is a humanised, radiolabelled monoclonal antibody Fab' fragment with high affinity and specificity for the D-dimer domain of cross-linked fibrin. The purpose of this study was to evaluate the safety, pharmacokinetics and dosimetry of four increasing doses of (99m)Tc-DI-80B3 Fab' in healthy volunteers. Thirty-two healthy volunteers (18-70 years; 16 male, 16 female) received a single intravenous injection of 0.5, 1.0, 2.0 or 4.0 mg of (99m)Tc-DI-80B3 Fab'. Safety outcomes (vital signs, electrocardiography, haematology, biochemistry, adverse events and development of human anti-human antibodies) were assessed up to 30 days post injection. Blood and urine samples were collected up to 48 h post injection. Gamma camera images were acquired at 0.5, 1, 2, 4, 6 and 24 h post injection. Dosimetry was performed using standard MIRD methodology. No adverse events considered to be drug related were observed. Human anti-human antibody was not detectable in any subject during the follow-up period. (99m)Tc-DI-80B3 Fab' had a rapid initial plasma clearance (t (1/2)alpha=1 h). The pharmacokinetic profile of the Fab' fragment was generally linear across the four dose cohorts. By 24 h, 30-35% of the administered radioactivity appeared in the urine. There was marked renal accumulation with time, but no specific uptake was identified within other normal tissues. The effective dose was 9 mSv/750 MBq. (99m)Tc-DI-80B3 Fab' is well tolerated, is rapidly cleared and exhibits clinically acceptable dosimetry-characteristics well suited to a potential thrombus imaging agent.

  8. Pharmacokinetics and safety of ixazomib plus lenalidomide-dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study.

    PubMed

    Gupta, Neeraj; Goh, Yeow Tee; Min, Chang-Ki; Lee, Jae Hoon; Kim, Kihyun; Wong, Raymond S M; Chim, Chor Sang; Hanley, Michael J; Yang, Huyuan; Venkatakrishnan, Karthik; Hui, Ai-Min; Esseltine, Dixie-Lee; Chng, Wee Joo

    2015-09-04

    The oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in multiple myeloma (MM) in combination with lenalidomide-dexamethasone. This study was conducted to investigate the pharmacokinetic and safety profiles of ixazomib, administered with lenalidomide-dexamethasone, in East Asian patients with relapsed/refractory MM. Adult patients with measurable disease who had received 1-3 prior lines of therapy received oral ixazomib on days 1, 8, and 15, lenalidomide (25 mg) on days 1-21, and dexamethasone (40 mg) on days 1, 8, 15, and 22, in 28-day cycles. Primary objectives were to characterize ixazomib plasma pharmacokinetics, determine the recommended phase 2/3 dose, and evaluate safety and tolerability. Forty-three patients were enrolled. No dose-limiting toxicities were reported for the first six patients receiving ixazomib (4.0 mg), confirming this as the recommended phase 2/3 dose. Ixazomib was rapidly absorbed with a median T max of 1.5 h on day 1 and 2.0 h on day 15 of cycle 1 and had a geometric mean terminal half-life of 6.1 days. Twenty-one (49%) patients had at least one drug-related grade ≥3 adverse event (AE); the most common were neutropenia (19%), diarrhea (14%), and thrombocytopenia (12%). Twenty-eight of 43 (65%) response-evaluable patients had at least a partial response. The recommended phase 2/3 dose for ixazomib was determined to be 4.0 mg. The all-oral combination of ixazomib plus lenalidomide-dexamethasone appeared active and well tolerated at 4.0 mg. Consequently, East Asian patients enrolled in phase 3 studies are receiving the same ixazomib dose as patients in other regions. This study is registered at NCT01645930.

  9. Investigation of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of a Long-Acting α-MSH Analog in Healthy Overweight and Obese Subjects

    PubMed Central

    Royalty, Jane E; Konradsen, Gitte; Eskerod, Ole; Wulff, Birgitte S; Hansen, Birgit S

    2014-01-01

    MC4-NN2-0453 is a novel, long-acting, selective, melanocortin-4-receptor agonist developed for treatment of obesity. This first-human-dose, randomized, double-blind, placebo-controlled trial investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of MC4-NN2-0453 in overweight to obese but otherwise healthy subjects. The trial included a single-dose part of ascending subcutaneous 0.03–1.50 mg/kg doses in overweight to obese but otherwise healthy men, and a multiple-dose part of ascending subcutaneous 0.75–3.0 mg/day doses in obese but otherwise healthy men/women. The single-dose part included 7 cohorts of 8 subjects, randomized 6:2 to active drug/placebo; the multiple-dose part included 4 cohorts of 20 subjects, randomized 16:4 to active drug/placebo. MC4-NN2-0453 was well tolerated and raised no safety concerns except for nonserious skin-related adverse events, this along with lack of weight loss effect led to premature termination of the trial. Headache, sexual–arousal disturbance, and penile erection were also reported. Single-dose pharmacokinetics showed dose-linearity and dose-proportionality. Maximum plasma concentration was observed after 50–100 hours, which then declined with a of approximately 250 hours. Plasma concentration reached steady state after 4 weeks for 0.75 and 1.5 mg/day multiple-dose cohorts, and the was similar to single dose. There were no significant pharmacodynamic effects, including effect on body weight. PMID:24166760

  10. A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia

    PubMed Central

    Springett, Gregory M.; Husain, Kazim; Neuger, Anthony; Centeno, Barbara; Chen, Dung-Tsa; Hutchinson, Tai Z.; Lush, Richard M.; Sebti, Saïd; Malafa, Mokenge P.

    2015-01-01

    Background Vitamin E δ-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity. Methods Patients received oral VEDT at escalating doses (from 200 to 3200 mg) daily for 13 days before surgery and one dose on the day of surgery. Dose escalation followed a three-plus-three trial design. Our primary endpoints were safety, VEDT pharmacokinetics, and monitoring of VEDT-induced neoplastic cell apoptosis (ClinicalTrials.gov number NCT00985777). Findings In 25 treated patients, no dose-limiting toxicity was encountered; thus no maximum-tolerated dose was reached. One patient had a drug-related adverse event (diarrhea) at a 3200-mg daily dose level. The effective half-life of VEDT was ~ 4 h. VEDT concentrations in plasma and exposure profiles were quite variable but reached levels that are bioactive in preclinical models. Biological activity, defined as significant induction of apoptosis in neoplastic cells as measured by increased cleaved caspase-3 levels, was seen in the majority of patients at the 400-mg to 1600-mg daily dose levels. Interpretation VEDT from 200 to 1600 mg daily taken orally for 2 weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for chemoprevention and/or therapy of pancreatic cancer. PMID:26844278

  11. Pharmacokinetics, Safety and Cognitive Function Profile of Rupatadine 10, 20 and 40 mg in Healthy Japanese Subjects: A Randomised Placebo-Controlled Trial

    PubMed Central

    Täubel, Jörg; Ferber, Georg; Fernandes, Sara; Lorch, Ulrike; Santamaría, Eva; Izquierdo, Iñaki

    2016-01-01

    Introduction Rupatadine is a marketed second generation antihistamine, with anti-PAF activity, indicated for symptomatic treatment of allergic rhinitis and urticaria. This study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of rupatadine in healthy Japanese subjects after single and multiple oral doses. Methods In this randomised, double-blind, placebo-controlled study, 27 male and female healthy Japanese subjects were administered single and multiple escalating rupatadine dose of 10, 20 and 40 mg or placebo. Blood samples were collected at different time points for PK measurements and subjects were assessed for safety and tolerability. The effect of rupatadine on cognitive functioning was evaluated by means of computerized cognitive tests: rapid visual information processing (RVP), reaction time (RT), spatial working memory (SWM) and visual analogue scales (VAS). Results Exposure to rupatadine as measured by Cmax and AUC was found to increase in a dose dependent manner over the dose range of 10–40 mg for both single and multiple dose administration. The safety assessments showed that all treatment related side effects were of mild intensity and there were no serious adverse events (SAEs) or withdrawals due to treatment–emergent adverse events (TEAEs) in this study. The therapeutic dose of rupatadine did not show any CNS impairment in any of the cognitive tests. Conclusions This study demonstrated that rupatadine is safe and well tolerated by Japanese healthy subjects. The PK-PD profile confirmed previous experience with rupatadine. PMID:27632557

  12. Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content.

    PubMed

    Li, Mingguang; Panagi, Zoi; Avgoustakis, Konstantinos; Reineke, Joshua

    2012-01-01

    Biodistribution of nanoparticles is dependent on their physicochemical properties (such as size, surface charge, and surface hydrophilicity). Clear and systematic understanding of nanoparticle properties' effects on their in vivo performance is of fundamental significance in nanoparticle design, development and optimization for medical applications, and toxicity evaluation. In the present study, a physiologically based pharmacokinetic model was utilized to interpret the effects of nanoparticle properties on previously published biodistribution data. Biodistribution data for five poly(lactic-co-glycolic) acid (PLGA) nanoparticle formulations prepared with varied content of monomethoxypoly (ethyleneglycol) (mPEG) (PLGA, PLGA-mPEG256, PLGA-mPEG153, PLGA-mPEG51, PLGA-mPEG34) were collected in mice after intravenous injection. A physiologically based pharmacokinetic model was developed and evaluated to simulate the mass-time profiles of nanoparticle distribution in tissues. In anticipation that the biodistribution of new nanoparticle formulations could be predicted from the physiologically based pharmacokinetic model, multivariate regression analysis was performed to build the relationship between nanoparticle properties (size, zeta potential, and number of PEG molecules per unit surface area) and biodistribution parameters. Based on these relationships, characterized physicochemical properties of PLGA-mPEG495 nanoparticles (a sixth formulation) were used to calculate (predict) biodistribution profiles. For all five initial formulations, the developed model adequately simulates the experimental data indicating that the model is suitable for description of PLGA-mPEG nanoparticle biodistribution. Further, the predicted biodistribution profiles of PLGA-mPEG495 were close to experimental data, reflecting properly developed property-biodistribution relationships.

  13. Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content

    PubMed Central

    Li, Mingguang; Panagi, Zoi; Avgoustakis, Konstantinos; Reineke, Joshua

    2012-01-01

    Biodistribution of nanoparticles is dependent on their physicochemical properties (such as size, surface charge, and surface hydrophilicity). Clear and systematic understanding of nanoparticle properties’ effects on their in vivo performance is of fundamental significance in nanoparticle design, development and optimization for medical applications, and toxicity evaluation. In the present study, a physiologically based pharmacokinetic model was utilized to interpret the effects of nanoparticle properties on previously published biodistribution data. Biodistribution data for five poly(lactic-co-glycolic) acid (PLGA) nanoparticle formulations prepared with varied content of monomethoxypoly (ethyleneglycol) (mPEG) (PLGA, PLGA-mPEG256, PLGA-mPEG153, PLGA-mPEG51, PLGA-mPEG34) were collected in mice after intravenous injection. A physiologically based pharmacokinetic model was developed and evaluated to simulate the mass-time profiles of nanoparticle distribution in tissues. In anticipation that the biodistribution of new nanoparticle formulations could be predicted from the physiologically based pharmacokinetic model, multivariate regression analysis was performed to build the relationship between nanoparticle properties (size, zeta potential, and number of PEG molecules per unit surface area) and biodistribution parameters. Based on these relationships, characterized physicochemical properties of PLGA-mPEG495 nanoparticles (a sixth formulation) were used to calculate (predict) biodistribution profiles. For all five initial formulations, the developed model adequately simulates the experimental data indicating that the model is suitable for description of PLGA-mPEG nanoparticle biodistribution. Further, the predicted biodistribution profiles of PLGA-mPEG495 were close to experimental data, reflecting properly developed property–biodistribution relationships. PMID:22419876

  14. Phase 1 safety, tolerability, and pharmacokinetic study of single ascending doses of XM17 (recombinant human follicle-stimulating hormone) in downregulated healthy women

    PubMed Central

    Lammerich, Andreas; Bias, Peter; Gertz, Beate

    2015-01-01

    Background XM17 is a recombinant human follicle-stimulating hormone (follitropin alfa) for stimulation of multifollicular development in women undergoing controlled ovarian hyper-stimulation during assisted reproductive therapy and for treatment of anovulation. Manufactured using Chinese hamster ovary cells transfected with the human follicle-stimulating hormone gene, XM17 has an identical amino acid sequence to that of the human protein as well as to those of the other approved recombinant human follicle-stimulating hormone products. Glycosylation patterns may differ slightly between products. The objectives of this first-in-human study were to assess the safety, tolerability, pharmacokinetics, and dose-proportionality of single ascending subcutaneous doses of XM17 in healthy young female volunteers. Methods Endogenous follicle-stimulating hormone was downregulated by implanting a 1-month depot of goserelin acetate 3.6 mg on day 0 in eligible subjects. On day 14 of the experimental period, subjects received one of four ascending doses of XM17. Blood sampling to obtain the pharmacokinetic profile of XM17 was done at frequent intervals until 168 hours post-dose. Results Following downregulation of endogenous follicle-stimulating hormone to <4 IU/L, 40 subjects (of mean age 29±5.4 years) received single subcutaneous doses of 37.5 (n=4, pilot group), 75, 150, or 300 IU (n=12 each) of XM17. The mean serum concentration-time profiles of XM17 revealed dose-related increases in maximum concentration (Cmax) within 24 hours followed by monoexponential decay for the three higher dose levels. Slopes estimated by linear regression for Cmax and AUC0–168h were ~1.0 (0.9052 IU/L and 1.0964 IU·h/L, respectively). For each IU of XM17 administered, Cmax and AUC0–168h rose by 0.032 IU/L and 2.60 IU·h/L, respectively. Geometric mean elimination half-life ranged from 54 to 90 hours. No antibodies to XM17 were detected. The most common treatment-emergent adverse events were

  15. Evaluation of the safety and pharmacokinetic profile of a new, pasteurized, human tetanus immunoglobulin administered as sham, postexposure prophylaxis of tetanus.

    PubMed

    Forrat, R; Dumas, R; Seiberling, M; Merz, M; Lutsch, C; Lang, J

    1998-02-01

    In a monocentric, double-blind, randomized trial, we examined the safety and pharmacokinetic profile of a new, pasteurized, human tetanus immunoglobulin (P-HTIG). As part of the purification process, P-HTIG has undergone a heat treatment step (10 h at 60 degrees C) and the removal of Merthiolate. Forty-eight adults with a history of tetanus vaccination were randomized into four groups (n = 12 per group) to receive one of two different batches of this P-HTIG simultaneously with either tetanus-diphtheria (Td) vaccine (sham, postexposure prophylaxis of tetanus) or placebo. Local reactions at the injection site were followed for the first 3 days after injection, and systemic reactions were followed during the entire study period, i.e., up to 42 days posttreatment. Blood samples for tetanus antibody titer determination (enzyme-linked immunosorbent assay method) were drawn prior to treatment on day 0 and on days 1, 2, 3, 7, 14, 21, 28, 35, and 42. A normalization of tetanus antibody titers (subtraction of the day 0 value for each subject at each time period) was performed to assess the additive effect of P-HTIG on tetanus antibody titers. The pharmacokinetic parameters were determined by both a compartmental analysis (modelization) and a noncompartmental analysis. No severe adverse reactions were reported. The rate of local reactions at the P-HTIG injection site was 27%. All local reactions were mild and resolved within 2 days. In contrast, local reactions at the vaccine injection site were seen in 79% of the subjects. The rate of systemic reactions was similar in the P-HTIG plus Td vaccine group (33%) and in the P-HTIG plus placebo group (21%), and all these reactions were mild. In the P-HTIG plus placebo group, tetanus antibody titers rose to a maximum of 0.313+/-2.49 IU/ml after 4.4 days; in the P-HTIG plus Td vaccine group, a maximum concentration of 15.2+/-2.42 IU/ml was reached 19 days postinjection. In both groups, 100% of the patients had seroprotective levels of

  16. Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study.

    PubMed

    Massard, Christophe; Penttinen, Heidi M; Vjaters, Egils; Bono, Petri; Lietuvietis, Vilnis; Tammela, Teuvo L; Vuorela, Annamari; Nykänen, Pirjo; Pohjanjousi, Pasi; Snapir, Amir; Fizazi, Karim

    2016-05-01

    ODM-201 is a novel second-generation androgen receptor inhibitor for the treatment of metastatic castration-resistant prostate cancer (mCRPC). To evaluate the pharmacokinetics of ODM-201 tablet products and preliminary long-term safety, tolerability, and antitumor activity of ODM-201 in chemotherapy-naive men with mCRPC. Thirty patients were enrolled in this open-label phase 1 trial. Patients received a single 600-mg dose of ODM-201 in capsules with food and one 600-mg dose of ODM-201 tablet product (TabA or TabB) with food and in the fasted state in a random order. In the extension, patients received 600mg twice daily ODM-201 taken with food in capsules. We analyzed the pharmacokinetics of ODM-201 tablet formulations. Safety and tolerability were assessed until disease progression or an intolerable adverse event (AE). Antitumor activity was assessed by prostate-specific antigen (PSA) levels and imaging. The capsule:TabA ratio of area under the concentration-time curve from time zero to the last sample at 48h was 1.06 (90% confidence interval [CI], 0.91-1.24); the capsule:TabB ratio was 0.97 (90% CI, 0.82-1.14). At week 12, 25 of 30 patients (83%) had a PSA response (≥50% reduction from baseline). Median time to radiographic progression was 66 wk (95% CI, 41-79). Most common AEs were fatigue (n=4 [13%]) and nausea (n=4 [13%]). The study showed that the tablet formulation of ODM-201 had similar pharmacokinetics compared with the capsule. Treatment with a 600-mg twice daily dose of ODM-201 provided anticancer activity and was well tolerated in men with chemotherapy-naive mCRPC. The findings of this study showed that ODM-201 is well tolerated and provided antitumor activity in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) and that the 300-mg tablet formulation can be used in further clinical studies. A phase 3 trial with ODM-201 600mg twice daily in patients with non-mCRPC is ongoing. Copyright © 2015 European Association

  17. The pharmacokinetic and safety profiles of blonanserin in healthy Chinese volunteers after single fasting doses and single and multiple postprandial doses.

    PubMed

    Chen, Xia; Wang, Hongyun; Jiang, Ji; Chen, Rui; Zhou, Ying; Zhong, Wen; Liu, Hongzhong; Hu, Pei

    2014-03-01

    Blonanserin is a novel atypical antipsychotic drug acting as a mixed serotonin 5-HT2A and dopamine D2 receptor antagonist. This study investigated the pharmacokinetics and safety of blonanserin in healthy Chinese males. This was an open-label trial with two parts. Twenty-four subjects were enrolled in part A to receive a single fasting dose of 4 or 8 mg blonanserin (each n = 12); part B recruited 12 subjects and administered single and sequentially twice-daily multiple postprandial doses of blonanserin 2 mg for 9 days. Serial blood samples were taken for the bioassay of plasma blonanserin and its four metabolites during both sub-studies. Safety was assessed, including repeat measurements of fasting serum prolactin, insulin, triglyceride and cholesterol. Blonanserin was rapidly absorbed, accompanied with immediate plasma concentration elevation of the N-oxide form (M2) and gradual rises of the N-deethylated form (M1) and its downstream metabolites. The mean elimination half-life of blonanserin (7.7-11.9 h) was much longer than that of M2 (1.2-1.3 h) but shorter than that of M1 (26.4-31.4 h) after single fasting doses. After food intake, a single dose of 2 mg blonanserin resulted in total exposure and peak concentrations of blonanserin similar to those observed with a single fasting dose of blonanserin 4 mg. Moreover, the relationship of metabolite over parent compound ratio was different between M1 and M2 after single and multiple postprandial administrations (single dose vs multiple dose: M1, 0.33 vs 0.75; M2, 0.13 vs 0.067). Mild but transient increases of prolactin, insulin and triglyceride were observed. The pharmacokinetics of blonanserin in Chinese subjects were similar to those observed in Japanese subjects. This study suggested that food intake not only increases the bioavailability of blonanserin but differently affects the pharmacokinetics of its metabolites as well. The drug was safe and well tolerated in healthy Chinese males.

  18. Determination of Appropriate Weight-Based Cutoffs for Empiric Cefazolin Dosing Using Data from a Phase 1 Pharmacokinetics and Safety Study of Cefazolin Administered for Surgical Prophylaxis in Pediatric Patients Aged 10 to 12 Years

    PubMed Central

    Schmitz, Michael L.; Blumer, Jeffrey L.; Cetnarowski, Wes

    2015-01-01

    Despite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to <50 kg received a 1-g dose, and patients weighing ≥50 to ≤85 kg received a 2-g dose. Postdose pharmacokinetic and safety assessments were conducted following drug administration. Cefazolin concentration-time data were analyzed by using both noncompartmental and population pharmacokinetics methods. Monte Carlo simulations were performed to identify appropriate weight-based cutoffs for the dosing of children aged 10 to 17 years of age. Twelve patients were enrolled in this study and provided the requisite pharmacokinetic data. In general, cefazolin was well tolerated. The mean cefazolin terminal elimination half-life, clearance, and area under the concentration-time curve from time zero to infinity in this population were 1.95 h, 0.804 ml/min/kg, and 607 mg · h/liter, respectively. Patients weighing 50 to 60 kg exhibited elevated cefazolin exposures. Observed pharmacokinetic parameters and simulation results indicated that a weight-based cutoff of 60 kg is predicted to provide cefazolin exposure consistent with that observed in normal, healthy adults at recommended doses for surgical prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01904357.) PMID:25941220

  19. Determination of appropriate weight-based cutoffs for empiric cefazolin dosing using data from a phase 1 pharmacokinetics and safety study of cefazolin administered for surgical prophylaxis in pediatric patients aged 10 to 12 years.

    PubMed

    Schmitz, Michael L; Blumer, Jeffrey L; Cetnarowski, Wes; Rubino, Christopher M

    2015-07-01

    Despite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to <50 kg received a 1-g dose, and patients weighing ≥50 to ≤85 kg received a 2-g dose. Postdose pharmacokinetic and safety assessments were conducted following drug administration. Cefazolin concentration-time data were analyzed by using both noncompartmental and population pharmacokinetics methods. Monte Carlo simulations were performed to identify appropriate weight-based cutoffs for the dosing of children aged 10 to 17 years of age. Twelve patients were enrolled in this study and provided the requisite pharmacokinetic data. In general, cefazolin was well tolerated. The mean cefazolin terminal elimination half-life, clearance, and area under the concentration-time curve from time zero to infinity in this population were 1.95 h, 0.804 ml/min/kg, and 607 mg · h/liter, respectively. Patients weighing 50 to 60 kg exhibited elevated cefazolin exposures. Observed pharmacokinetic parameters and simulation results indicated that a weight-based cutoff of 60 kg is predicted to provide cefazolin exposure consistent with that observed in normal, healthy adults at recommended doses for surgical prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01904357.). Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  20. Safety and Pharmacokinetics of the Anti-Orthopoxvirus Compound ST-246 following a Single Daily Oral Dose for 14 Days in Human Volunteers

    PubMed Central

    Chinsangaram, Jarasvech; Honeychurch, Kady M.; Tyavanagimatt, Shanthakumar R.; Leeds, Janet M.; Bolken, Tove' C.; Jones, Kevin F.; Jordan, Robert; Marbury, Thomas; Ruckle, Jon; Mee-Lee, Denis; Ross, Eric; Lichtenstein, Israel; Pickens, Margaret; Corrado, Michael; Clarke, Jean M.; Frimm, Annie M.

    2012-01-01

    ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (Cmax) and relative exposure for each dosing interval (AUCτ) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application. PMID:22777041

  1. Safety and pharmacokinetics of the anti-orthopoxvirus compound ST-246 following a single daily oral dose for 14 days in human volunteers.

    PubMed

    Chinsangaram, Jarasvech; Honeychurch, Kady M; Tyavanagimatt, Shanthakumar R; Leeds, Janet M; Bolken, Tove' C; Jones, Kevin F; Jordan, Robert; Marbury, Thomas; Ruckle, Jon; Mee-Lee, Denis; Ross, Eric; Lichtenstein, Israel; Pickens, Margaret; Corrado, Michael; Clarke, Jean M; Frimm, Annie M; Hruby, Dennis E

    2012-09-01

    ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (C(max)) and relative exposure for each dosing interval (AUC(τ)) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application.

  2. A 4-week study assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of the glucagon receptor antagonist PF-06291874 administered as monotherapy in subjects with type 2 diabetes mellitus.

    PubMed

    Bergman, Arthur; Tan, Beesan; Somayaji, Veena R; Calle, Roberto A; Kazierad, David J

    2017-04-01

    The glucagon receptor antagonist PF-06291874 has demonstrated robust glucose reductions in subjects with type 2 diabetes mellitus (T2DM) on background metformin. This study assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-06291874 administered as monotherapy in subjects with T2DM. After a ≥4-week antidiabetic therapy washout period, 172 subjects were randomized to placebo or PF-06291874 15, 35, 75, or 150mg once daily for 28days. Mean daily glucose (MDG), fasting plasma glucose (FPG), and predefined safety endpoints were assessed at baseline and day 28. Dose-dependent reductions (placebo-adjusted) from baseline in MDG ranged from 40.3 to 68.8mg/dL and in FPG from 27.1 to 57.2mg/dL after 28days of dosing with PF-06291874. There were no significant changes in low-density lipoprotein cholesterol at doses ≤75mg relative to placebo. Small, dose-dependent increases in alanine aminotransferase and aspartate aminotransferase were observed; however, the incidence of these values >3×upper limit of normal was similar across doses. PF-06291874 exposures were consistent with previous studies and PF-06291874 was well tolerated, with minimal incidence of hypoglycemia. PF-06291874 as monotherapy was well tolerated and produced robust reductions in plasma glucose following 4weeks of dosing in subjects with T2DM. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.

    PubMed

    Stoch, S Aubrey; Zajic, Stefan; Stone, Julie A; Miller, Deborah L; van Bortel, Lucas; Lasseter, Kenneth C; Pramanik, Barnali; Cilissen, Caroline; Liu, Qi; Liu, Lida; Scott, Boyd B; Panebianco, Deborah; Ding, Yu; Gottesdiener, Keith; Wagner, John A

    2013-05-01

    To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction. Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing. © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. British Journal of

  4. Safety and Pharmacokinetics of an Intramuscular Monoclonal Antibody (SB 209763) against Respiratory Syncytial Virus (RSV) in Infants and Young Children at Risk for Severe RSV Disease

    PubMed Central

    Meissner, H. Cody; Groothuis, Jessie R.; Rodriguez, William J.; Welliver, Robert C.; Hogg, Geoff; Gray, Peter H.; Loh, Richard; Simoes, Eric A. F.; Sly, Peter; Miller, Ann K.; Nichols, Alice I.; Jorkasky, Diane K.; Everitt, Daniel E.; Thompson, Kathleen A.

    1999-01-01

    We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (≤35 weeks’ gestation) or exhibited bronchopulmonary dysplasia were administered either single or repeat (two doses, 8 weeks apart) intramuscular injections of SB 209763 at a concentration of 0.25, 1.25, 5.0, or 10.0 mg/kg or of a placebo. Four of 229 adverse events were considered related to the study drug, including purpura (n = 3) and thrombocytosis (n = 1). No subject developed a detectable level of anti-SB 209763 antibody. Approximately 1 week after administration of the second dose of SB 209763 at 10 mg/kg, the mean plasma concentration (n = 9) was 68.5 μg/ml. The terminal half-life (T1/2) determined by noncompartmental analysis ranged from 22 to 50 days. The population pharmacokinetics for SB 209763 following intramuscular administration was appropriately described by a one-compartment model with first-order input and elimination. Higher values for clearance and volume of distribution at steady state were observed for younger patients, with values decreasing to 0.143 (ml/h)/kg and 161 mL/kg, respectively, by a mean age of 298 days (∼10 months). The mean T1/2 of SB 209763 for the study population was 32.5 days. No other factor (dose, weight, gender, race, premature birth, or bronchopulmonary dysplasia) was observed to alter the population pharmacokinetics of SB 209763 in this study of infants and young children. The mean neutralization titer on day 6 was 286, and the mean fusion inhibition titer was 36. At least 57% of subjects dosed at 1.25 to 10.0 mg of SB 209763 per kg of body weight who were seronegative at baseline experienced a fourfold or greater increase in fusion inhibition titer. Nine RSV infections were documented

  5. Safety, pharmacokinetics and pharmacodynamics of remogliflozin etabonate, a novel SGLT2 inhibitor, and metformin when co-administered in subjects with type 2 diabetes mellitus

    PubMed Central

    2013-01-01

    Background The sodium-dependent glucose co-transporter-2 (SGLT2) is expressed in absorptive epithelia of the renal tubules. Remogliflozin etabonate (RE) is the prodrug of remogliflozin, the active entity that inhibits SGLT2. An inhibitor of this pathway would enhance urinary glucose excretion (UGE), and potentially improve plasma glucose concentrations in diabetic patients. RE is intended for use for the treatment of type 2 diabetes mellitus (T2DM) as monotherapy and in combination with existing therapies. Metformin, a dimethylbiguanide, is an effective oral antihyperglycemic agent widel