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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. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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

  10. [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.

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys

    PubMed Central

    Ahlstedt, Jonas; Tran, Thuy A; Strand, Filip; Holmqvist, Bo; Strand, Sven-Erik; Gram, Magnus; Åkerström, Bo

    2015-01-01

    Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected 125I- and non-labelled recombinant human A1M and the 111In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT. PMID:26269772

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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

  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. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. [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.

  7. 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.

  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. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. 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 ...

  1. 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…

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  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. 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.

  14. 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.

  15. 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.

  16. 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).

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. (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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  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. An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib

    PubMed Central

    Magee, Mindy He; Shearn, Shawn; Shaddinger, Bonnie; Fang, Zixing; Glaser, Ruchira

    2014-01-01

    Aim/Methods This was a phase 1, open label, non-randomized study designed to assess the pharmacokinetics and safety/tolerability of 10 consecutive once daily 40 mg oral doses of darapladib in subjects with moderate hepatic impairment (n = 12) compared with matched healthy volunteers (n = 12). Results For total darapladib, a small increase in total and peak exposure was observed in the subjects with moderate hepatic impairment compared with the subjects with normal hepatic function. The area under the plasma concentration−time curve during a dosing interval of duration τ (AUC(0,τ), geometric mean 223 ng ml−1 h [90% CI 158, 316 ng ml−1 h], in moderate hepatic impaired subjects, vs. geometric mean 186 ng ml−1 h [90% CI 159, 217 ng ml−1 h], in healthy subjects) and maximum concentration (Cmax) were 20% and 7% higher, respectively, in the subjects with moderate hepatic impairment than in the healthy control subjects and there was no change in time to maximum concentration (tmax). Protein binding was performed to measure the amount of unbound drug vs. bound. Steady-state was achieved by day 10 for darapladib and its metabolites (M4, M3 and M10). Darapladib was generally well tolerated, with adverse events (AEs) reported by seven subjects in the hepatic impairment group and three subjects in the healthy matched group (five and one of which were drug-related AEs, respectively). The most common AEs were gastrointestinal. These AEs were mostly mild to moderate and there were no deaths, serious AEs or withdrawals due to AEs. Conclusions The results of this phase 1 study show that darapladib (40 mg) is well tolerated and its pharmacokinetics remain relatively unchanged in patients with moderate hepatic impairment. PMID:24938621

  5. 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)

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. 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.).

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. (18)F-tetrafluoroborate ((18)F-TFB), 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; O' Doherty, Michael; Cook, Gary; Blower, Philip; Lewington, Val

    2017-04-06

    Rationale: 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 with thyroid cancer were acquired prior to surgery for up to 4 hours 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 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 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 similar biodistribution to (99m)Tc-pertechnetate, a known non-organified hNIS tracer, and is pharmacologically and radiobiologically safe in humans. Phase 2 trials as a hNIS imaging agent are warranted.

  8. [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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. [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.

  18. 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…

  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, 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).

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  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. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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.

  13. 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

  14. A phase I safety and pharmacokinetic study of ATX-101: injectable, synthetic deoxycholic acid for submental contouring.

    PubMed

    Walker, Patricia; Fellmann, Jere; Lizzul, Paul F

    2015-03-01

    ATX-101 (deoxycholic acid [DCA] injection) is a proprietary formulation of pure synthetic DCA. When injected into subcutaneous fat, ATX-101 results in focal adipocytolysis, the targeted destruction of fat cells. ATX-101 is undergoing investigation as an injectable drug for contouring the submental area by reducing submental fat (SMF). The purpose of this study was to evaluate the safety and pharmacokinetics (PK) of the maximal therapeutic dose of ATX-101 (100 mg total dose). Following PK evaluation of endogenous DCA, subjects (N=24) received subcutaneous injections of ATX-101 (2 mg/cm2, with or without 0.9% benzyl alcohol) into SMF; PK evaluation was repeated periodically over 24 hours. Endogenous DCA plasma concentrations measured prior to injection were highly variable within and between subjects. Similarly, following ATX-101 injection, DCA plasma concentrations were highly variable, peaked rapidly, and returned to the range observed for endogenous values by 24 hours postdose. All subjects experienced at least 1 adverse event (AE). No death, serious AE, or AE-related discontinuations occurred. The majority of AEs were transient, associated with the area treated, and of mild or moderate severity. No clinically significant changes were reported for laboratory test results, vital signs, or Holter electrocardiograms postdosing. These data support the favorable safety and efficacy observations of ATX-101 as an injectable drug to reduce SMF.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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

  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. [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.

  20. 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.

  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. 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.

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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.

  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. 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.

  8. 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

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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 widely used for the treatment of T2DM. Methods This was a randomized, open-label, repeat-dose, two-sequence, cross-over study in 13 subjects with T2DM. Subjects were randomized to one of two treatment sequences in which they received either metformin alone, RE alone, or both over three, 3-day treatment periods separated by two non-treatment intervals of variable duration. On the evening before each treatment period, subjects were admitted and confined to the clinical site for the duration of the 3-day treatment period. Pharmacokinetic, pharmacodynamic (urine glucose and fasting plasma glucose), and safety (adverse events, vital signs, ECG, clinical laboratory parameters including lactic acid) assessments were performed at check-in and throughout the treatment periods. Pharmacokinetic sampling occurred on Day 3 of each treatment period. Results This study demonstrated the lack of effect of RE on steady state metformin pharmacokinetics. Metformin did not affect the AUC of RE, remogliflozin, or its active metabolite, GSK279782, although Cmax values were slightly lower for remogliflozin and its metabolite after co-administration with metformin compared with administration of RE alone. Metformin did not alter the pharmacodynamic effects (UGE) of RE. Concomitant administration of metformin and RE was well tolerated with minimal hypoglycemia, no serious adverse events, and no increase in lactic

  20. Population pharmacokinetics, tolerability, and safety of dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine-piperaquine in pregnant and nonpregnant Papua New Guinean women.

    PubMed

    Benjamin, John M; Moore, Brioni R; Salman, Sam; Page-Sharp, Madhu; Tawat, Somoyang; Yadi, Gumal; Lorry, Lina; Siba, Peter M; Batty, Kevin T; Robinson, Leanne J; Mueller, Ivo; Davis, Timothy M E

    2015-07-01

    The tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine (SP)-PQ (three daily PQ doses, single dose of SP). All dose adminstrations were observed, and subjects fasted for 2 h postdose. Plasma PQ was assayed by using high-performance liquid chromatography, and DHA was assessed by using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in the rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two nonpregnant women had Plasmodium falciparum parasitemia which cleared within 48 h, and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths; these obstetric outcomes are consistent with those in the general population. The area under the plasma PQ concentration-time curve (AUC0-∞) was lower in the pregnant patients (median [interquartile range], 23,721 μg · h/liter [21,481 to 27,951 μg · h/liter] versus 35,644 μg · h/liter [29,546 to 39,541 μg · h/liter]; P < 0.001) in association with a greater clearance relative to bioavailability (73.5 liters/h [69.4 to 78.4] versus 53.8 liters/h [49.7 to 58.2]; P < 0.001), but pregnancy did not influence the pharmacokinetics of DHA. The apparent pharmacokinetic differences between the present study and results from other studies of women with uncomplicated malaria that showed no effect of pregnancy on the AUC0-∞ of PQ and greater bioavailability may reflect differences in postdose fat intake, proportions of women with malaria, and/or racial differences in drug

  1. 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

  2. Preliminary safety, pharmacokinetics, and efficacy of regorafenib, cisplatin, and pemetrexed in patients with advanced non-squamous non-small cell lung cancers

    PubMed Central

    Hellmann, Matthew D; Sturm, Isrid; Trnkova, Zuzana Jirakova; Lettieri, John; Diefenbach, Konstanze; Rizvi, Naiyer A.; Gettinger, Scott N.

    2016-01-01

    Structured Abstract Purpose The addition of bevacizumab, an anti-angiogenesis agent, to cytotoxic chemotherapy improves survival in patients with advanced non-squamous non-small cell lung cancers (nsNSCLCs). Regorafenib is an oral multi-targeted kinase inhibitor with potent anti-angiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. This phase I trial evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. Methods Chemotherapy-naïve patients with advanced nsNSCLCs were treated with regorafenib 60mg/day continuously and cisplatin 75mg/m2 plus pemetrexed 500mg/m2 once every three weeks for up to six cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. Results Nine patients enrolled prior to premature termination of the study due to slow recruitment and a change in the development strategy of regorafenib by the study sponsor, partially due to slow enrollment. Five patients experienced at least one treatment-related Grade 3 adverse event. No grade 4–5 toxicity occurred. 5 of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range 1.5–15.1). Minor pharmacokinetic (PK) interactions between regorafenib and chemotherapy were observed. Conclusions Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naïve patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results. PMID:26003007

  3. Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects.

    PubMed

    Stone, Nimalie D; Dunaway, Shelia B; Flexner, Charles; Tierney, Camlin; Calandra, Gary B; Becker, Stephen; Cao, Ying-Jun; Wiggins, Ilene P; Conley, Jeanne; MacFarland, Ron T; Park, Jeong-Gun; Lalama, Christina; Snyder, Sally; Kallungal, Beatrice; Klingman, Karin L; Hendrix, Craig W

    2007-07-01

    AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P < or = 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an E(max) model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.

  4. Intranasal Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users

    PubMed Central

    Cipriano, Alessandra; Colucci, Salvatore V.; Kapil, Ram P.; Geoffroy, Pierre; Hopyan, Talar; Levy-Cooperman, Naama

    2016-01-01

    Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo. Design. Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. Methods. During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics. Results. Insufflation of both HYD coarse and fine particles led to lower “At this Moment” Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists. Conclusions. HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder. PMID:26814240

  5. Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma.

    PubMed

    Yau, Thomas; Cheng, Paul N; Chan, Pierre; Chen, Li; Yuen, Jimmy; Pang, Roberta; Fan, Sheung Tat; Wheatley, Denys N; Poon, Ronnie T

    2015-04-01

    This study was designed to evaluate the efficacy, safety profile, pharmacokinetics, pharmacodynamics and quality of life of pegylated recombinant human arginase 1 (Peg-rhAgr1) in patients with advanced hepatocellular carcinoma (HCC). Patients were given weekly doses of Peg-rhAgr1 (1600 U/kg). Tumour response was assessed every 8 weeks using RECIST 1.1 and modified RECIST criteria. A total of 20 patients were recruited, of whom 15 were deemed evaluable for treatment efficacy. Eighteen patients (90%) were hepatitis B carriers. Median age was 61.5 (range 30-75). Overall disease control rate was 13%, with 2 of the 15 patients achieving stable disease for >8 weeks. The median progression-free survival (PFS) was 1.7 (95% CI: 1.67-1.73) months, with median overall survival (OS) of all 20 enrolled patients being 5.2 (95% CI: 3.3-12.0) months. PFS was significantly prolonged in patients with adequate arginine depletion (ADD) >2 months versus those who had ≤2 months of ADD (6.4 versus 1.7 months; p = 0.01). The majority of adverse events (AEs) were grade 1/2 non-hematological toxicities. Transient liver dysfunctions (25%) were the most commonly reported serious AEs and likely due to disease progression. Pharmacokinetic and pharmacodynamic data showed that Peg-rhAgr1 induced rapid and sustained arginine depletion. The overall quality of life of the enrolled patients was well preserved. Peg-rhAgr1 is well tolerated with a good toxicity profile in patients with advanced HCC. A weekly dose of 1600 U/kg is sufficient to induce ADD. Significantly longer PFS times were recorded for patients who had ADD for >2 months.

  6. Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles

    NASA Astrophysics Data System (ADS)

    Kang, Homan; Mintri, Shrutika; Menon, Archita Venugopal; Lee, Hea Yeon; Choi, Hak Soo; Kim, Jonghan

    2015-11-01

    Nanoparticles (NPs) are considered a promising tool in both diagnosis and therapeutics. Theranostic NPs possess the combined properties of targeted imaging and drug delivery within a single entity. While the categorization of theranostic NPs is based on their structure and composition, the pharmacokinetics of NPs are significantly influenced by the physicochemical properties of theranostic NPs as well as the routes of administration. Consequently, altered pharmacokinetics modify the pharmacodynamic efficacy and toxicity of NPs. Although theranostic NPs hold great promise in nanomedicine and biomedical applications, a lack of understanding persists on the mechanisms of the biodistribution and adverse effects of NPs. To better understand the diagnostic and therapeutic functions of NPs, this review discusses the factors that influence the pharmacokinetics, pharmacodynamics and toxicology of theranostic NPs, along with several strategies for developing novel diagnostic and therapeutic modalities.

  7. Safety and Upper Respiratory Pharmacokinetics of the Hemagglutinin Stalk-Binding Antibody VIS410 Support Treatment and Prophylaxis Based on Population Modeling of Seasonal Influenza A Outbreaks

    PubMed Central

    Wollacott, Andrew M.; Boni, Maciej F.; Szretter, Kristy J.; Sloan, Susan E.; Yousofshahi, Mona; Viswanathan, Karthik; Bedard, Sylvain; Hay, Catherine A.; Smith, Patrick F.; Shriver, Zachary; Trevejo, Jose M.

    2016-01-01

    Background Seasonal influenza is a major public health concern in vulnerable populations. Here we investigated the safety, tolerability, and pharmacokinetics of a broadly neutralizing monoclonal antibody (VIS410) against Influenza A in a Phase 1 clinical trial. Based on these results and preclinical data, we implemented a mathematical modeling approach to investigate whether VIS410 could be used prophylactically to lessen the burden of a seasonal influenza epidemic and to protect at-risk groups from associated complications. Methods Using a single-ascending dose study (n = 41) at dose levels from 2 mg/kg–50 mg/kg we evaluated the safety as well as the serum and upper respiratory pharmacokinetics of a broadly-neutralizing antibody (VIS410) against influenza A (ClinicalTrials.gov identifier NCT02045472). Our primary endpoints were safety and tolerability of VIS410 compared to placebo. We developed an epidemic microsimulation model testing the ability of VIS410 to mitigate attack rates and severe disease in at risk-populations. Findings VIS410 was found to be generally safe and well-tolerated at all dose levels, from 2–50 mg/kg. Overall, 27 of 41 subjects (65.9%) reported a total of 67 treatment emergent adverse events (TEAEs). TEAEs were reported by 20 of 30 subjects (66.7%) who received VIS410 and by 7 of 11 subjects (63.6%) who received placebo. 14 of 16 TEAEs related to study drug were considered mild (Grade 1) and 2 were moderate (Grade 2). Two subjects (1 subject who received 30 mg/kg VIS410 and 1 subject who received placebo) experienced serious AEs (Grade 3 or 4 TEAEs) that were not related to study drug. VIS410 exposure was approximately dose-proportional with a mean half-life of 12.9 days. Mean VIS410 Cmax levels in the upper respiratory tract were 20.0 and 25.3 μg/ml at the 30 mg/kg and 50 mg/kg doses, respectively, with corresponding serum Cmax levels of 980.5 and 1316 μg/mL. Using these pharmacokinetic data, a microsimulation model showed

  8. Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients

    PubMed Central

    Armstrong, Jon; Arrieta, Antonio; Bishai, Raafat; Das, Shampa; Delair, Shirley; Edeki, Timi; Holmes, William C.; Li, Jianguo; Moffett, Kathryn S.; Mukundan, Deepa; Perez, Norma; Romero, José R.; Speicher, David; Sullivan, Janice E.; Zhou, Diansong

    2016-01-01

    This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0–∞) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.) PMID:27503642

  9. Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: Efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study.

    PubMed

    Hibi, Toshifumi; Hirohata, Shunsei; Kikuchi, Hirotoshi; Tateishi, Ukihide; Sato, Noriko; Ozaki, Kunihiko; Kondo, Kazuoki; Ishigatsubo, Yoshiaki

    2016-06-01

    Behçet disease (BD) is a multisystem disease associated with a poor prognosis in cases of gastrointestinal, neurological, or vascular involvement. We conducted a multicenter, prospective, open-label, single-arm phase 3 study to determine the efficacy, safety, and pharmacokinetics of infliximab (IFX) in BD patients with these serious complications who had displayed poor response or intolerance to conventional therapy.IFX at 5 mg/kg was administered to 18 patients (11 intestinal BD, 3 neurological BD [NBD], and 4 vascular BD [VBD]) at weeks 0, 2, and 6 and every 8 weeks thereafter until week 46. In patients who showed inadequate responses to IFX after week 30, the dose was increased to 10 mg/kg. We then calculated the percentage of complete responders according to the predefined criteria depending on the symptoms and results of examinations (ileocolonoscopy, brain magnetic resonance imaging, computed tomography angiography, positron emission tomography, cerebrospinal fluid, or serum inflammatory markers), exploring the percentage of complete responders at week 30 (primary endpoint).The percentage of complete responders was 61% (11/18) at both weeks 14 and 30 and remained the same until week 54. Intestinal BD patients showed improvement in clinical symptoms along with decrease in C-reactive protein (CRP) levels after week 2. Consistently, scarring or healing of the principal ulcers was found in more than 80% of these patients after week 14. NBD patients showed improvement in clinical symptoms, imaging findings, and cerebrospinal fluid examinations. VBD patients showed improvement in clinical symptoms after week 2 with reductions in CRP levels and erythrocyte sedimentation rate. Imaging findings showed reversal of inflammatory changes in 3 of the 4 VBD patients. Irrespective of the type of BD, all patients achieved improvement in quality of life, leading to the dose reduction or withdrawal of steroids. IFX dose was increased to 10 mg/kg in 3 intestinal BD

  10. Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults

    PubMed Central

    Yu, Xiang-Qing; Robbie, Gabriel J.; Wu, Yuling; Esser, Mark T.; Jensen, Kathryn; Schwartz, Howard I.; Bellamy, Terramika; Hernandez-Illas, Martha

    2016-01-01

    ABSTRACT MEDI4893 is an investigational immunoglobulin G1(κ) monoclonal antibody that specifically binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor. A triple-amino-acid substitution, M252Y/S254T/T256E, was engineered into the MEDI4893 Fc region to extend its serum half-life. A phase 1, double-blind, dose escalation study was designed to evaluate the safety, tolerability, pharmacokinetics, anti-alpha-toxin-neutralizing activity, and antidrug antibody (ADA) response of MEDI4893 following a single intravenous infusion in healthy adults 18 to 65 years of age. Thirty-three subjects were randomly assigned to receive MEDI4893 at 225 mg (n = 3), 750 mg (n = 3), 2,250 mg (n = 8), or 5,000 mg (n = 12) or placebo (n = 7) and were followed for 360 days. Adverse events were mild or moderate in severity; none were serious. The MEDI4893 peak serum concentration increased dose proportionally from 77.2 μg/ml (225-mg dose) to 1,784 μg/ml (5,000-mg dose). The area under the concentration-time curve from 0 to 360 days also increased dose proportionally, from 4,840 μg · day/ml (225-mg dose) to 91,493 μg · day/ml (5,000-mg dose), indicating linear pharmacokinetics. MEDI4893's terminal half-life was estimated to be 80 to 112 days, which is approximately 4-fold longer than the half-lives of other human immunoglobulin G antibodies. The alpha-toxin-neutralizing activity in serum correlated highly with the MEDI4893 concentrations in serum. Three adults transiently tested positive for ADA on day 151, but this did not have an impact on MEDI4893 serum concentrations or the MEDI4893 safety profile; no subjects exhibited serum ADA at the study end. These data support the continued development of MEDI4893 for the prevention of S. aureus-mediated pneumonia. (This study has been registered at ClinicalTrials.gov under identifier NCT02296320.) PMID:27795368

  11. Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: Efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study

    PubMed Central

    Hibi, Toshifumi; Hirohata, Shunsei; Kikuchi, Hirotoshi; Tateishi, Ukihide; Sato, Noriko; Ozaki, Kunihiko; Kondo, Kazuoki; Ishigatsubo, Yoshiaki

    2016-01-01

    Abstract Behçet disease (BD) is a multisystem disease associated with a poor prognosis in cases of gastrointestinal, neurological, or vascular involvement. We conducted a multicenter, prospective, open-label, single-arm phase 3 study to determine the efficacy, safety, and pharmacokinetics of infliximab (IFX) in BD patients with these serious complications who had displayed poor response or intolerance to conventional therapy. IFX at 5 mg/kg was administered to 18 patients (11 intestinal BD, 3 neurological BD [NBD], and 4 vascular BD [VBD]) at weeks 0, 2, and 6 and every 8 weeks thereafter until week 46. In patients who showed inadequate responses to IFX after week 30, the dose was increased to 10 mg/kg. We then calculated the percentage of complete responders according to the predefined criteria depending on the symptoms and results of examinations (ileocolonoscopy, brain magnetic resonance imaging, computed tomography angiography, positron emission tomography, cerebrospinal fluid, or serum inflammatory markers), exploring the percentage of complete responders at week 30 (primary endpoint). The percentage of complete responders was 61% (11/18) at both weeks 14 and 30 and remained the same until week 54. Intestinal BD patients showed improvement in clinical symptoms along with decrease in C-reactive protein (CRP) levels after week 2. Consistently, scarring or healing of the principal ulcers was found in more than 80% of these patients after week 14. NBD patients showed improvement in clinical symptoms, imaging findings, and cerebrospinal fluid examinations. VBD patients showed improvement in clinical symptoms after week 2 with reductions in CRP levels and erythrocyte sedimentation rate. Imaging findings showed reversal of inflammatory changes in 3 of the 4 VBD patients. Irrespective of the type of BD, all patients achieved improvement in quality of life, leading to the dose reduction or withdrawal of steroids. IFX dose was increased to 10 mg/kg in 3

  12. Chitosan-Stearic Acid Based Polymeric Micelles for the Effective Delivery of Tamoxifen: Cytotoxic and Pharmacokinetic Evaluation.

    PubMed

    Thotakura, Nagarani; Dadarwal, Mukesh; Kumar, Pramod; Sharma, Gajanand; Guru, Santosh Kumar; Bhushan, Shashi; Raza, Kaisar; Katare, Om Prakash

    2017-04-01

    Chitosan is a widely employed polysaccharide with positive zeta-potential and better tissue/cell adhesion. Its hydrophilicity, high viscosity, and insolubility at physiological pH are major hurdles in proper utilization of this macromolecule. Therefore, it was conjugated with biocompatible stearic acid and the conjugate was employed to develop polymeric micelles for delivery of tamoxifen to breast cancer cells. The conjugate was characterized by FT-IR and NMR, and the nanocarrier was characterized for micromeritics, surface charge, drug loading, and morphological attributes. The efficacy was evaluated by in vitro MTT studies, safety by erythrocyte compatibility, and biodistribution by in vivo pharmacokinetic studies. Despite better drug loading and sustained drug release, cytotoxicity on MCF-7 breast cancer cells was substantially enhanced and the pharmacokinetic profile was significantly modified. The AUC was enhanced manifolds along with reduced clearance. The findings are unique and provide an alternative to the conventional lipid-based nanocarriers for better dose delivery, tissue adhesion, and desired pharmacokinetic modulation.

  13. Impact on abiraterone pharmacokinetics and safety: Open-label drug-drug interaction studies with ketoconazole and rifampicin.

    PubMed

    Bernard, Apexa; Vaccaro, Nicole; Acharya, Milin; Jiao, James; Monbaliu, Johan; De Vries, Ronald; Stieltjes, Hans; Yu, Margaret; Tran, Namphuong; Chien, Caly

    2015-01-01

    We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of abiraterone in two studies in healthy men. All subjects received 1,000 mg of abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11-16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8-13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, abiraterone exposure increased by 9% for maximum plasma concentration (Cmax ) and 15% for area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration (AUClast ) and AUC from time 0 to infinity (AUC∞ ) compared to abiraterone acetate alone. Study B: When given with rifampicin, abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on abiraterone exposure. Rifampicin decreased abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with abiraterone acetate.

  14. Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function

    PubMed Central

    Kunz, Christina; Luedtke, Doreen; Unseld, Anna; Hamilton, Alan; Halabi, Atef; Wein, Martina; Formella, Stephan

    2016-01-01

    Purpose In two trials, the influences of hepatic and renal impairment on the pharmacokinetics of olodaterol, a novel long-acting inhaled β2-agonist for treatment of COPD, were investigated. Subjects and methods The first trial included eight subjects with mild hepatic function impairment (Child–Pugh A), eight subjects with moderate impairment (Child–Pugh B), and 16 matched healthy subjects with normal hepatic function. The second trial included eight subjects with severe renal impairment (creatinine clearance <30 mL·min−1) and 14 matched healthy subjects with normal renal function. Subjects received single doses of 20 or 30 μg olodaterol administered with the Respimat Soft Mist inhaler. Results Olodaterol was well tolerated in all subjects. The geometric mean ratios and 90% confidence intervals of dose-normalized area under the plasma concentration-time curve from time zero to 4 hours (AUC0–4) for subjects with mild and moderate hepatic impairment compared to healthy subjects were 97% (75%–125%) and 105% (79%–140%), respectively. Corresponding values for dose-normalized maximum concentration (Cmax) were 112% (84%–151%) (mild impairment) and 99% (73%–135%) (moderate impairment). The geometric mean ratio (90% confidence interval) of AUC0–4 for subjects with severe renal impairment compared to healthy subjects was 135% (94%–195%), and for Cmax was 137% (84%–222%). There was no significant relationship between creatinine clearance and AUC0–4 or Cmax. Renal clearance of olodaterol was reduced to 20% of normal in severe renal impairment. Conclusion Mild to moderate hepatic function impairment or severe renal function impairment did not result in a clinically relevant increase of olodaterol systemic exposure after a single inhaled dose. PMID:27051282

  15. Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study

    PubMed Central

    Mehta, Rashmi; Hardes, Kelly; Brealey, Noushin; Tombs, Lee; Preece, Andrew; Kelleher, Dennis

    2015-01-01

    Background Umeclidinium and vilanterol, long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease, are primarily eliminated via the hepatic route; however, severe renal impairment may adversely affect some elimination pathways other than the kidney. Objectives To evaluate the effect of severe renal impairment on the pharmacokinetics of umeclidinium and umeclidinium/vilanterol. Methods Nine patients with severe renal impairment (creatinine clearance <30 mL/min) and nine matched healthy volunteers received a single dose of umeclidinium 125 μg; and after a 7- to 14-day washout, a single dose of umeclidinium/vilanterol 125/25 μg. Results No clinically relevant increases in plasma umeclidinium or vilanterol systemic exposure (area under the curve or maximum observed plasma concentration) were observed following umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration. On average, the amount of umeclidinium excreted in 24 hours in urine (90% confidence interval) was 88% (81%–93%) and 89% (81%–93%) lower in patients with severe renal impairment compared with healthy volunteers following umeclidinium 125 μg and umeclidinium/vilanterol 125/25 μg administration, respectively. Treatments were well tolerated in both populations. Conclusion Umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration to patients with severe renal impairment did not demonstrate clinically relevant increases in systemic exposure compared with healthy volunteers. No dose adjustment for umeclidinium and umeclidinium/vilanterol is warranted in patients with severe renal impairment. PMID:25565796

  16. An open-label clinical trial of the effects of age and gender on the pharmacodynamics, pharmacokinetics and safety of the ghrelin receptor agonist anamorelin

    PubMed Central

    Leese, Philip T; Trang, John M; Blum, Robert A; de Groot, Eleanor

    2015-01-01

    Purpose To assess the effect of age and gender on the pharmacokinetics (PK) of the ghrelin receptor agonist anamorelin. Methods Three demographic cohorts of healthy subjects were enrolled in this single-center, open-label study. Subjects received a single oral dose (25 mg) of anamorelin HCl. Serial blood samples were collected over 24 hours to assess anamorelin PK and circulating growth hormone (GH) levels. Data were compared with a reference cohort. Results Anamorelin was rapidly absorbed in all cohorts; peak concentrations were observed 30–45 minutes and 2–4 hours post-dose, which declined biexponentially with mean terminal half-lives of 6–7 hours. An age effect on Cmax and AUC∞ was not apparent; however, mean AUC∞ values were approximately 1.8–1.9-fold higher in the female cohorts than in the reference male cohort. GH increase was rapid and virtually identical in both sexes, though attenuated in elderly subjects. No clinically significant safety or tolerability findings were observed. Conclusions While PK parameters do suggest higher exposure in females, this effect is considered to be modest given the variability of the 6–8 subjects per cohort. Moreover, no such effect was observed in the pharmacodynamic responses, thus, dose adjustment for age and gender is considered unnecessary. PMID:26640742

  17. Safety, tolerability, and pharmacokinetics of 6-month daily dosing of an oral formulation of cyclosporine (ATOPICA for cats®) in cats

    PubMed Central

    Roberts, E S; VanLare, K A; Strehlau, G; Peyrou, M; Roycroft, L M; King, S

    2014-01-01

    Cyclosporine was proven efficacious in the treatment of feline hypersensitivity dermatitis. This target animal study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ATOPICA for Cats® (cyclosporine oral solution, USP) MODIFIED following 6-month daily dosing in cats. Forty healthy cats (four cats/sex/group) received 0, 8 (1×), 16 (2×), 24 (3×), or 40 (5×) mg/kg cyclosporine once daily for 6 months (183 days). Body weight, food consumption, ophthalmoscopic, physical examinations including neurological assessments, blood pressure, electrocardiography, clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), organ weights, and macroscopic and microscopic examinations were performed and assessed. In addition, blood concentrations of cyclosporine were measured at the pretreatment trough on Days 1, 2, 7, 14, 31, 91, 154, and 182, and post-treatment on Days 1, 31, and 182. Adverse effects possibly related to treatment included prolonged APTT and one report each of bone marrow hypocellularity and lymphoma; all occurred in cats treated with doses more than 16 mg/kg. There was no significant accumulation of cyclosporine beyond the first week of treatment. Results confirm that ATOPICA for Cats is safe and well tolerated in cats without unexpected accumulation beyond the first week of treatment when administered as directed. PMID:24134659

  18. Phase I randomised double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases - safety, pharmacokinetics and pharmacodynamics

    PubMed Central

    Howells, L. M.; Berry, D. P.; Elliott, P.J.; Jacobson, E. W.; Hoffmann, E.; Hegarty, B.; Brown, K.; Steward, W. P.; Gescher, A. J.

    2011-01-01

    The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism, may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given at 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1942±1422 ng/mL, exceeding those published for equivalent doses of non-micronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2287 ng/g). Cleaved caspase-3, a marker of apoptosis, was significantly increased by 39% in malignant hepatic tissue following SRT501 treatment, compared to tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility. PMID:21680702

  19. A Multicenter, Randomized, Open-Label, Pharmacokinetics and Safety Study of Pantoprazole Tablets in Children and Adolescents Aged 6 Through 16 Years With GERD

    PubMed Central

    Ward, Robert M.; Kearns, Gregory L.; Tammara, Brinda; Bishop, Phyllis; O’Gorman, Molly A.; James, Laura P.; Katz, Mitchell H.; Maguire, Mary K.; Rath, Natalie; Meng, Xu; Comer, Gail M.

    2011-01-01

    SUMMARY Children with GERD may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drug’s kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed-release tablets in pediatric patients with GERD aged ≥6 through 11 years (study 1) and 12 through 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose, and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar toPK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug-associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults. PMID:20852004

  20. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial

    PubMed Central

    Mannucci, Pier Mannuccio; Kempton, Christine; Millar, Carolyn; Romond, Edward; Shapiro, Amy; Birschmann, Ingvild; Ragni, Margaret V.; Gill, Joan Cox; Yee, Thynn Thynn; Klamroth, Robert; Wong, Wing-Yen; Chapman, Miranda; Engl, Werner; Turecek, Peter L.; Suiter, Tobias M.

    2013-01-01

    Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF–binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post–rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved. This trial was registered at www.clinicaltrials.gov as #NCT00816660. PMID:23777763

  1. Safety, tolerability, and pharmacokinetics of 6-month daily dosing of an oral formulation of cyclosporine (ATOPICA for cats®) in cats.

    PubMed

    Roberts, E S; Vanlare, K A; Strehlau, G; Peyrou, M; Roycroft, L M; King, S

    2014-04-01

    Cyclosporine was proven efficacious in the treatment of feline hypersensitivity dermatitis. This target animal study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ATOPICA for Cats® (cyclosporine oral solution, USP) MODIFIED following 6-month daily dosing in cats. Forty healthy cats (four cats/sex/group) received 0, 8 (1×), 16 (2×), 24 (3×), or 40 (5×) mg/kg cyclosporine once daily for 6 months (183 days). Body weight, food consumption, ophthalmoscopic, physical examinations including neurological assessments, blood pressure, electrocardiography, clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), organ weights, and macroscopic and microscopic examinations were performed and assessed. In addition, blood concentrations of cyclosporine were measured at the pretreatment trough on Days 1, 2, 7, 14, 31, 91, 154, and 182, and post-treatment on Days 1, 31, and 182. Adverse effects possibly related to treatment included prolonged APTT and one report each of bone marrow hypocellularity and lymphoma; all occurred in cats treated with doses more than 16 mg/kg. There was no significant accumulation of cyclosporine beyond the first week of treatment. Results confirm that ATOPICA for Cats is safe and well tolerated in cats without unexpected accumulation beyond the first week of treatment when administered as directed.

  2. An Exploratory Dose-Escalating Study Investigating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous Atacicept in Patients with Systemic Lupus Erythematosus

    PubMed Central

    Pena-Rossi, C; Nasonov, E; Stanislav, M; Yakusevich, V; Ershova, O; Lomareva, N; Saunders, H; Hill, J; Nestorov, I

    2009-01-01

    Atacicept, a recombinant fusion protein containing the extracellular, ligand-binding portion of the transmembrane activator and calcium modulator and cyclophilin-ligand interactor receptor, and the Fc portion of human immunoglobulin (Ig) G, is designed to block the activity of B-lymphocyte stimulator and a proliferation-inducing ligand, and may have utility as a treatment for B-cellmediated diseases, such as systemic lupus erythematosus (SLE). This Phase Ib study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of intravenous (i.v.) atacicept in patients with mild-to-moderate SLE. Patients (n = 24) were randomised (5:1) to receive atacicept (single dose: 3, 9 or 18 mg/kg; or multiple dose: 2 × 9 mg/kg) or matching placebo. Patients were followed for 6 weeks after dosing (9 weeks in the 2 × 9 mg/kg cohort). Local tolerability of atacicept was comparable with that of placebo, with only mild injection-site reactions reported with atacicept. Atacicept i.v. was generally well tolerated, both systemically and locally, in patients with mild-to-moderate SLE. Atacicept displayed non-linear PK, which was predictable across doses and between single and repeat doses. The biological activity of atacicept was demonstrated by its marked effect in reducing B-cells and Ig levels in patients with SLE. This supports the utility of this therapeutic approach in the treatment of autoimmune diseases, such as SLE. PMID:19395457

  3. A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic

    PubMed Central

    Buda, Jeffrey J; Carroll, F I; Kosten, Thomas R; Swearingen, Dennis; Walters, Bradford B

    2015-01-01

    Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator (WSF)); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard instrument was administered predose and daily postdose Days 1–6. At 1 mg, 2 of the 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests that NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine whether a significant JDTic human cardiac effect indeed exists, and if so, whether it is specific to JDTic or represents a KORAn class effect. PMID:25628006

  4. An open-label, two-period comparative study on pharmacokinetics and safety of a combined ethinylestradiol/gestodene transdermal contraceptive patch.

    PubMed

    Zhang, Chao; Li, Haiyan; Xiong, Xin; Zhai, Suodi; Wei, Yudong; Zhang, Shuang; Zhang, Yuanyuan; Xu, Lin; Liu, Li

    2017-01-01

    We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet(®)) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration (Cmax), extended time to reach the Cmax and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration-time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations.

  5. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease.

    PubMed

    Maertens, Johan; Cornely, Oliver A; Ullmann, Andrew J; Heinz, Werner J; Krishna, Gopal; Patino, Hernando; Caceres, Maria; Kartsonis, Nicholas; Waskin, Hetty; Robertson, Michael N

    2014-07-01

    This was a phase 1B, dose-ranging, multicenter, pharmacokinetics, and safety study of cyclodextrin-based posaconazole intravenous (i.v.) solution administered through a central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3]). Initially, the safety and tolerability of single-dose posaconazole i.v. 200 mg (n = 10) were compared with those of a placebo (n = 11). Subsequently, 2 doses were evaluated, posaconazole i.v. 200 mg once daily (q.d.) (n = 21) and 300 mg q.d. (n = 24). The subjects received twice-daily (b.i.d.) posaconazole i.v. on day 1, followed by 13 days of posaconazole i.v. q.d., then 14 days of posaconazole oral suspension 400 mg b.i.d. The steady-state (day 14) exposure target (average concentration [areas under concentration-time curve {AUCs}/24 h, average concentrations at steady state {Cavgs}], of ≥ 500 to ≤ 2,500 ng/ml in ≥ 90% of the subjects) was achieved by 94% of the subjects for 200 mg posaconazole q.d. and by 95% of subjects for 300 mg posaconazole q.d. The desired exposure target (mean steady-state Cavg, ∼ 1,200 ng/ml) was 1,180 ng/ml in the 200-mg dosing cohort and was exceeded in the 300-mg dosing cohort (1,430 ng/ml). Posaconazole i.v. was well tolerated. Posaconazole i.v. 300 mg q.d. was selected for the phase 3 study segment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01075984.).

  6. Safety and pharmacokinetic profiles of phosphorodiamidate morpholino oligomers with activity against ebola virus and marburg virus: results of two single-ascending-dose studies.

    PubMed

    Heald, Alison E; Iversen, Patrick L; Saoud, Jay B; Sazani, Peter; Charleston, Jay S; Axtelle, Tim; Wong, Michael; Smith, William B; Vutikullird, Apinya; Kaye, Edward

    2014-11-01

    Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence.

  7. An open-label, two-period comparative study on pharmacokinetics and safety of a combined ethinylestradiol/gestodene transdermal contraceptive patch

    PubMed Central

    Zhang, Chao; Li, Haiyan; Xiong, Xin; Zhai, Suodi; Wei, Yudong; Zhang, Shuang; Zhang, Yuanyuan; Xu, Lin; Liu, Li

    2017-01-01

    We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet®) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration (Cmax), extended time to reach the Cmax and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration–time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations. PMID:28331292

  8. Virtual Clinical Trial Toward Polytherapy Safety Assessment: Combination of Physiologically Based Pharmacokinetic/Pharmacodynamic-Based Modeling and Simulation Approach With Drug-Drug Interactions Involving Terfenadine as an Example.

    PubMed

    Wiśniowska, Barbara; Polak, Sebastian

    2016-11-01

    A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro-in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration. ten Tusscher's human ventricular cardiomyocyte model was used to simulate the pseudo-ECG traces and further predict the pharmacodynamic consequences of DDI. Consistent with clinical observations, predicted plasma concentration profiles of terfenadine show considerable intra-subject variability with recorded Cmax values below 5 ng/mL for most virtual subjects. The pharmacokinetic and pharmacodynamic effects of inhibitors were predicted with reasonable accuracy. In all cases, a combination of the physiologically based pharmacokinetic and physiology-based pharmacodynamic models was able to differentiate between the terfenadine alone and terfenadine + inhibitor scenario. The range of QT prolongation was comparable in the clinical and virtual studies. The results indicate that mechanistic in vitro-in vivo correlation can be applied to predict the clinical effects of DDI even without comprehensive knowledge on all mechanisms contributing to the interaction.

  9. Safety and Pharmacokinetics of Quick-Dissolving Polymeric Vaginal Films Delivering the Antiretroviral IQP-0528 for Preexposure Prophylaxis

    PubMed Central

    Srinivasan, Priya; Zhang, Jining; Martin, Amy; Kelley, Kristin; McNicholl, Janet M.; Buckheit, Robert W.; Smith, James M.

    2016-01-01

    For human immunodeficiency virus (HIV) prevention, microbicides or drugs delivered as quick-dissolving films may be more acceptable to women than gels because of their compact size, minimal waste, lack of an applicator, and easier storage and transport. This has the potential to improve adherence to promising products for preexposure prophylaxis. Vaginal films containing IQP-0528, a nonnucleoside reverse transcriptase inhibitor, were evaluated for their pharmacokinetics in pigtailed macaques. Polymeric films (22 by 44 by 0.1 mm; providing 75% of a human dose) containing IQP-0528 (1.5%, wt/wt) with and without poly(lactic-co-glycolic acid) (PLGA) nanoparticle encapsulation were inserted vaginally into pigtailed macaques in a crossover study design (n = 6). With unencapsulated drug, the median (range) vaginal fluid concentrations of IQP-0528 were 160.97 (2.73 to 2,104), 181.79 (1.86 to 15,800), and 484.50 (8.26 to 4,045) μg/ml at 1, 4, and 24 h after film application, respectively. Median vaginal tissue IQP-0528 concentrations at 24 h were 3.10 (0.03 to 222.58) μg/g. The values were similar at locations proximal, medial, and distal to the cervix. The IQP-0528 nanoparticle-formulated films delivered IQP-0528 in vaginal tissue and secretions at levels similar to those obtained with the unencapsulated formulation. A single application of either formulation did not disturb the vaginal microflora or the pH (7.24 ± 0.84 [mean ± standard deviation]). The high mucosal IQP-0528 levels delivered by both vaginal film formulations were between 1 and 5 log higher than the in vitro 90% inhibitory concentration (IC90) of 0.146 μg/ml. The excellent coverage and high mucosal levels of IQP-0528, well above the IC90, suggest that the films may be protective and warrant further evaluation in a vaginal repeated low dose simian-human immunodeficiency virus (SHIV) transmission study in macaques and clinically in women. PMID:27139475

  10. Effect of Coadministered Fat on the Tolerability, Safety, and Pharmacokinetic Properties of Dihydroartemisinin-Piperaquine in Papua New Guinean Children with Uncomplicated Malaria

    PubMed Central

    Moore, B. R.; Benjamin, J. M.; Salman, S.; Griffin, S.; Ginny, E.; Page-Sharp, M.; Robinson, L. J.; Siba, P.; Batty, K. T.; Mueller, I.

    2014-01-01

    Coadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/kg doses were given with water (n = 14, group A) or milk (n = 16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was generally well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC0–∞) for PQ (median, 41,906 versus 36,752 μg · h/liter in groups A and B, respectively; P = 0.24) or DHA (4,047 versus 4,190 μg · h/liter; P = 0.67). There were also no significant between-group differences in prolongation of the corrected electrocardiographic QT interval (QTc) initially during follow-up, but the QTc tended to be higher in group B children at 24 h (mean ± standard deviation [SD], 15 ± 10 versus 6 ± 15 ms0.5 in group A, P = 0.067) and 168 h (10 ± 18 versus 1 ± 23 ms0.5, P = 0.24) when plasma PQ concentrations were relatively low. A small amount of fat does not change the bioavailability of DHA-PQ in children, but a delayed persistent effect on ventricular repolarization cannot be excluded. PMID:25049242

  11. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study.

    PubMed

    Walsh, T J; Goodman, J L; Pappas, P; Bekersky, I; Buell, D N; Roden, M; Barrett, J; Anaissie, E J

    2001-12-01

    We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (C(max)) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 microg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC(24)) changed to 692, 1,062, 860, and 554 microg x h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of >or=7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n

  12. Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected Patients

    PubMed Central

    2006-01-01

    Context Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily. Setting Twenty-six centers in the United States, Canada, and Puerto Rico. Patients A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week, phase 3, open-label, randomized study. Main Outcome Measure Proportion of patients with HIV-RNA levels < 50 copies/mL. The pharmacokinetic profile of saquinavir-SGC was analyzed in a subset of randomly selected patients. Results In the primary intent-to-treat population at week 48, 51% (38/75) and 71% (55/77) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNA suppression < 50 copies/mL (P = .5392, 95% 1-sided confidence interval [CI] = -33.5%). In the on-treatment (OT) population, 73% (38/52) and 93% (54/58) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression < 50 copies/mL (P = .5015, 95% 1-sided CI = -33.4%). Mean CD4+ cell counts increased by 239 and 204 cells/microliters (mcL), in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P = .058). Both regimens were reasonably well tolerated, although more gastrointestinal adverse events were reported with saquinavir-SGC/ritonavir. Pharmacokinetic profiles in 6 patients showed an observed median Cmin at 24 hours of 429 ng/mL (range, 681750 ng/mL). Conclusion Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in the saquinavir-SGC/ritonavir arm of the study.

  13. Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected Patients

    PubMed Central

    Montaner, Julio S.G.; Schutz, Malte; Schwartz, Robert; Jayaweera, Dushyantha T.; Burnside, Alfred F.; Walmsley, Sharon; Saag, Michael S.

    2006-01-01

    Context Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily. Setting Twenty-six centers in the United States, Canada, and Puerto Rico. Patients A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week, phase 3, open-label, randomized study. Main Outcome Measure Proportion of patients with HIV-RNA levels < 50 copies/mL. The pharmacokinetic profile of saquinavir-SGC was analyzed in a subset of randomly selected patients. Results In the primary intent-to-treat population at week 48, 51% (38/75) and 71% (55/77) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNA suppression < 50 copies/mL (P = .5392, 95% 1-sided confidence interval [CI] = −33.5%). In the on-treatment (OT) population, 73% (38/52) and 93% (54/58) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression < 50 copies/mL (P = .5015, 95% 1-sided CI = −33.4%). Mean CD4+ cell counts increased by 239 and 204 cells/microliters (mcL), in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P = .058). Both regimens were reasonably well tolerated, although more gastrointestinal adverse events were reported with saquinavir-SGC/ritonavir. Pharmacokinetic profiles in 6 patients showed an observed median Cmin at 24 hours of 429 ng/mL (range, 68-1750 ng/mL). Conclusions Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in the saquinavir-SGC/ritonavir arm of the study. PMID:16926775

  14. Pharmacokinetics and Safety of Nelfinavir When Used in Combination with Zidovudine and Lamivudine in HIV-Infected Pregnant Women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353

    PubMed Central

    Bryson, Y.J.; Mirochnick, M.; Stek, A.; Mofenson, L.M.; Connor, J.; Capparelli, E.; Watts, D.H.; Huang, S.; Hughes, M.D.; Kaiser, K.; Purdue, L.; Asfaw, Y.; Keller, M.; Smith, E.

    2014-01-01

    Background Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. Method HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0–24 > 30 μg · h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. Results Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 μg/mL vs. 5.01 μg/mL, p < .05) and AUC0–24 (56.6 vs. 86.8 μg · h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. Conclusion NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and

  15. Phase 1, Open-Label, Dose Escalation, Safety, and Pharmacokinetics Study of ME-344 as a Single Agent in Patients With Refractory Solid Tumors

    PubMed Central

    Bendell, Johanna C; Patel, Manish R; Infante, Jeffrey R; Kurkjian, Carla D; Jones, Suzanne F; Pant, Shubham; Burris, Howard A; Moreno, Ofir; Esquibel, Vanessa; Levin, Wendy; Moore, Kathleen N

    2015-01-01

    Background The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. Methods Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle. Results A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥31 weeks]). Conclusions The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy. The

  16. Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected with Aspergillus Species and Other Filamentous Fungi: Maximum Tolerated Dose Study

    PubMed Central

    Walsh, Thomas J.; Goodman, Jesse L.; Pappas, Peter; Bekersky, Ihor; Buell, Donald N.; Roden, Maureen; Barrett, John; Anaissie, Elias J.

    2001-01-01

    We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (Cmax) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 μg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC24) changed to 692, 1,062, 860, and 554 μg · h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of ≥7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n = 31). These

  17. Pharmacokinetics and 48-Week Safety and Efficacy of Raltegravir for Oral Suspension in Human Immunodeficiency Virus Type-1-Infected Children 4 Weeks to 2 Years of Age

    PubMed Central

    Nachman, Sharon; Alvero, Carmelita; Acosta, Edward P.; Teppler, Hedy; Homony, Brenda; Graham, Bobbie; Fenton, Terence; Xu, Xia; Rizk, Matthew L.; Spector, Stephen A.; Frenkel, Lisa M.; Worrell, Carol; Handelsman, Edward; Wiznia, Andrew

    2015-01-01

    Background IMPAACT P1066 is a Phase I/II open-label multicenter trial to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple raltegravir (RAL) formulations in human immunodeficiency virus (HIV)-infected youth. Methods Dose selection of the oral suspension formulation for each cohort (IV: 6 months to <2 years and V: 4 weeks to <6 months) was based on review of short-term safety (4 weeks) and intensive PK 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 from baseline at Week 24 (Success). For Cohort IV, optimized background therapy (OBT) could have been initiated with RAL either at study entry or after intensive PK sampling was completed at Day 5–12. An OBT was started when RAL was initiated for Cohort V subjects because they were not permitted to have received direct antiretroviral therapy before enrollment. Results Total accrual was 27 subjects in these 2 cohorts, including 1 subject who was enrolled but never started study drug (excluded from the analyses). The targeted PK parameters (area under the curve [AUC]0−12hr and C12hr) were achieved for each cohort allowing for dose selection. Through Week 48, there were 10 subjects with Grade 3+ AEs. Two were judged related to study drug. There was 1 discontinuation due to an AE of skin rash, 1 event of immune reconstitution syndrome, and no drug-related deaths. At Week 48, for Cohorts IV and V, 87.5% of subjects achieved virologic success and 45.5% had HIV RNA <50 copies/mL. At Week 48, gains in CD4 cells of 527.6 cells/mm3 and 7.3% were observed. Conclusions A total of 6 mg/kg per dose twice daily of RAL for oral suspension was well tolerated and showed favorable virologic and immunologic responses. PMID:26582887

  18. Comparison of the pharmacokinetics, safety, and immunogenicity of MSB11022, a biosimilar of adalimumab, with Humira® in healthy subjects

    PubMed Central

    Mant, Tim; Vlachos, Pantelis; Attkins, Neil; Ullmann, Martin; Roy, Sanjeev; Wagner, Volker

    2016-01-01

    Aims The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of the proposed adalimumab biosimilar MSB11022 (Merck) with Humira® (AbbVie), sourced from both the US (US reference product [US‐RP]) and Europe (European reference medicinal product [EU‐RMP]). Methods In this phase 1 double‐blind, parallel group trial (EMR200588‐001), 213 healthy volunteers were randomized 1 : 1 : 1 to receive a single dose (40 mg) of MSB11022, US‐RP or EU‐RMP in order to achieve 80% power assuming a 5% difference among groups and a 10% dropout rate. Following a preplanned blinded sample size re‐assessment after more than 50% of the originally planned subjects had been observed, the sample size was increased to 237 (79 per arm) to ensure 213 completers. Primary PK endpoints analyzed by non‐compartmental methods, were area under the curve (AUC) from time 0 extrapolated to infinity (AUC(0,∞)), maximum observed concentration (C max), and AUC from time 0 to the last quantifiable concentration (AUC(0,t last)). PK equivalence was declared if the 90% CI for the test : reference ratio lay within the 80–125% equivalence margin. Bioequivalence was demonstrated if all three PK parameters met the PK equivalence criteria. Safety and tolerability were also evaluated. Results Mean serum concentration–time profiles for the three treatments were similar. MSB11022 demonstrated PK equivalence to US‐RP and EU‐RMP for all primary endpoints. The geometric means of AUC(0,∞), C max and AUC(0,t last) following a single dose of MSB11022 were 2276.05 μg ml–1 h, 3.44 μg ml–1  and 1983.90 μg ml–1 h, respectively. Adverse events (AEs) were similar across all groups, with treatment‐emergent AEs (TEAEs) reported by 62.8%, 56.3% and 62.0% of subjects within the MSB11022, US‐RP and EU‐RMP groups, respectively. Most of the TEAEs were considered mild and unrelated to study drug. No deaths or severe AEs related to the study drug were

  19. Physiologically Based Pharmacokinetic Model for Long-Circulating Inorganic Nanoparticles.

    PubMed

    Liang, Xiaowen; Wang, Haolu; Grice, Jeffrey E; Li, Li; Liu, Xin; Xu, Zhi Ping; Roberts, Michael S

    2016-02-10

    A physiologically based pharmacokinetic model was developed for accurately characterizing and predicting the in vivo fate of long-circulating inorganic nanoparticles (NPs). This model is built based on direct visualization of NP disposition details at the organ and cellular level. It was validated with multiple data sets, indicating robust inter-route and interspecies predictive capability. We suggest that the biodistribution of long-circulating inorganic NPs is determined by the uptake and release of NPs by phagocytic cells in target organs.

  20. Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies

    PubMed Central

    Borte, M.; Kriván, G.; Derfalvi, B.; Maródi, L.; Harrer, T.; Jolles, S.; Bourgeois, C.; Engl, W.; Leibl, H.; McCoy, B.; Gelmont, D.

    2016-01-01

    Summary A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2–67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0·022/patient‐year, P < 0·0001); the rate of all infections was 4·38/patient‐year. Median trough IgG concentrations were ≥ 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non‐serious AEs occurred at a rate of 0·101 event/infusion. The incidence of local related AEs was 0·069 event/infusion (0·036 event/infusion, when excluding a 13‐year‐old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0·032 event/infusion. Most related AEs were mild, none were severe. For 64·6% of patients and in 94·8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0·95 (range = 0·3‐4·1) h using mainly one to two administration sites [median = 2 sites (range = 1–5)]. Almost all infusions (99·8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well‐tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment. PMID:27613250

  1. Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men

    PubMed Central

    Scott, Graham; Ahmad, Irfan; Howard, Katy; MacLean, David; Oliva, Cristina; Warrington, Steve; Wilbraham, Darren; Worthington, Paul

    2013-01-01

    Aims Two randomized, double-blind, placebo-controlled studies were performed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the investigational metastin analogue, TAK-683, in healthy men. Methods We first investigated a single subcutaneous (s.c.) dose of TAK-683 (0.01–2.0 mg) in 60 subjects (TAK-683, n = 42; placebo, n = 18). We then assessed a single s.c. bolus of 0.03–1.0 mg TAK-683 on day 1, followed by a 0.01–2.0 mg day−1 continuous infusion on days 2–13, to simulate a depot formulation, in 30 subjects (TAK-683, n = 25; placebo, n = 5) for 14 days. Results TAK-683 was well tolerated up to a dose of 2.0 mg day−1 by continuous s.c. infusion for 14 days. Adverse events were similar between TAK-683 and placebo subjects at all dose levels. TAK-683 plasma concentrations generally increased in proportion to dose with single and continuous dosing, with steady-state concentrations achieved by day 2 of continuous dosing. TAK-683 at 2.0 mg day−1 suppressed testosterone below castration level (<50 ng dl−1) in four of five subjects by day 7 of continuous dosing. Luteinizing hormone and follicle stimulating hormone concentrations were suppressed with TAK-683 continuous dosing compared with placebo by up to 70 and 43%, respectively, but this was not consistently dose-dependent. Conclusions In healthy men, s.c. administration of TAK-683 was well tolerated at all dose levels. The PK profile of TAK-683 was favourable, and TAK-683 suppressed testosterone profoundly during continuous dosing. Further investigation of metastin analogues is warranted for the treatment of castration-resistant prostate cancer. PMID:22803642

  2. Pharmacokinetics, safety, and tolerability of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, following multiple ascending subcutaneous administrations in healthy subjects.

    PubMed

    Marier, Jean-Francois; Beliveau, Martin; Mouksassi, Mohamad-Samer; Shaw, Paula; Cyran, Jane; Kesavan, Jothi; Wallens, John; Zahir, Hamim; Wells, David; Caminis, John

    2008-11-01

    Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treatment of short-bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N = 64) were assessed following daily subcutaneous administrations for 8 days in a double-blinded, randomized, placebo-controlled, ascending-dose study. Teduglutide treatments were administered as a 50-mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20-mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once-daily repeated administrations. The apparent clearance of teduglutide following administration of the 50-mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20-mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50-mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies.

  3. Phase I clinical studies of S-1108: safety and pharmacokinetics in a multiple-administration study with special emphasis on the influence on carnitine body stores.

    PubMed Central

    Nakashima, M; Uematsu, T; Oguma, T; Yoshida, T; Mizojiri, K; Matsuno, S; Yamamoto, S

    1992-01-01

    S-1108, the prodrug of S-1006, was given to healthy volunteers three times a day (TID) for 8 days in a dose of 200 mg in a crossover placebo-controlled study. The safety of S-1108 and the pharmacokinetics of S-1006 and pivalic acid liberated from pivaloyloxymethyl ester of S-1108 were investigated. There were no abnormal symptoms or signs, as observed by physical and laboratory tests. The half-life and area under the concentration-time curve of S-1006 was reduced from 1.11 +/- 0.17 h at the first dose to 0.87 +/- 0.18 h at the last dose and from 7.30 +/- 1.10 to 5.20 +/- 0.85 micrograms.h/ml, respectively. However, there was no significant difference in the peak concentration between the two doses. Pivalic acid was found to be completely detoxified by conjugation with carnitine. The total urinary recovery of pivalic acid as pivaloylcarnitine was 98.7 +/- 3.6%, resulting in an increase of daily carnitine urinary excretion two- to threefold the predose value. During the multiple administration of S-1108, the plasma carnitine concentration was reduced to and maintained at 50 to 70% of the control value, suggesting that there might be enough carnitine store in the body to detoxify the pivalic acid in a dose of 200 mg TID. Moreover, the reduced plasma carnitine was rapidly returned to the control value within a few days after the cessation of the administration of 200 mg TID. PMID:1503438

  4. Pharmacokinetics, Safety, and Antiviral Effects of Hypericin, a Derivative of St. John's Wort Plant, in Patients with Chronic Hepatitis C Virus Infection

    PubMed Central

    Jacobson, Jeffrey M.; Feinman, Lawrence; Liebes, Leonard; Ostrow, Nancy; Koslowski, Victoria; Tobia, Alfonso; Cabana, Bernard E.; Lee, Dong-Hun; Spritzler, John; Prince, Alfred M.

    2001-01-01

    Hypericin is a natural derivative of the common St. Johns wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). We conducted a phase I dose escalation study to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day. At the end of the 8-week period of treatment, no subject had a change of plasma HCV RNA level of more than 1.0 log10. Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg) and mean area under the curve determinations of 1.5 and 3.1 μg/ml × hr, respectively. In sum, hypericin given orally in doses of 0.05 and 0.10 mg/kg/d caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection. PMID:11158749

  5. Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John's wort plant, in patients with chronic hepatitis C virus infection.

    PubMed

    Jacobson, J M; Feinman, L; Liebes, L; Ostrow, N; Koslowski, V; Tobia, A; Cabana, B E; Lee, D; Spritzler, J; Prince, A M

    2001-02-01

    Hypericin is a natural derivative of the common St. Johns wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). We conducted a phase I dose escalation study to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day. At the end of the 8-week period of treatment, no subject had a change of plasma HCV RNA level of more than 1.0 log(10). Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg) and mean area under the curve determinations of 1.5 and 3.1 microg/ml x hr, respectively. In sum, hypericin given orally in doses of 0.05 and 0.10 mg/kg/d caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection.

  6. Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of a selective Lp-PLA2 inhibitor (GSK2647544) in healthy volunteers

    PubMed Central

    Wu, Kai; Xu, Jianfeng; Fong, Regan; Yao, Xiaozhou; Xu, Yanmei; Guiney, William; Gray, Frank; Lockhart, Andrew

    2016-01-01

    Abstract. Objective: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). Methods: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 – 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2. Results: Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively. Conclusions: GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2. PMID:27719741

  7. Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies.

    PubMed

    Borte, M; Kriván, G; Derfalvi, B; Maródi, L; Harrer, T; Jolles, S; Bourgeois, C; Engl, W; Leibl, H; McCoy, B; Gelmont, D; Yel, L

    2017-01-01

    A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0·022/patient-year, P < 0·0001); the rate of all infections was 4·38/patient-year. Median trough IgG concentrations were ≥ 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0·101 event/infusion. The incidence of local related AEs was 0·069 event/infusion (0·036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0·032 event/infusion. Most related AEs were mild, none were severe. For 64·6% of patients and in 94·8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0·95 (range = 0·3-4·1) h using mainly one to two administration sites [median = 2 sites (range = 1-5)]. Almost all infusions (99·8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment.

  8. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults.

    PubMed

    Jacobson, Jeffrey M; Kuritzkes, Daniel R; Godofsky, Eliot; DeJesus, Edwin; Larson, Jeffrey A; Weinheimer, Steven P; Lewis, Stanley T

    2009-02-01

    Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log(10)) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4(+) T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4(+) T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.

  9. A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients.

    PubMed

    Davis, Gary L; Nelson, David R; Terrault, Norah; Pruett, Timothy L; Schiano, Thomas D; Fletcher, Courtney V; Sapan, Christine V; Riser, Laura N; Li, Yufeng; Whitley, Richard J; Gnann, John W

    2005-08-01

    Chronic hepatitis C is the most common indication for liver transplantation, but viral recurrence is universal and progressive graft injury occurs in most recipients. Our aim was to assess the safety, pharmacokinetics (PK), and antiviral effects of high doses of a human hepatitis C antibody enriched immune globulin product (HCIG) in patients undergoing liver transplantation for chronic hepatitis C. This was a multicenter, randomized, open-label, controlled trial conducted at 4 transplant centers in the United States. A total of 18 patients with chronic hepatitis C, who underwent liver transplantation, were randomized to receive low-dose HCIG (75 mg/kg) or high-dose HCIG (200 mg/kg), or no treatment. A total of 17 infusions of HCIG were administered in each treated patient over 14 weeks using a time-dependent dosing strategy based on the PK of anti-hepatitis B immune globulin in liver transplant recipients. Hepatitis C virus levels, liver enzymes, and liver biopsies were obtained serially throughout the study period. PK profiles of HCV antibodies were determined on days 4, 10, and 98. HCIG infusions were safe and tolerated. The infusion rate could not be maximized because of symptoms for 18% to 30% of the doses. The half-life of HCIG was extremely short immediately after transplantation but was gradually prolonged. In the high-dose group, serum alanine aminotransferase (ALT) levels normalized in most subjects and no patient developed hepatic fibrosis. However, serum HCV RNA levels were not suppressed at either dose. In conclusion, HCIG, an anti-HCV enriched immune globulin product, appears to be safe in patients with chronic hepatitis C undergoing liver transplantation. Further studies are required to determine whether the drug has beneficial effects in this group of patients.

  10. In Vitro, Pharmacokinetic, Pharmacodynamic, and Safety Comparisons of Single and Combined Administration of Tiotropium and Salmeterol in COPD Patients Using Different Dry Powder Inhalers.

    PubMed

    Horhota, Stephen T; van Noord, Jan A; Verkleij, Cynthia B; Bour, Loek J; Sharma, Ashish; Trunk, Michael; Cornelissen, Piet J G

    2015-07-01

    In vitro Andersen cascade impactor-sized mass (ISM) and aerodynamic fine particle mass (FPM) <5 μm for tiotropium and salmeterol combined in a novel inhalation powder formulation containing 7.5 μg tiotropium/25 μg salmeterol (TSHH) were similar (within ±15%) to reference products containing 18 μg of tiotropium (Spiriva® HandiHaler®) (TioHH) and 50 μg of salmeterol (Serevent® Diskus®) (SalD). The pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of the novel fixed-dose TSHH formulation administered once daily was compared with the single-agent therapies TioHH (once daily [qd]) and SalD (twice daily [bid]) and with the jointly administered combination of TioHH (qd) plus SalD (bid) in a randomized, 22-week, open-label, four-way crossover study in 50 patients with chronic obstructive pulmonary disease (COPD). For tiotropium, TSHH and TioHH were bioequivalent based on mean steady-state plasma area under the plasma concentration-time curves (AUC), while the urinary excretion amount was higher for TSHH and not bioequivalent to TioHH. Tiotropium peak plasma concentrations at steady state (C max,ss) were 40% higher with TSHH. For salmeterol, substantial differences were observed in plasma AUCs and Cmax,ss. No significant differences in 8-h forced expiratory volume in 1 s or forced vital capacity were detected for the TSHH (qd) against the combination of TioHH (qd) with SalD (bid). Maintenance therapy with tiotropium plus salmeterol as TSHH or as the jointly administered reference products is superior to either agent alone, safe, and well tolerated in COPD patients. In vitro results were not predictive of clinical PK findings for both tiotropium and salmeterol for the TSHH dry powder inhaler product.

  11. Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug

    PubMed Central

    Shafiq, N.; Rajagopalan, S.; Kushwaha, H. N.; Mittal, N.; Chandurkar, N.; Bhalla, A.; Kaur, S.; Pandhi, P.; Puri, G. D.; Achuthan, S.; Pareek, A.; Singh, S. K.; Srivastava, J. S.; Gaur, S. P. S.; Malhotra, S.

    2014-01-01

    Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T1/2, MRT, and AUC0−∞ of the active metabolite 97/63 were 11.85 ± 1.94 h, 13.77 ± 2.05 h, and 878.74 ± 133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials. PMID:24800100

  12. Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques.

    PubMed

    Greig, Jenny A; Nordin, Jayme Ml; Bote, Erin; Makaron, Leah; Garnett, Mason E; Kattenhorn, Lisa M; Bell, Peter; Goode, Tamara; Wilson, James M

    2016-01-01

    Systemically delivered adeno-associated viral (AAV) vectors are now in early-phase clinical trials for a variety of diseases. While there is a general consensus on inclusion and exclusion criteria for each of these trials, the conditions under which vectors are infused vary significantly. In this study, we evaluated the impact of intravenous infusion rate of AAV8 vector in cynomolgus macaques on transgene expression, vector clearance from the circulation, and potential activation of the innate immune system. The dose of AAV8 vector in terms of genome copies per kilogram body weight and its concentration were fixed, while the rate of infusion varied to deliver the entire dose over different time periods, including 1, 10, or 90 minutes. Analyses during the in-life phase of the experiment included sequential evaluation of whole blood for vector genomes and appearance of proinflammatory cytokines. Liver tissues were analyzed at the time of necropsy for enhanced green fluorescent protein (eGFP) expression and vector genomes. The data were remarkable with a relative absence of any statistically significant effect of infusion time on vector transduction, safety, and clearance. However, some interesting and unexpected trends did emerge.

  13. Treatment of acute uncomplicated falciparum malaria with artemether-lumefantrine in nonimmune populations: a safety, efficacy, and pharmacokinetic study.

    PubMed

    Hatz, Christoph; Soto, Jaime; Nothdurft, Hans Dieter; Zoller, Thomas; Weitzel, Thomas; Loutan, Louis; Bricaire, Francois; Gay, Frederick; Burchard, Gerd-Dieter; Andriano, Kim; Lefèvre, Gilbert; De Palacios, Patricia Ibarra; Genton, Blaise

    2008-02-01

    The efficacy and safety of artemether-lumefantrine for the treatment of malaria in nonimmune populations are not well defined. In this study, 165 nonimmune patients from Europe and non-malarious areas of Colombia with acute, uncomplicated falciparum malaria or mixed infection including P. falciparum were treated with the six-dose regimen of artemether-lumefantrine. The parasitologic cure rate at 28 days was 96.0% for the per protocol population (119/124 patients). Median times to parasite clearance and fever clearance were 41.5 and 36.8 hours, respectively. No patient had gametocytes after Day 7. Treatment was well tolerated; most adverse events were mild to moderate and seemed to be related to malaria. There were few serious adverse events, none of which were considered to be drug-related. No significant effects on ECG or laboratory parameters were observed. In conclusion, the six-dose regimen of artemether-lumefantrine was effective and well tolerated in the treatment of acute uncomplicated falciparum malaria in nonimmune patients.

  14. Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques

    PubMed Central

    Greig, Jenny A; Nordin, Jayme ML; Bote, Erin; Makaron, Leah; Garnett, Mason E; Kattenhorn, Lisa M; Bell, Peter; Goode, Tamara; Wilson, James M

    2016-01-01

    Systemically delivered adeno-associated viral (AAV) vectors are now in early-phase clinical trials for a variety of diseases. While there is a general consensus on inclusion and exclusion criteria for each of these trials, the conditions under which vectors are infused vary significantly. In this study, we evaluated the impact of intravenous infusion rate of AAV8 vector in cynomolgus macaques on transgene expression, vector clearance from the circulation, and potential activation of the innate immune system. The dose of AAV8 vector in terms of genome copies per kilogram body weight and its concentration were fixed, while the rate of infusion varied to deliver the entire dose over different time periods, including 1, 10, or 90 minutes. Analyses during the in-life phase of the experiment included sequential evaluation of whole blood for vector genomes and appearance of proinflammatory cytokines. Liver tissues were analyzed at the time of necropsy for enhanced green fluorescent protein (eGFP) expression and vector genomes. The data were remarkable with a relative absence of any statistically significant effect of infusion time on vector transduction, safety, and clearance. However, some interesting and unexpected trends did emerge. PMID:27933307

  15. The Safety, Pharmacokinetics, and Nervous System Effects of Two Natural Sources of Caffeine in Healthy Adult Males.

    PubMed

    Krieger, D R; Kalman, D S; Feldman, S; Arnillas, L; Goldberg, D; Gisbert, O; Nader, S

    2016-06-20

    This double-blind crossover clinical trial randomized 12 adult males to receive 200 mg of caffeine from a green coffee extract, a guayusa leaf extract, and a synthetic control to compare their safety, absorption, and effect on neurotransmitters. The results showed no statistically significant changes in blood pressure or heart rate from baseline to 120 min postdose of each natural source compared with changes from baseline in the control (0.094 < = P < = 0.910). The ratios of Cmax , AUC0-4 , and AUC0-∞ of each natural source to the control were bioequivalent by US Food and Drug Administration standards (90% CI within 80-125%). The guayusa leaf extract stimulated a significantly lower increase in epinephrine compared with the control (+0.5 vs. +2.78 μg/gCr, P = 0.04), while the green coffee extract provoked an increase in epinephrine similar to the control (+3.21 vs. +2.78 μg/gCr, P = 0.569). Implications for future clinical research are discussed.

  16. Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial

    PubMed Central

    Meininger, Vincent; Pradat, Pierre-François; Corse, Andrea; Al-Sarraj, Safa; Rix Brooks, Benjamin; Caress, James B.; Cudkowicz, Merit; Kolb, Stephen J.; Lange, Dale; Leigh, P. Nigel; Meyer, Thomas; Milleri, Stefano; Morrison, Karen E.; Orrell, Richard W.; Peters, Gary; Rothstein, Jeffrey D.; Shefner, Jeremy; Lavrov, Arseniy; Williams, Nicola; Overend, Phil; Price, Jeffrey; Bates, Stewart; Bullman, Jonathan; Krull, David; Berges, Alienor; Abila, Bams; Meno-Tetang, Guy; Wurthner, Jens

    2014-01-01

    The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co

  17. Transport of recombinant human CD4-immunoglobulin G across the human placenta: pharmacokinetics and safety in six mother-infant pairs in AIDS clinical trial group protocol 146.

    PubMed Central

    Shearer, W T; Duliege, A M; Kline, M W; Hammill, H; Minkoff, H; Ammann, A J; Chen, S; Izu, A; Mordenti, J

    1995-01-01

    Recombinant CD4-immunoglobulin G (rCD4-IgG) is a 98-kDa human immunoglobulin-like protein that is produced by fusing the gp120 binding domain of CD4 to the Fc portion of the human IgG1 heavy chain. This hybrid molecule was given to human immunodeficiency virus (HIV)-infected pregnant women at the onset of labor by intravenous bolus at 1 mg/kg of body weight (group A; n = 3) and 1 week prior to and at the onset of labor by the same route and at the same dose (group B; n = 3). In addition to pharmacokinetic studies, safety in the mothers and infants was determined through routine chemistries, hematology, and urinalysis; immunologic and HIV infection statuses in the infants were assessed through lymphocyte cultures, p24 antigen level determination, culture of HIV from plasma, PCR, lymphocyte subset enumeration, quantitative immunoglobulin analysis, and lymphocyte proliferation. Thirty minutes after the rCD4-IgG injection, concentrations in maternal serum were 12 to 23 micrograms/ml. These concentrations declined slowly, with initial and terminal half-lives (mean +/- standard deviation) of 9.95 +/- 3.23 and 47.6 +/- 22.3 h, respectively. Infants were born 2.6 to 46.5 h after rCD4-IgG administration; concentrations of rCD4-IgG in cord blood ranged from 28 to 107 ng/ml. The half-life of rCD4-IgG in infants ranged from 5 to 29 h. These data demonstrate that the transfer of rCD4-IgG from the mother to the fetus is rapid and that newborns do not appear to have any difficulty eliminating rCD4-IgG. No safety concerns in mothers or infants were encountered. Although the study did not address the question of efficacy, none of the infants was HIV type 1 infected 36 months later. In summary, these findings document that bifunctional immune molecules can be transported across the placenta, and this general approach may be used in the future to block vertical transmission of HIV type 1. PMID:7664172

  18. First‐in‐human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males

    PubMed Central

    Boland, Katja; Feifel, Ulrich; Hoch, Anja; Zimdahl‐Gelling, Heike; Sand, Michael

    2016-01-01

    Aims The aim of the present study was to investigate the safety, tolerability, dose proportionality and relative bioavailability of tablet and oral solution formulations of BI 409306 in healthy male subjects, and to compare the safety and pharmacokinetics in subjects who were extensive metabolizers (EMs) or poor metabolizers (PMs) of cytochrome P450 (CYP)‐2C19. Methods The present randomized, double‐blind, placebo‐controlled, single‐centre study evaluated single rising doses of BI 409306 (0.5–500 mg) administered as a tablet or oral solution to EMs or PMs. Results Of 80 enrolled subjects (mean age 36.7 years), 79 (CYP2C19 EMs, 71; CYP2C19 PMs, eight) received treatment and completed the study. Adverse events (AEs) were mild to moderate in intensity. Overall, 17/71 (23.9%) EMs and 6/8 (75.0%) PMs experienced 28 and eight AEs, respectively, of which, 25 and seven AEs, respectively, were considered to be drug related. The most frequently reported AEs were nervous system and eye disorders; all occurred shortly (20–30 min) after administration and mostly resolved within 1–2 h. No serious AEs occurred. BI 409306 systemic absorption and elimination were rapid; peak plasma concentration (Cmax) was reached <1 h after drug administration, and the half‐life ranged from 0.99 h to 2.71 h. Both the tablet and oral solution resulted in similar exposures. In PMs, at dose levels of 10 mg and 100 mg, Cmax was 2.2–2.3‐fold higher, and the area under the plasma concentration–time curve over the time interval 0 extrapolated to infinity was 4.1–5.0‐fold higher compared with EMs. Conclusions In healthy male subjects, BI 409306 was generally safe and well tolerated, with rapid absorption and elimination. Systemic exposure was higher in CYP2C19 PMs than EMs at the same dose level. PMID:27378314

  19. The Safety and Pharmacokinetics of Carprofen, Flunixin and Phenylbutazone in the Cape Vulture (Gyps coprotheres) following Oral Exposure

    PubMed Central

    Fourie, Tamsyn; Cromarty, Duncan; Duncan, Neil; Wolter, Kerri; Naidoo, Vinny

    2015-01-01

    The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 ± 620.7 ng/ml, 335.9 ± 36.3 ng/ml and 11150 ± 2474.9 ng/ml at 4 ± 4.3, 0.45 ± 0.02 and 5.3 ± 5.2 hours (Tmax) respectively and a half-life of elimination of 13.3 ±5, 1.8±1 and 18.7 ±11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half-lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern. PMID:26512724

  20. The Safety and Pharmacokinetics of Carprofen, Flunixin and Phenylbutazone in the Cape Vulture (Gyps coprotheres) following Oral Exposure.

    PubMed

    Fourie, Tamsyn; Cromarty, Duncan; Duncan, Neil; Wolter, Kerri; Naidoo, Vinny

    2015-01-01

    The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 ± 620.7 ng/ml, 335.9 ± 36.3 ng/ml and 11150 ± 2474.9 ng/ml at 4 ± 4.3, 0.45 ± 0.02 and 5.3 ± 5.2 hours (Tmax) respectively and a half-life of elimination of 13.3 ±5, 1.8±1 and 18.7 ±11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half-lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern.

  1. Development of safety profile evaluating pharmacokinetics, pharmacodynamics and toxicity of a combination of pioglitazone and olmesartan medoxomil in Wistar albino rats.

    PubMed

    Sengupta, Pinaki; Nandi, Utpal; Pal, Tapan Kumar

    2012-02-01

    Pioglitazone (PIO), an antidiabetic drug and olmesartan medoxomil (OLM), an antihypertensive drug were administered orally alone and in combination to Wistar albino rats for evaluation of pharmacokinetics, pharmacodynamics and repeated dose 28-day oral toxicity of individual drugs and their combination. Pharmacokinetic study was performed by orally administering PIO and OLM at single dose of 3 and 2mg/kg, respectively alone and in combination analyzing the plasma samples using LC-MS/MS. Antidiabetic activity evaluation was done in type-2 diabetes mellitus induced animals at same dose level as in pharmacokinetic study daily for 30 days. PIO and/or OLM were administered orally to animals at daily doses of 50, 100 and 150 mg/kg for 28 days for toxicity study. There was no significant alteration in the pharmacokinetic parameters of either drug indicating absence of any pharmacokinetic interaction when co-administered. Positive pharmacodynamic interaction between PIO and OLM was established in this study. Two drugs in combination showed no evidence of potentiation of 28-day repeated dose toxicity in animals. Again, drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and histopathological change was not found in the experiment performed. In conclusion, PIO and OLM combination can primarily be stated as safe in terms of present toxicity and pharmacokinetics findings.

  2. Synthesis and biodistribution of radioiodinated nicotine analogs

    SciTech Connect

    Chan, S.M.; Basmadjian, G.P.; Marten, D.F.; Sadek, S.; Magarian, R.A.; Grunder, J.R.; Ice, R.D.

    1984-01-01

    The authors reported previously on the synthesis and biodistribution of radioiodinated 5-iodonicotine. In their continuous effort to search for a potential brain as well as adrenal medulla imaging agent, the authors synthesized four radioiodinated nicotine analogs. The labeled compounds were prepared by brominating nicotinic acid, and reacting the acylated product with the appropriate amines to give the respective amides which were then reduced with diborane to the amines. I-125 labeling was done by halogen exchange. Biodistribution studies performed in female Sprague-Dawley rats showed that all these compounds were taken up rapidly by the brain and the adrenal. The highest uptake of all these compounds in both organs occurred at 2 minutes after tail vein injections. The organ:blood ratios at 2 minutes and the T/sub 1/3/ (min.) of radioactivity in these organs were compared.

  3. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vilanterol, a Novel Inhaled Long-Acting β-Agonist, in Children Aged 5–11 Years with Persistent Asthma: A Randomized Trial

    PubMed Central

    Oliver, Amanda; VanBuren, Sandi; Allen, Ann; Hamilton, Melanie; Tombs, Lee; Kempsford, Rodger; Qaqundah, Paul

    2014-01-01

    This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study was designed to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of single and once-daily repeat doses of vilanterol 25 µg in children aged 5–11 years. Twenty-eight children with persistent asthma received a single inhaled dose of vilanterol 25 µg or placebo via the ELLIPTA™ dry powder inhaler (DPI) on Day 1, followed 7 days later by once-daily treatment for 7 days. Nine (33%) subjects reported adverse events (AEs) with vilanterol 25 µg and 6 (23%) with placebo. No serious or drug-related AEs were reported; 3 subjects experienced upper respiratory tract infection (URTI) with vilanterol 25 µg versus none with placebo. Similar pharmacokinetic profiles of vilanterol 25 µg were observed irrespective of age or gender. No clinically relevant changes in heart rate, Fridericia's correction (QTcF), maximum glucose or minimum potassium parameters were observed during treatment with vilanterol 25 µg compared with placebo treatment. Vilanterol was well-tolerated and no long-acting ß2-agonist (LABA)-mediated AEs were observed. The pharmacokinetic profile of vilanterol 25 µg suggests exposure is similar regardless of age or gender in a pediatric population aged 5–11 years. PMID:26097789

  4. Pharmacokinetics & Neurophysiology

    ERIC Educational Resources Information Center

    Davis, Andrew S.; Salpekar, Jay A.

    2009-01-01

    Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

  5. Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study

    PubMed Central

    Goemans, Nathalie M.; Tulinius, Már; van den Hauwe, Marleen; Kroksmark, Anna-Karin; Buyse, Gunnar; Wilson, Rosamund J.; van Deutekom, Judith C.; de Kimpe, Sjef J.; Lourbakos, Afrodite; Campion, Giles

    2016-01-01

    Background Drisapersen induces exon 51 skipping during dystrophin pre-mRNA splicing and allows synthesis of partially functional dystrophin in Duchenne muscular dystrophy (DMD) patients with amenable mutations. Methods This 188-week open-label extension of the dose-escalation study assessed the long-term efficacy, safety, and pharmacokinetics of drisapersen (PRO051/GSK2402968), 6 mg/kg subcutaneously, in 12 DMD subjects. Dosing was once weekly for 72 weeks. All subjects had a planned treatment interruption (weeks 73–80), followed by intermittent dosing (weeks 81–188). Results Subjects received a median (range) total dose of 5.93 (5.10 to 6.02) mg/kg drisapersen. After 177 weeks (last efficacy assessment), median (mean [SD]) six-minute walk distance (6MWD) improved by 8 (-24.5 [161]) meters for the 10 subjects able to complete the 6MWD at baseline (mean age [SD]: 9.5 [1.9] years). These statistics include 2 subjects unable to complete the test at later visits and who scored “zero”. When only the 8 ambulant subjects at week 177 were taken into account, a median (mean [SD]) increase of 64 (33 [121]) meters in 6MWD was observed. Of 7 subjects walking ≥330 m at extension baseline, 5 walked farther at week 177. Of 3 subjects walking <330 m, 2 lost ambulation, while 1 declined overall but walked farther at some visits. Over the 188 weeks, the most common adverse events were injection-site reactions, raised urinary α1-microglobulin and proteinuria. Dystrophin expression was detected in all muscle biopsies obtained at week 68 or 72. Conclusion Drisapersen was generally well tolerated over 188 weeks. Possible renal effects, thrombocytopenia and injection-site reactions warrant continued monitoring. Improvements in the 6MWD at 12 weeks were sustained after 3.4 years of dosing for most patients. For a small, uncontrolled study, the outcomes are encouraging, as natural history studies would anticipate a decline of over 100 meters over a 3-year period in a comparable

  6. New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies.

    PubMed

    Nallathamby, Prakash D; Mortensen, Ninell P; Palko, Heather A; Malfatti, Mike; Smith, Catherine; Sonnett, James; Doktycz, Mitchel J; Gu, Baohua; Roeder, Ryan K; Wang, Wei; Retterer, Scott T

    2015-04-21

    described here is applicable to the synthesis of a large class of nanomaterials with multiple core and surface functionalities. This work combined with the biodistribution data suggests that the radiolabeling schemes carried out in this study have broad implications for use in pharmacokinetic studies for a variety of nanomaterials.

  7. New Surface Radiolabeling Schemes of Super Paramagnetic Iron Oxide Nanoparticles (SPIONs) for Biodistribution Studies

    DOE PAGES

    Nallathamby, Prakash D.; Mortensen, Ninell P.; Palko, Heather A.; ...

    2015-01-01

    approach described here is applicable to the synthesis of a large class of nanomaterials with multiple core and surface functionalities. This work combined with the biodistribution data suggests that the radiolabeling schemes carried out in this study have broad implications for use in pharmacokinetic studies for a variety of nanomaterials.« less

  8. New Surface Radiolabeling Schemes of Super Paramagnetic Iron Oxide Nanoparticles (SPIONs) for Biodistribution Studies

    SciTech Connect

    Nallathamby, Prakash D.; Mortensen, Ninell P.; Palko, Heather A.; Malfatti, Mike; Smith, Catherine; Sonnett, Jim; Doktycz, Mitchel John; Gu, Baohua; Roeder, Ryan; Wang, Wei; Retterer, Scott T.

    2015-01-01

    radiolabeling approach described here is applicable to the synthesis of a large class of nanomaterials with multiple core and surface functionalities. This work combined with the biodistribution data suggests that the radiolabeling schemes carried out in this study have broad implications for use in pharmacokinetic studies for a variety of nanomaterials.

  9. New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies†

    PubMed Central

    Nallathamby, Prakash D.; Mortensen, Ninell P.; Palko, Heather A.; Malfatti, Mike; Smith, Catherine; Sonnett, James; Doktycz, Mitchel J.; Gu, Baohua; Roeder, Ryan K.; Wang, Wei; Retterer, Scott T.

    2016-01-01

    described here is applicable to the synthesis of a large class of nanomaterials with multiple core and surface functionalities. This work combined with the biodistribution data suggests that the radiolabeling schemes carried out in this study have broad implications for use in pharmacokinetic studies for a variety of nanomaterials. PMID:25790032

  10. Using a PBPK model to study the influence of different characteristics of nanoparticles on their biodistribution

    NASA Astrophysics Data System (ADS)

    Li, D.; Emond, C.; Johanson, G.; Jolliet, O.

    2013-04-01

    The studies on potential health risks possessed by engineered nanoparticles (NPs) have been growing rapidly. However, detailed and systemic knowledge on the uptake and biodistribution of NPs in body is still limited. Moreover, there is a need to characterize the relation between the characteristics of NPs (size, surface modifications, etc.) and their behaviours in the body. The aim of this study is to explore how these characteristics will influence the NPs uptake and biodistribution. We have successfully developed a Physiologically Based Pharmacokinetic (PBPK) model for the biodistribution of polyethylene glycol-coated polyacrylamide NPs in rats, modelling the capture and removal of NPs by phagocytizing cells. Based on this PBPK model, the behaviours of other nanoparticles (polymeric, quantum dot, silver, titanium oxide and cerium oxide NPs) are investigated, based on data from several experiments published in the literature. Size is one of the important properties to consider. Our model parameterization suggests that the uptake rate by phagocytizing cells will decrease as the size of nanoparticles increases when the removal rates for these nanoparticles are similar. This could indicate that the phagocytizing cells are saturated by the number of NPs rather than absolute mass. Nevertheless, surface modification, such as polyethylene glycol coating, may reduce the uptake rate by phagocytizing cells. With phagocytizing cells serving as a deposit of NPs, these influences of different characteristics of NPs to the behavior of phagocytizing cells could affect the fate of NPs in the body not only during the initial uptake within the first hour but also in long-term at the kinetic and dynamic levels.

  11. Radiolabeling of Cramoll 1,4: Evaluation of the Biodistribution

    PubMed Central

    Ferreira de Carvalho Patricio, Beatriz; Lima-Ribeiro, Maria Helena Madruga; dos Santos Correia, Maria Tereza; dos Anjos Carneiro-Leão, Ana Maria; de Souza Albernaz, Marta; Barboza, Thiago; de Souza, Sergio Augusto Lopes; Santos-Oliveira, Ralph

    2011-01-01

    The cramoll 1,4 is a well-studied lectin. However, few studies about its biodistribution have been done before. In this study, we radiolabeled the cramol 1,4 with Tc-99m and analyzed the biodistribution. The results showed that the cramol has an abnormal uptake by the bowel with reflections on its clearance mechanism. PMID:21760823

  12. [In vivo imaging for biodistribution and metabolism evaluations of new chemical entities].

    PubMed

    Corot, C; Idée, J-M; Raynaud, J-S; Salazar, J-F; Catoen, S

    2012-01-01

    Due to numerous technical developments, in vivo imaging is suitable for pharmacokinetic and metabolism studies of new chemical entities as well as for evaluating their pharmacological or biological effects. MRI, nuclear medicine, X-Ray, ultrasound and optical imaging are available for both clinical and experimental imaging with even higher performance. For all these imaging modalities, diagnostic agents are useful to improve contrast and specificity. Specific targeting of biological events is addressed by molecular imaging. From a pharmacodynamic perspective, radiolabeling of a new chemical entity allows in vivo visualization quantitative measure of its biodistribution, its elimination and its specific molecular binding. Non-invasive imaging methods are useful for longitudinal investigations of biological changes. Based on nanotechnologies, specificity of drug delivery can be monitored by imaging. New developments in hybrid imaging technologies as well as multimodal contrast agents reinforce in vivo experimental and clinical proof of mechanism of new chemical entities.

  13. [Elements of pharmacodynamics and pharmacokinetics].

    PubMed

    Piette, F; Soubrie, C

    1990-05-21

    A knowledge of pharmacokinetic data is particularly important with drugs that have a narrow margin of safety. Exhaustive pre-marketing pharmacokinetic investigations and pharmacokinetic studies in populations are the two principal means of acquiring such knowledge. Although popular, the concept of half-life which decreases with age for many drugs is insufficient to calculate dosage in elderly people. Measurements of creatinine clearance provide an almost mathematical approach to the dosage of drugs that are excreted exclusively by the kidneys. In contrast, changes in hepatic metabolism with age and pathology are difficult to evaluate, and their consequences are often vaguely perceived. Our knowledge of relationships between age and pharmacodynamics is still in infancy. Owing to the wide consumption of medicine by elderly people, drug interactions are frequent at all stages, including absorption, metabolization, transport and site of action.

  14. Cyclotron production of cesium radionuclides as analogues for francium-221 biodistribution

    NASA Astrophysics Data System (ADS)

    Finn, R.; McDevitt, M.; Sheh, Y.; Lom, C.; Qiao, J.; Cai, S.; Burnazi, E.; Nacca, A.; Pillarsetty, N.; Jaggi, J.; Scheinberg, D.

    2005-12-01

    In our clinical investigations focussing on improved therapeutic treatment of specific tumors we have concentrated on a targeted therapy approach utilizing designed radiolabeled monoclonal antibodies as the cytotoxic reagent. The physical characteristics of the alpha particle emitting radionuclide bismuth-213 including the short half-life of 45.6 min, has shown promise for the treatment of specific cancers such as leukemias and lymphomas or micrometastatic carcinomas. In an effort to increase the cytocidal effect of the HuM195, a humanized monoclonal antibody carrier to the CD33 antigen expressed on leukemia cells, our focus is directed toward an "internal" nano-generator composed of Ac-225 radionuclide, the parent of the bismuth-213. The actinium-225 radionuclide decays through several short-lived, alpha emitting daughters including francium-221, astatine-217 and bismuth-213. In order to study the biodistribution and the pharmacokinetics of the individual daughter nuclide, francium-221, the cyclotron production and separation of cesium radionuclides, specifically cesium-132, from a natural xenon gas target was undertaken. The choice of cesium as an analogue for francium was predicated upon both elements being in Group 1A alkali metals and cesium radionuclide possesses a sufficient half-life to allow biodistribution studies to be performed. The preliminary experimental results of this investigation are presented.

  15. Heterogeneity in nanoparticles influences biodistribution and targeting

    PubMed Central

    Adjei, Isaac M; Peetla, Chiranjeevi; Labhasetwar, Vinod

    2013-01-01

    Aim A large fraction of the administered dose of nanoparticles (NPs) localizes into nontarget tissue, which could be due to the heterogeneous population of NPs. Materials & methods To investigate the impact of the above issue, we simultaneously tracked the biodistribution using optical imaging of two different sized poly (d,l-lactide co-glycolide) NPs, which also varied in their surface charge and texture, in a prostate tumor xenograft mouse model. Results Although formulated using the same polymer and emulsifier concentration, small NPs were neutral (S-neutral-NPs) whereas large NPs were anionic (L-anionic-NPs). Simultaneous injection of these NPs, representing heterogeneity, shows significantly different biodistribution. S-neutral-NPs demonstrated longer circulation time than L-anionic-NPs (t1/2 = 96 vs 13 min); accounted for 75% of total NPs accumulated in the tumor, and showed 13-fold greater tumor to liver signal intensity ratio than L-anionic-NPs. Conclusion The data underscore the importance of formulating nanocarriers of specific properties to enhance their targeting efficacy. PMID:23799984

  16. Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy

    PubMed Central

    Li, Tianyuzi; Gendelman, Howard E; Zhang, Gang; Puligujja, Pavan; McMillan, JoEllyn M; Bronich, Tatiana K; Edagwa, Benson; Liu, Xin-Ming; Boska, Michael D

    2015-01-01

    Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory’s development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery. PMID:26082630

  17. New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies

    NASA Astrophysics Data System (ADS)

    Nallathamby, Prakash D.; Mortensen, Ninell P.; Palko, Heather A.; Malfatti, Mike; Smith, Catherine; Sonnett, James; Doktycz, Mitchel J.; Gu, Baohua; Roeder, Ryan K.; Wang, Wei; Retterer, Scott T.

    2015-04-01

    here is applicable to the synthesis of a large class of nanomaterials with multiple core and surface functionalities. This work combined with the biodistribution data suggests that the radiolabeling schemes carried out in this study have broad implications for use in pharmacokinetic studies for a variety of nanomaterials.Nanomaterial based drug delivery systems allow for the independent tuning of the surface chemical and physical properties that affect their biodistribution in vivo and the therapeutic payloads that they are intended to deliver. Additionally, the added therapeutic and diagnostic value of their inherent material properties often provides extra functionality. Iron based nanomaterials with their magnetic properties and easily tailorable surface chemistry are of particular interest as model systems. In this study the core radius of the iron oxide nanoparticles (NPs) was 14.08 +/- 3.92 nm while the hydrodynamic radius of the NPs, as determined by Dynamic Light Scattering (DLS), was between 90-110 nm. In this study, different approaches were explored to create radiolabeled NPs that are stable in solution. The NPs were functionalized with polycarboxylate or polyamine surface functional groups. Polycarboxylate functionalized NPs had a zeta potential of -35 mV and polyamine functionalized NPs had a zeta potential of +40 mV. The polycarboxylate functionalized NPs were chosen for in vivo biodistribution studies and hence were radiolabeled with 14C, with a final activity of 0.097 nCi mg-1 of NPs. In chronic studies, the biodistribution profile is tracked using low level radiolabeled proxies of the nanoparticles of interest. Conventionally, these radiolabeled proxies are chemically similar but not chemically identical to the non-radiolabeled NPs of interest. This study is novel as different approaches were explored to create radiolabeled NPs that are stable, possess a hydrodynamic radius of <100 nm and most importantly they exhibit an identical surface chemical

  18. Two Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Studies To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza A Virus Monoclonal Antibody, MHAA4549A, in Healthy Volunteers

    PubMed Central

    Deng, Rong; Derby, Michael A.; Larouche, Richard; Horn, Priscilla; Anderson, Malia; Maia, Mauricio; Carrier, Stephanie; Pelletier, Isabelle; Burgess, Tracy; Kulkarni, Priya; Newton, Elizabeth; Tavel, Jorge A.

    2016-01-01

    Hospitalized patients with severe influenza are at significant risk for morbidity and mortality. MHAA4549A is a human monoclonal immunoglobulin (Ig) G1 antibody that binds to a highly conserved stalk region of the influenza A virus hemagglutinin protein and neutralizes all tested seasonal human influenza A virus strains. Two phase 1 trials examined the safety, tolerability, and pharmacokinetics of MHAA4549A in healthy volunteers. Both single ascending-dose trials were randomized, double blinded, and placebo controlled. Trial 1 randomized 21 healthy adults into four cohorts receiving a single intravenous dose of 1.5, 5, 15, or 45 mg/kg MHAA4549A or placebo. Trial 2 randomized 14 healthy adults into two cohorts receiving a single intravenous fixed dose of 8,400 mg or 10,800 mg of MHAA4549A or placebo. Subjects were followed for 120 days after dosing. No subject was discontinued in either trial, and no serious adverse events were reported. The most common adverse event in both studies was mild headache (trial 1, 4/16 subjects receiving MHAA4549A and 1/5 receiving placebo; trial 2, 4/8 subjects receiving MHAA4549A and 2/6 receiving placebo). MHAA4549A produced no relevant time- or dose-related changes in laboratory values or vital signs compared to those with placebo. No subjects developed an antitherapeutic antibody response following MHAA4549A administration. MHAA4549A showed linear serum pharmacokinetics, with a mean half-life of 22.5 to 23.7 days. MHAA4549A is safe and well tolerated in healthy volunteers up to a single intravenous dose of 10,800 mg and demonstrates linear serum pharmacokinetics consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (These trials have been registered at ClinicalTrials.gov under registration no. NCT01877785 and NCT02284607). PMID:27381392

  19. Bioavailability and biodistribution of nanodelivered lutein

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of the study was to evaluate the ability of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) to enhance lutein bioavailability. The bioavailability of free lutein and PLGA-NP lutein in rats was assessed by determining plasma pharmacokinetics and deposition in selected tissues. Lutein ...

  20. Safety.

    ERIC Educational Resources Information Center

    Education in Science, 1996

    1996-01-01

    Discusses safety issues in science, including: allergic reactions to peanuts used in experiments; explosions in lead/acid batteries; and inspection of pressure vessels, such as pressure cookers or model steam engines. (MKR)

  1. Opioid receptor modulation of hedonic taste preference and food intake: a single-dose safety, pharmacokinetic, and pharmacodynamic investigation with GSK1521498, a novel μ-opioid receptor inverse agonist.

    PubMed

    Nathan, Pradeep J; O'Neill, Barry V; Bush, Mark A; Koch, Annelize; Tao, Wenli X; Maltby, Kay; Napolitano, Antonella; Brooke, Allison C; Skeggs, Andrew L; Herman, Craig S; Larkin, Andrew L; Ignar, Diane M; Richards, Duncan B; Williams, Pauline M; Bullmore, Edward T

    2012-04-01

    Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.

  2. Pharmacokinetics, efficacy, and safety of a plasma-derived VWF/FVIII concentrate (VONCENTO) for on-demand and prophylactic treatment in patients with von Willebrand disease (SWIFT-VWD study).

    PubMed

    Lissitchkov, Toshko J; Buevich, Evgeny; Kuliczkowski, Kazimierz; Stasyshyn, Oleksandra; Cerqueira, Monica Hermida; Klukowska, Anna; Joch, Christine; Seifert, Wilfried

    2017-03-01

    VONCENTO (CSL Behring Gmbh, Marburg, Germany) is a plasma-derived, high concentration, lower volume [relative to HAEMATE P (CSL Behring)], high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a VWF/FVIII ratio similar to HAEMATE P. This open-label, multicentre study investigated the pharmacokinetic, haemostatic efficacy, and safety profiles of VONCENTO in study participants at least 12 years of age with von Willebrand disease (VWD) who required treatment of nonsurgical bleeding (NSB) events or underwent surgery or prophylaxis. The first 12-month on-demand treatment period comprised a pharmacokinetic investigation and an efficacy analysis. After 12 months, qualifying study participants were switched to prophylactic therapy and included in a further 12-month efficacy analysis. In total, 21 study participants (including three adolescents, and 13 study participants with VWD type 3) received VONCENTO as on-demand treatment for 12 months. 'Excellent'/'good' haemostatic efficacy was achieved in 98.3% of the 407 NSB events assessed by investigators. Following the switch to prophylactic treatment, the total number of NSBs in eight patients markedly decreased from 304 to 10 (with haemostatic efficacy judged to be 'excellent' for all). The annualised bleeding rate also significantly decreased from a median of 26.5 events to one event. Safety assessments showed no inhibitory antibodies to either FVIII or VWF, no transmission of infectious agents, no thromboembolic events and no treatment-related serious adverse events. VONCENTO was shown to be well tolerated and provided excellent haemostatic efficacy in the treatment of bleeds or during prophylaxis in study participants with VWD, including also those with type 3, the severest form of VWD.

  3. Pharmacokinetics, efficacy, and safety of a plasma-derived VWF/FVIII concentrate (VONCENTO) for on-demand and prophylactic treatment in patients with von Willebrand disease (SWIFT-VWD study)

    PubMed Central

    Lissitchkov, Toshko J.; Buevich, Evgeny; Kuliczkowski, Kazimierz; Stasyshyn, Oleksandra; Cerqueira, Monica Hermida; Klukowska, Anna; Joch, Christine; Seifert, Wilfried

    2017-01-01

    VONCENTO (CSL Behring Gmbh, Marburg, Germany) is a plasma-derived, high concentration, lower volume [relative to HAEMATE P (CSL Behring)], high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a VWF/FVIII ratio similar to HAEMATE P. This open-label, multicentre study investigated the pharmacokinetic, haemostatic efficacy, and safety profiles of VONCENTO in study participants at least 12 years of age with von Willebrand disease (VWD) who required treatment of nonsurgical bleeding (NSB) events or underwent surgery or prophylaxis. The first 12-month on-demand treatment period comprised a pharmacokinetic investigation and an efficacy analysis. After 12 months, qualifying study participants were switched to prophylactic therapy and included in a further 12-month efficacy analysis. In total, 21 study participants (including three adolescents, and 13 study participants with VWD type 3) received VONCENTO as on-demand treatment for 12 months. ‘Excellent’/‘good’ haemostatic efficacy was achieved in 98.3% of the 407 NSB events assessed by investigators. Following the switch to prophylactic treatment, the total number of NSBs in eight patients markedly decreased from 304 to 10 (with haemostatic efficacy judged to be ‘excellent’ for all). The annualised bleeding rate also significantly decreased from a median of 26.5 events to one event. Safety assessments showed no inhibitory antibodies to either FVIII or VWF, no transmission of infectious agents, no thromboembolic events and no treatment-related serious adverse events. VONCENTO was shown to be well tolerated and provided excellent haemostatic efficacy in the treatment of bleeds or during prophylaxis in study participants with VWD, including also those with type 3, the severest form of VWD. PMID:27203734

  4. Novel methodology for labelling mesoporous silica nanoparticles using the 18F isotope and their in vivo biodistribution by positron emission tomography

    NASA Astrophysics Data System (ADS)

    Rojas, Santiago; Gispert, Juan Domingo; Menchón, Cristina; Baldoví, Herme G.; Buaki-Sogo, Mireia; Rocha, Milagros; Abad, Sergio; Victor, Victor Manuel; García, Hermenegildo; Herance, José Raúl

    2015-03-01

    Nanoparticles have been proposed for several biomedical applications due to their potential as drug carriers, diagnostic and therapeutic agents. However, only a few of them have been approved for their use in humans. In order to gauge the potential applicability of a specific type of nanoparticle, in vivo biodistribution studies to characterize their pharmacokinetic properties are essential. In this regard, mesoporous silica nanoparticles (30-130 nm) have been functionalized with amino groups in order to react with N-succinimidyl 4-[18F]fluorobenzoate and thus anchor the 18F positron emission isotope by using a novel and easy labelling strategy. In vivo biodistribution was characterized in mice after intravenous administration of radiolabelled nanoparticles by positron emission tomography. Our results indicated that radiolabelled mesoporous silica nanoparticles were excreted into bile and urine and accumulated mainly in the organs of the reticuloendothelial system and lungs.

  5. Mathematical modeling and simulation in animal health - Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment.

    PubMed

    Lin, Z; Gehring, R; Mochel, J P; Lavé, T; Riviere, J E

    2016-10-01

    This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed-effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.

  6. Pharmacokinetics Application in Biophysics Experiments

    NASA Astrophysics Data System (ADS)

    Millet, Philippe; Lemoigne, Yves

    Among the available computerised tomography devices, the Positron Emission Tomography (PET) has the advantage to be sensitive to pico-molar concentrations of radiotracers inside living matter. Devices adapted to small animal imaging are now commercially available and allow us to study the function rather than the structure of living tissues by in vivo analysis. PET methodology, from the physics of electron-positron annihilation to the biophysics involved in tracers, is treated by other authors in this book. The basics of coincidence detection, image reconstruction, spatial resolution and sensitivity are discussed in the paper by R. Ott. The use of compartment analysis combined with pharmacokinetics is described here to illustrate an application to neuroimaging and to show how parametric imaging can bring insight on the in vivo bio-distribution of a radioactive tracer with small animal PET scanners. After reporting on the use of an intracerebral β+ radiosensitive probe (βP), we describe a small animal PET experiment used to measure the density of 5HT 1 a receptors in rat brain.

  7. Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects.

    PubMed

    Munjal, Sagar; Gautam, Anirudh; Okumu, Franklin; McDowell, James; Allenby, Kent

    2016-01-01

    In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0-inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product.

  8. Pharmacokinetics and tolerability (Study 1) with particular reference to ocular safety (Study 2) of tiotropium Respimat soft mist inhaler: findings from two dose-ranging studies in healthy men.

    PubMed

    Feifel, Ulrich; Wallenstein, Gudrun; Rominger, Karl-Ludwig; Trommeshauser, Dirk; Platz, Juliane

    2008-01-01

    Data are presented from two randomized, double-blind, placebo-controlled studies in which the tolerability of tiotropium Respimat Soft MistTM Inhaler (SMI), a new-generation, propellant-free device for use in COPD, and the ocular safety oftiotropium were examined. In Study 1, 36 healthy males received tiotropium 8, 16, or 32 microg (n = 9/dose) or placebo (n = 3/dose level), administered once daily via Respimat SMI for 14 days. Safety and pharmacokinetics were evaluated. In Study 2, 48 healthy males received tiotropium 0.02, 0.04, 0.08, 0.16, 0.28, or 0.40 microg (n = 6/dose) or placebo (n = 2/dose level), applied as two drops to one eye (the highest dose was a significant multiple of a percentage of the proposed Respimat SMI clinical dose that could be inadvertently deposited in the eye). Ocular parameters were measured over 24 hours. Tiotropium Respimat SMI at doses up to 32 microg was well tolerated in Study 1; typical dose-dependent anticholinergic adverse events of mild-to-moderate intensity were observed. In Study 2, ocular tiotropium administration did not affect pupil diameter, pupillary reflex, intraocular pressure, or accommodation. Tiotropium Respimat SMI was well tolerated. Inadvertent ocular exposure to tiotropium up to 0.40 g is unlikely to result in ocular adverse effects.

  9. Biodistribution of titanium dioxide from biologic compartments.

    PubMed

    Olmedo, Daniel G; Tasat, Deborah R; Guglielmotti, María Beatriz; Cabrini, Rómulo Luis

    2008-09-01

    The layer of titanium dioxide (TiO(2)) of the implant is chronically exposed to the internal electrolyte milieu in the peri-implant biological compartment. Corrosion results from electrochemical attack and ensuing gradual degradation of the metallic materials and is thus of biological interest when these biomaterials are employed in clinical implantology. Herein we evaluated and compared the chronic effect and the biodistribution of TiO(2) administered subcutaneously or intraperitoneally. We propose that the compartmentalization of titanium in the area of subcutaneous injection would reproduce the biological compartment of the implant and its microenvironment from which metal ions could be released and migrate systemically. Potential TiO(2) deposits were identified and characterized in skin, liver and lung by histological and EDX analyses. After both treatments, the skin, liver, and lungs exhibited histological evidence of TiO(2) deposits. In order to characterize in situ macrophage-like cells, tissue sections were immunohistochemically stained for CD68. Tissue specimens from all organs assayed showed positive staining for anti-macrophage monoclonal antibody CD68 (PGM1). Despite the compartmentalization of titanium within nodular areas in rats treated subcutaneously, systemic migration occurred. We concluded that systemic migration of TiO(2) occurred regardless of the administration route.

  10. Safety and pharmacokinetics of 120 mg/kg versus 60 mg/kg weekly intravenous infusions of alpha-1 proteinase inhibitor in alpha-1 antitrypsin deficiency: a multicenter, randomized, double-blind, crossover study (SPARK).

    PubMed

    Campos, Michael A; Kueppers, Friedrich; Stocks, James M; Strange, Charlie; Chen, Junliang; Griffin, Rhonda; Wang-Smith, Laurene; Brantly, Mark L

    2013-12-01

    Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha1-PI), achieves a trough serum level of 11 μM in individuals with alpha-1 antitrypsin deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum alpha1-PI concentrations following 120 mg/kg weekly IV alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 μM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.

  11. Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B.

    PubMed

    Windyga, J; Lissitchkov, T; Stasyshyn, O; Mamonov, V; Rusen, L; Lamas, J L; Oh, M-S; Chapman, M; Fritsch, S; Pavlova, B G; Wong, W-Y; Abbuehl, B E

    2014-01-01

    BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12-65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC(0-72) h per dose. Twice-weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg(-1) per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.

  12. Biodistribution and radiation dosimetry of 11C-labelled docetaxel in cancer patients

    PubMed Central

    Hendrikse, N. Harry; Smit, Egbert F.; Mooijer, Martien P. J.; Rijnders, Anneloes Y.; Gerritsen, Winald R.; van der Hoeven, Jacobus J. M.; Windhorst, Albert D.; Lammertsma, Adriaan A.; Lubberink, Mark

    2010-01-01

    Purpose Docetaxel is an important chemotherapeutic agent used for the treatment of several cancer types. As radiolabelled anticancer agents provide a potential means for personalized treatment planning, docetaxel was labelled with the positron emitter 11C. Non-invasive measurements of [11C]docetaxel uptake in organs and tumours may provide additional information on pharmacokinetics and pharmacodynamics of the drug docetaxel. The purpose of the present study was to determine the biodistribution and radiation absorbed dose of [11C]docetaxel in humans. Methods Biodistribution of [11C]docetaxel was measured in seven patients (five men and two women) with solid tumours using PET/CT. Venous blood samples were collected to measure activity in blood and plasma. Regions of interest (ROI) for various source organs were defined on PET (high [11C]docetaxel uptake) or CT (low [11C]docetaxel uptake). ROI data were used to generate time-activity curves and to calculate percentage injected dose and residence times. Radiation absorbed doses were calculated according to the MIRD method using OLINDA/EXM 1.0 software. Results Gall bladder and liver demonstrated high [11C]docetaxel uptake, whilst uptake in brain and normal lung was low. The percentage injected dose at 1 h in the liver was 47 ± 9%. [11C]docetaxel was rapidly cleared from plasma and no radiolabelled metabolites were detected. [11C]docetaxel uptake in tumours was moderate and highly variable between tumours. Conclusion The effective dose of [11C]docetaxel was 4.7 µSv/MBq. As uptake in normal lung is low, [11C]docetaxel may be a promising tracer for tumours in the thoracic region. PMID:20508935

  13. A Single-Dose, Open-Label Study of the Pharmacokinetics, Safety, and Tolerability of Lisdexamfetamine Dimesylate in Individuals With Normal and Impaired Renal Function

    PubMed Central

    Ermer, James; Corcoran, Mary; Lasseter, Kenneth; Marbury, Thomas; Yan, Brian

    2016-01-01

    Background: Lisdexamfetamine (LDX) and d-amphetamine pharmacokinetics were assessed in individuals with normal and impaired renal function after a single LDX dose; LDX and d-amphetamine dialyzability was also examined. Methods: Adults (N = 40; 8/group) were enrolled in 1 of 5 renal function groups [normal function, mild impairment, moderate impairment, severe impairment/end-stage renal disease (ESRD) not requiring hemodialysis, and ESRD requiring hemodialysis] as estimated by glomerular filtration rate (GFR). Participants with normal and mild to severe renal impairment received 30 mg LDX; blood samples were collected predose and serially for 96 hours. Participants with ESRD requiring hemodialysis received 30 mg LDX predialysis and postdialysis separated by a washout period of 7–14 days. Predialysis blood samples were collected predose, serially for 72 hours, and from the dialyzer during hemodialysis; postdialysis blood samples were collected predose and serially for 48 hours. Pharmacokinetic end points included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from time 0 to infinity (AUC0–∞) or to last assessment (AUClast). Results: Mean LDX Cmax, AUClast, and AUC0–∞ in participants with mild to severe renal impairment did not differ from those with normal renal function; participants with ESRD had higher mean Cmax and AUClast than those with normal renal function. d-amphetamine exposure (AUClast and AUC0–∞) increased and Cmax decreased as renal impairment increased. Almost no LDX and little d-amphetamine were recovered in the dialyzate. Conclusions: There seems to be prolonged d-amphetamine exposure after 30 mg LDX as renal impairment increases. In individuals with severe renal impairment (GFR: 15 ≤ 30 mL·min−1·1.73 m−2), the maximum LDX dose is 50 mg/d; in patients with ESRD (GFR: <15 mL·min−1·1.73 m−2), the maximum LDX dose is 30 mg/d. Neither LDX nor d-amphetamine is dialyzable. PMID

  14. Pharmacokinetics-pharmacology disconnection of herbal medicines and its potential solutions with cellular pharmacokinetic-pharmacodynamic strategy.

    PubMed

    Zhang, Jingwei; Zhou, Fang; Lu, Meng; Ji, Wei; Niu, Fang; Zha, Weibin; Wu, Xiaolan; Hao, Haiping; Wang, Guangji

    2012-06-01

    Recently, there is a global trend of using herbal medicines to treat various chronic diseases and promote health. But the controversy over the safety and efficacy of herbal medicines is a focus of attention, primarily because of the many unknown and unrevealed natures of herbal medicines, which strongly restricts their application and development. Pharmacokinetics is a bridge linking the herbal medicines and their pharmacological responses. It is assumed in traditional pharmacokinetics that an excellent drug should have appropriate pharmacokinetic behaviours and its pharmacological effect is related with plasma drug concentrations. However, most herbal medicines exhibit excellent pharmacological responses despite poor pharmacokinetic behaviours. As most drugs are intracellulartargeted, we put forward cellular pharmacokinetic-pharmacodynamic strategy, which is focused on the intracellular fate of drugs. This strategy could partially explain the marked pharmacological activities of herbal medicines from their intracellular pharmacokinetic behaviours, rather than their plasma concentrations. It is a helpful complementarity to traditional pharmacokinetics, and takes a potential role in the research and development of new herb-origined drugs. In this review, the pharmacokinetics-pharmacology disconnections of herbal medicines (such as ginseng, berberine and danshen) are retrospected. Then our proposed cellular pharmacokineticpharmacodynamic strategy, its characteristics, as well as its research procedures are described, followed by the subcellular distributions of drug transporters and metabolic enzymes which are the determinants of cellular pharmacokinetics-pharmacodynamics. Finally, our successful applications of cellular pharmacokinetic-pharmacodynamic strategy in elucidating ginsenoside Rh2 as an adjuvant agent and tanshinone IIA as an anticancer agent are illustrated.

  15. Antithrombin III: biodistribution in healthy volunteers.

    PubMed

    Knot, E A; de Jong, E; ten Cate, J W; Gie, L K; van Royen, E A

    1987-12-18

    Five healthy volunteers were injected intravenously with 73-90 uCi purified human 131I-Antithrombin III (AT III), specific biological activity 5.6 U/mg. The tracer data were analysed using a three compartment model. The plasma radioactivity half life was 66.2 +/- 1.2 (sem) h, the fractional catabolic rate constant of the plasma pool was 0.025 +/- 0.002 (sem) h-1. These data were comparable with those described in the literature. Because of the difficulty in translating the mathematical analysis of various compartments into the biological model, biodistribution was monitored by a gamma camera linked to a DEC PDP 11/34 computer system. Dynamic and static images were obtained at fixed time intervals following the injection of 131I-AT III. Whole body scanning at intervals between the time of injection (t = 0) and t = 24.5 h showed 131I-AT III distribution over the heart, lungs, liver, spleen and great vessels. Dynamic scanning was performed over the heart, spleen and liver. Overlayed frames in the first ten minutes after the 131I-AT III injection showed the following radioactivity expressed as percentage of the injected dose; 5.9% +/- 0.3 (sem) over the heart, 10.6% +/- 0.9 (sem) over the liver and 1.1% +/- 0.1 (sem) over the spleen. A slower decline of the radioactivity between t = 0 and t = 24 h; (19%) was measured over the liver compared with the radioactivity disappearance over the heart region. This shows, in combination with the fact that the radioactivity disappearance over the heart was identical with the radioactivity decline measured in the plasma samples that retention of 131I-AT III occurred in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Effects of surface charges of gold nanoclusters on long-term in vivo biodistribution, toxicity, and cancer radiation therapy

    PubMed Central

    Wang, Jun-Ying; Chen, Jie; Yang, Jiang; Wang, Hao; Shen, Xiu; Sun, Yuan-Ming; Guo, Meili; Zhang, Xiao-Dong

    2016-01-01

    Gold nanoclusters (Au NCs) have exhibited great advantages in medical diagnostics and therapies due to their efficient renal clearance and high tumor uptake. The in vivo effects of the surface chemistry of Au NCs are important for the development of both nanobiological interfaces and potential clinical contrast reagents, but these properties are yet to be fully investigated. In this study, we prepared glutathione-protected Au NCs of a similar hydrodynamic size but with three different surface charges: positive, negative, and neutral. Their in vivo biodistribution, excretion, and toxicity were investigated over a 90-day period, and tumor uptake and potential application to radiation therapy were also evaluated. The results showed that the surface charge greatly influenced pharmacokinetics, particularly renal excretion and accumulation in kidney, liver, spleen, and testis. Negatively charged Au NCs displayed lower excretion and increased tumor uptake, indicating a potential for NC-based therapeutics, whereas positively charged clusters caused transient side effects on the peripheral blood system. PMID:27555769

  17. Blood circulation and tissue biodistribution of lipid--quantum dot (L-QD) hybrid vesicles intravenously administered in mice.

    PubMed

    Al-Jamal, Wafa' T; Al-Jamal, Khuloud T; Cakebread, Andrew; Halket, John M; Kostarelos, Kostas

    2009-09-01

    The present work describes the pharmacokinetics of recently developed liposome-quantum dot (L-QD) hybrid vesicles in nude mice following systemic administration. Hydrophobic QD were incorporated into different bilayer compositions, and the serum stability of such hybrid vesicles was evaluated using turbidity and carboxyfluorescein release measurements. L-QD hybrid blood profile and organ biodistribution were also determined by elemental (cadmium) analysis. Following intravenous administration, different tissue biodistribution profiles and tissue affinities were observed depending on the L-QD lipid bilayer characteristics. Immediate blood clearance was observed with cationic (DOTAP/DOPE/Chol) hybrid with rapid lung accumulation, while incorporation of PEG at the surface of zwitterionic vesicles dramatically prolonged their blood circulation half-life after systemic administration. Overall, the L-QD hybrid vesicle system is considered a viable platform that allows QD delivery to different tissues through facile modulation of the hybrid vesicle characteristics. In addition, L-QD offers many opportunities for the development of combinatory therapeutic and imaging (theranostic) modalities by incorporating both drug molecules and QD within the different compartments of a single vesicle.

  18. A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin.

    PubMed

    Veal, G J; Griffin, M J; Price, E; Parry, A; Dick, G S; Little, M A; Yule, S M; Morland, B; Estlin, E J; Hale, J P; Pearson, A D; Welbank, H; Boddy, A V

    2001-04-20

    Pre-clinical studies indicate that cisplatin encapsulated in STEALTH((R))liposomes (SPI-77) retains anti-tumour activity, but has a much reduced toxicity, compared to native cisplatin. A phase I study was conducted to determine the toxicity and pharmacokinetics of SPI-77 administered to children with advanced cancer not amenable to other treatment. Paediatric patients were treated at doses ranging from 40 to 320 mg m(-2)by intravenous infusion every 4 weeks. Blood samples taken during, and up to 3 weeks after, administration and plasma and ultrafiltrate were prepared immediately. Urine was collected, when possible, for 3 days after administration. SPI-77 administration was well tolerated with the major toxicity being an infusion reaction which responded to modification of the initial infusion rate of SPI-77. Limited haematological toxicity and no nephrotoxicity were observed. No responses to treatment were seen during the course of this phase I study. Measurement of total plasma platinum showed that cisplatin was retained in the circulation with a half life of up to 134 h, with maximum plasma concentrations approximately 100-fold higher than those reported following comparable doses of cisplatin. Comparison of plasma and whole blood indicated that cisplatin was retained in the liposomes and there was no free platinum measurable in the ultrafiltrate. Urine recovery was less than 4% of the dose administered over 72 h. Results from this phase I study indicate that high doses of liposomal cisplatin can safely be given to patients, but further studies are required to address the issue of reformulation of liposomally bound cisplatin.

  19. A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin

    PubMed Central

    Veal, G J; Griffin, M J; Price, E; Parry, A; Dick, G S; Little, M A; Yule, S M; Morland, B; Estlin, E J; Hale, J P; Pearson, A D J; Welbank, H; Boddy, A V

    2001-01-01

    Pre-clinical studies indicate that cisplatin encapsulated in STEALTH®liposomes (SPI-77) retains anti-tumour activity, but has a much reduced toxicity, compared to native cisplatin. A phase I study was conducted to determine the toxicity and pharmacokinetics of SPI-77 administered to children with advanced cancer not amenable to other treatment. Paediatric patients were treated at doses ranging from 40 to 320 mg m−2by intravenous infusion every 4 weeks. Blood samples taken during, and up to 3 weeks after, administration and plasma and ultrafiltrate were prepared immediately. Urine was collected, when possible, for 3 days after administration. SPI-77 administration was well tolerated with the major toxicity being an infusion reaction which responded to modification of the initial infusion rate of SPI-77. Limited haematological toxicity and no nephrotoxicity were observed. No responses to treatment were seen during the course of this phase I study. Measurement of total plasma platinum showed that cisplatin was retained in the circulation with a half life of up to 134 h, with maximum plasma concentrations approximately 100-fold higher than those reported following comparable doses of cisplatin. Comparison of plasma and whole blood indicated that cisplatin was retained in the liposomes and there was no free platinum measurable in the ultrafiltrate. Urine recovery was less than 4% of the dose administered over 72 h. Results from this phase I study indicate that high doses of liposomal cisplatin can safely be given to patients, but further studies are required to address the issue of reformulation of liposomally bound cisplatin. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11308249

  20. Preclinical Study of Single-Dose Moxidectin, a New Oral Treatment for Scabies: Efficacy, Safety, and Pharmacokinetics Compared to Two-Dose Ivermectin in a Porcine Model

    PubMed Central

    Bernigaud, Charlotte; Aho, Ludwig Serge; Dreau, Dominique; Kelly, Andrew; Sutra, Jean-François; Moreau, Francis; Lilin, Thomas; Botterel, Françoise; Guillot, Jacques; Chosidow, Olivier

    2016-01-01

    Background Scabies is one of the commonest dermatological conditions globally; however it is a largely underexplored and truly neglected infectious disease. Foremost, improvement in the management of this public health burden is imperative. Current treatments with topical agents and/or oral ivermectin (IVM) are insufficient and drug resistance is emerging. Moxidectin (MOX), with more advantageous pharmacological profiles may be a promising alternative. Methodology/Principal Findings Using a porcine scabies model, 12 pigs were randomly assigned to receive orally either MOX (0.3 mg/kg once), IVM (0.2 mg/kg twice) or no treatment. We evaluated treatment efficacies by assessing mite count, clinical lesions, pruritus and ELISA-determined anti-S. scabiei IgG antibodies reductions. Plasma and skin pharmacokinetic profiles were determined. At day 14 post-treatment, all four MOX-treated but only two IVM-treated pigs were mite-free. MOX efficacy was 100% and remained unchanged until study-end (D47), compared to 62% (range 26–100%) for IVM, with one IVM-treated pig remaining infected until D47. Clinical scabies lesions, pruritus and anti-S. scabiei IgG antibodies had completely disappeared in all MOX-treated but only 75% of IVM-treated pigs. MOX persisted ~9 times longer than IVM in plasma and skin, thereby covering the mite’s entire life cycle and enabling long-lasting efficacy. Conclusions/Significance Our data demonstrate that oral single-dose MOX was more effective than two consecutive IVM-doses, supporting MOX as potential therapeutic approach for scabies. PMID:27732588

  1. Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature.

    PubMed

    Giorda, Carlo B; Nada, Elisa; Tartaglino, Barbara

    2014-08-01

    Renal or hepatic impairment, often encountered in patients with type 2 diabetes, influences the pharmacokinetics and bioavailability of antihyperglycemic agents. An emerging concern is whether pharmacotherapy with incretin-based agents, the most recent drug classes to be introduced for type 2 diabetes, can be safely used in patients with renal insufficiency or hepatic damage. This literature review examines the results of studies on these novel drug classes, with a view to provide the practitioner with a balanced, evidence-based position when considering incretin-based therapies in patients with type 2 diabetes and impaired kidney or liver function. All currently available dipeptidyl peptidase-4 (DPP-4) inhibitors appear to be appropriate pharmacotherapeutic choices in patients with declining renal function, with linagliptin affording the added advantage of not requiring dose adjustment or periodic monitoring of drug-related kidney function. In contrast, caution is warranted with the use of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with moderate or severe renal impairment. The slightly wider evidence base for liraglutide than for exenatide or lixisenatide is not sufficient to support its use in severe renal impairment. What little evidence there is for incretin-based therapies in hepatic impairment has come from a few past hoc analysis of clinical trials, with most precautions and warnings reflecting the paucity of knowledge about incretin efficacy or safety in this condition.

  2. Toxicity and biodistribution of activated and non-activated intravenous iron oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Tate, J. A.; Ogden, J. A.; Strawbridge, R. R.; Pierce, Z. E.; Hoopes, P. J.

    2009-02-01

    The use of nanoparticles in medical treatment has prompted the question of their safety. In this study, the pathophysiology and biodistribution of three different concentrations of intravenously-delivered dextran-coated Fe3O4 iron oxide nanoparticles (IONP) were evaluated in mice. Some groups of mice were exposed to an AC magnetic field (AMF) at levels comparable with those proposed for cancer treatments. Iron biodistribution analysis for both AMF and non-AMF treated mice was performed for all three concentrations used (.6 mg Fe/mouse, 1.8 mg Fe/mouse, and 5.6 mg Fe/mouse). Blood urea nitrogen, alanine transaminase, alkaline phosphatase, total serum protein, and creatinine were also assessed at 4 hours, 7 days, and 14 days post-injection. Histological analysis of lung, spleen, heart, liver, and kidney tissue was conducted at 7 and 14 days post-injection. Prussian blue and H&E stains were used to histomorphometrically assess iron content in the tissues studied. Preliminary results demonstrate small temporary elevation in liver enzymes and hepatocyte vacuolization at all iron concentrations studied. Liver and spleen were the primary sites of IONP deposition. None of the animals demonstrated systemic or local toxicity or illness, with or without AMF activation.

  3. Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors.

    PubMed

    Mahalingam, Devalingam; Mita, Monica; Sarantopoulos, John; Wood, Leslie; Amaravadi, Ravi K; Davis, Lisa E; Mita, Alain C; Curiel, Tyler J; Espitia, Claudia M; Nawrocki, Steffan T; Giles, Francis J; Carew, Jennifer S

    2014-08-01

    We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and VOR in patients with advanced solid tumors. Of 27 patients treated in the study, 24 were considered fully evaluable for study assessments and toxicity. Patients were treated orally with escalating doses of HCQ daily (QD) (d 2 to 21 of a 21-d cycle) in combination with 400 mg VOR QD (d one to 21). Treatment-related adverse events (AE) included grade 1 to 2 nausea, diarrhea, fatigue, weight loss, anemia, and elevated creatinine. Grade 3 fatigue and/or myelosuppression were observed in a minority of patients. Fatigue and gastrointestinal AE were dose-limiting toxicities. Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen. One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease. The addition of HCQ did not significantly impact the PK profile of VOR. Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors.

  4. Neural Stem Cell Tumorigenicity and Biodistribution Assessment for Phase I Clinical Trial in Parkinson’s Disease

    PubMed Central

    Garitaonandia, Ibon; Gonzalez, Rodolfo; Christiansen-Weber, Trudy; Abramihina, Tatiana; Poustovoitov, Maxim; Noskov, Alexander; Sherman, Glenn; Semechkin, Andrey; Snyder, Evan; Kern, Russell

    2016-01-01

    Human pluripotent stem cells (PSC) have the potential to revolutionize regenerative medicine. However undifferentiated PSC can form tumors and strict quality control measures and safety studies must be conducted before clinical translation. Here we describe preclinical tumorigenicity and biodistribution safety studies that were required by the US Food and Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA) prior to conducting a Phase I clinical trial evaluating the safety and tolerability of human parthenogenetic stem cell derived neural stem cells ISC-hpNSC for treating Parkinson’s disease (ClinicalTrials.gov Identifier NCT02452723). To mitigate the risk of having residual PSC in the final ISC-hpNSC population, we conducted sensitive in vitro assays using flow cytometry and qRT-PCR analyses and in vivo assays to determine acute toxicity, tumorigenicity and biodistribution. The results from these safety studies show the lack of residual undifferentiated PSC, negligible tumorigenic potential by ISC-hpNSC and provide additional assurance to their clinical application. PMID:27686862

  5. Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive.

    PubMed

    Ayoub, R; Page, S T; Swerdloff, R S; Liu, P Y; Amory, J K; Leung, A; Hull, L; Blithe, D; Christy, A; Chao, J H; Bremner, W J; Wang, C

    2017-03-01

    Dimethandrolone (DMA, 7α,11β-dimethyl-19-nortestosterone) has both androgenic and progestational activities, ideal properties for a male hormonal contraceptive. In vivo, dimethandrolone undecanoate (DMAU) is hydrolyzed to DMA. We showed previously that single oral doses of DMAU powder in capsule taken with food are well tolerated and effective at suppressing both LH and testosterone (T), but absorption was low. We compared the pharmacokinetics and pharmacodynamics of two new formulations of DMAU, in castor oil and in self-emulsifying drug delivery systems (SEDDS), with the previously tested powder formulation. DMAU was dosed orally in healthy adult male volunteers at two academic medical centers. For each formulation tested in this double-blind, placebo-controlled study, 10 men received single, escalating, oral doses of DMAU (100, 200, and 400 mg) and two subjects received placebo. All doses were evaluated for both fasting and with a high fat meal. All three formulations were well tolerated without clinically significant changes in vital signs, blood counts, or serum chemistries. For all formulations, DMA and DMAU showed higher maximum (p < 0.007) and average concentrations (p < 0.002) at the 400 mg dose, compared with the 200 mg dose. The powder formulation resulted in a lower conversion of DMAU to DMA (p = 0.027) compared with both castor oil and SEDDS formulations. DMAU in SEDDS given fasting resulted in higher serum DMA and DMAU concentrations compared to the other two formulations. Serum LH and sex hormone concentrations were suppressed by all formulations of 200 and 400 mg DMAU when administered with food, but only the SEDDS formulation was effectively suppressed serum T when given fasting. We conclude that while all three formulations of oral DMAU are effective and well tolerated when administered with food, DMAU in oil and SEDDS increased conversion to DMA, and SEDDS may have some effectiveness when given fasting. These properties might be

  6. A phase I dose‐escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC‐223 in patients with advanced solid tumors or multiple myeloma

    PubMed Central

    Bendell, Johanna C.; Kelley, Robin K.; Shih, Kent C.; Grabowsky, Jennifer A.; Bergsland, Emily; Jones, Suzanne; Martin, Thomas; Infante, Jeffrey R.; Mischel, Paul S.; Matsutani, Tomoo; Xu, Shuichan; Wong, Lilly; Liu, Yong; Wu, Xiaoling; Mortensen, Deborah S.; Chopra, Rajesh; Hege, Kristen

    2015-01-01

    BACKGROUND The mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1/mTORC2 inhibitor CC‐223 in patients with advanced cancer. METHODS Patients with advanced solid tumors or multiple myeloma received an initial dose of 7.5‐60 mg of CC‐223, followed by oral daily dosing in 28‐day cycles until disease progression. The primary objective was to determine the safety, tolerability, nontolerated dosage, maximum tolerated dosage (MTD), and preliminary pharmacokinetic profile. Secondary objectives were to evaluate pharmacodynamic effects and to describe preliminary efficacy. RESULTS Twenty‐eight patients were enrolled and received ≥1 dose of CC‐223. The most common treatment‐related grade 3 adverse events were hyperglycemia, fatigue, and rash. Four patients had dose‐limiting toxicities, including hyperglycemia, rash, fatigue, and mucositis. Therefore, 45 mg/d was determined to be the MTD. The pharmacokinetics of CC‐223 demonstrated a mean terminal half‐life ranging from 4.86 to 5.64 hours and maximum observed plasma concentration ranging from 269 to 480 ng/mL in patients who received CC‐223 ≥45 mg/d. Phosphorylation of mTORC1/mTORC2 pathway biomarkers in blood cells was inhibited by CC‐223 ≥30 mg/d with an exposure‐response relationship. Best responses included 1 partial response (breast cancer; response duration 220 days; 30‐mg/d cohort), stable disease (8 patients across ≥15 mg/d cohorts; response duration range, 36‐168 days), and progressive disease (12 patients). The disease control rate was 32%. CONCLUSIONS CC‐223 was tolerable, with manageable toxicities. Preliminary antitumor activity, including tumor regression, and evidence of mTORC1/mTORC2 pathway inhibition were observed. Cancer 2015;121:3435–43. © 2015 American Cancer Society. PMID:26177599

  7. PEGylated PRINT Nanoparticles: The Impact of PEG Density on Protein Binding, Macrophage Association, Biodistribution, and Pharmacokinetics

    PubMed Central

    Perry, Jillian L.; Reuter, Kevin G.; Kai, Marc P.; Herlihy, Kevin P.; Jones, Stephen W.; Luft, J. Chris; Napier, Mary; Bear, James E.; DeSimone, Joseph M.

    2014-01-01

    In this account, we varied PEGylation density on the surface of hydrogel PRINT nanoparticles and systematically observed the effects on protein adsorption, macrophage uptake, and circulation time. Interestingly, the density of PEGylation necessary to promote a long-circulating particle was dramatically less than what has been previously reported. Overall, our methodology provides a rapid screening technique to predict particle behavior in vivo and our results deliver further insight to what PEG density is necessary to facilitate long-circulation. PMID:22920324

  8. Improvement of drug safety by the use of lipid-based nanocarriers.

    PubMed

    Lim, Sok Bee; Banerjee, Amrita; Önyüksel, Hayat

    2012-10-10

    Drug toxicity is an important factor that contributes significantly to adverse drug events in current healthcare practice. Application of lipid-based nanocarriers in drug formulation is one approach to improve drug safety. Lipid-based delivery systems include micelles, liposomes, solid lipid nanoparticles, nanoemulsions and nanosuspensions. These carriers are generally composed of physiological lipids well tolerated by human body. Delivery of water-insoluble drugs in these formulations increases their solubility and stability in aqueous media and eliminates the need for toxic co-solvents or pH adjustment to solubilize hydrophobic drugs. Association or encapsulation of peptides/proteins within lipid-based carriers protects the labile biologics against enzymatic degradation, hence reducing the therapeutic dose required and risk of dose-dependent toxicity. Most importantly, lipid-based nanocarriers alter the pharmacokinetics and biodistribution of drugs through passive and active targeting, leading to increased drug accumulation at target sites while significantly decreasing non-specific distribution to other tissues. Furthermore, surface modification of these nanocarriers reduces immunogenicity of drug-carrier complexes, imparts stealth by preventing opsonization and removal by phagocytes and minimizes interaction with circulating blood components. In view of heightening attention on drug safety in patient treatment, lipid-based nanocarrier is therefore an important and promising option for formulation of pharmaceutical products to improve treatment safety and efficacy.

  9. Bioavailability and biodistribution of nanodelivered lutein.

    PubMed

    Kamil, Alison; Smith, Donald E; Blumberg, Jeffrey B; Astete, Carlos; Sabliov, Cristina; Oliver Chen, C-Y

    2016-02-01

    The aim of the study was to evaluate the ability of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) to enhance lutein bioavailability. The bioavailability of free lutein and PLGA-NP lutein in rats was assessed by determining plasma pharmacokinetics and deposition in selected tissues. Lutein uptake and secretion was also assessed in Caco-2 cells. Compared to free lutein, PLGA-NP increased the maximal plasma concentration (Cmax) and area under the time-concentration curve in rats by 54.5- and 77.6-fold, respectively, while promoting tissue accumulation in the mesenteric fat and spleen. In comparison with micellized lutein, PLGA-NP lutein improved the Cmax in rat plasma by 15.6-fold and in selected tissues by ⩾ 3.8-fold. In contrast, PLGA-NP lutein had a lower uptake and secretion of lutein in Caco-2 cells by 10.0- and 50.5-fold, respectively, compared to micellized lutein. In conclusion, delivery of lutein with polymeric NP may be an approach to improve the bioavailability of lutein in vivo.

  10. Pharmacokinetics of Exosomes-an Important Factor for Elucidating the Biological Roles of Exosomes and for the Development of Exosome-Based Therapeutics.

    PubMed

    Morishita, Masaki; Takahashi, Yuki; Nishikawa, Makiya; Takakura, Yoshinobu

    2017-03-07

    Exosomes are small membrane vesicles containing lipids, proteins, and nucleic acids. Recently, researchers have uncovered that exosomes are involved in various biological events, such as tumor growth, metastasis, and the immune response, by delivering their cargos to exosome-receiving cells. Moreover, exosomes are expected to be employed in therapeutic treatments, such as tissue regeneration therapy and antitumor immunotherapy, since exosomes are effective delivery vehicles for proteins, nucleic acids, and other bioactive compounds. To elucidate the biological functions of exosomes, and for the development of exosome-based therapeutics, the pharmacokinetics of exosomes is important. In this review, we aim to summarize current knowledge about the pharmacokinetics and biodistribution of exosomes. The pharmacokinetics of exogenously administered exosomes is discussed based on the tissue distribution, types of cells taking up exosomes, and key molecules in the pharmacokinetics of exosomes. In addition, recent progress in the methods to control the pharmacokinetics of exosomes is reviewed.

  11. Size dependent biodistribution and SPECT imaging of (111)In-labeled polymersomes.

    PubMed

    Brinkhuis, René P; Stojanov, Katica; Laverman, Peter; Eilander, Jos; Zuhorn, Inge S; Rutjes, Floris P J T; van Hest, Jan C M

    2012-05-16

    Polymersomes, self-assembled from the block copolymer polybutadiene-block-poly(ethylene glycol), were prepared with well-defined diameters between 90 and 250 nm. The presence of ~1% of diethylene triamine penta acetic acid on the polymersome periphery allowed to chelate radioactive (111)In onto the surface and determine the biodistribution in mice as a function of both the polymersome size and poly(ethylene glycol) corona thickness (i.e., PEG molecular weight). Doubling the PEG molecular weight from 1 kg/mol to 2 kg/mol did not change the blood circulation half-life significantly. However, the size of the different polymersome samples did have a drastic effect on the blood circulation times. It was found that polymersomes of 120 nm and larger become mostly cleared from the blood within 4 h, presumably due to recognition by the reticuloendothelial system. In contrast, smaller polymersomes of around 90 nm circulated much longer. After 24 h more than 30% of the injected dose was still present in the blood pool. This sharp transition in blood circulation kinetics due to size is much more abrupt than observed for liposomes and was additionally visualized by SPECT/CT imaging. These findings should be considered in the formulation and design of polymersomes for biomedical applications. Size, much more than for liposomes, will influence the pharmacokinetics, and therefore, long circulating preparations should be well below 100 nm.

  12. Controlling In Vivo Stability and Biodistribution in Electrostatically Assembled Nanoparticles for Systemic Delivery

    PubMed Central

    Poon, Zhiyong; Lee, Jong Bum; Morton, Stephen W; Hammond, Paula T

    2011-01-01

    This paper demonstrates the generation of systemically deliverable layer-by-layer (LbL) nanoparticles for cancer applications. LbL-based nanoparticles designed to navigate the body and deliver therapeutics in a programmable fashion are promising new and alternative systems for drug delivery; but there have been very few demonstrations of their systemic delivery in vivo due to a lack of knowledge in building LbL nanofilms that mimic traditional nanoparticle design to optimize delivery. The key to the successful application of these nanocarriers in vivo requires a systematic analysis of the influence of film architecture and adsorbed polyelectrolyte outer layer on their pharmacokinetics, which has thus far not been examined for this new approach to nanoparticle delivery. Herein, we have taken the first steps in stabilizing and controlling the systemic distribution of multilayer nanoparticles. Our findings highlight the unique character of LbL systems: the electrostatically assembled nanoparticles gain increased stability in vivo with larger numbers of deposited layers, and the final layer adsorbed generates a critical surface cascade, which dictates the surface chemistry and biological properties of the nanoparticle. This outer polyelectrolyte layer dramatically affects not only the degree of nonspecific particle uptake, but also the nanoparticle biodistribution. For hyaluronic acid (HA) outer layers, a long blood elimination half-life (~9 h) and low accumulation (~ 10–15 % recovered fluorescence/g) in the liver were observed, illustrating that these systems can be designed to be highly appropriate for clinical translation. PMID:21524115

  13. Biodistribution and metabolism of immunostimulatory oligodeoxynucleotide CPG 7909 in mouse and rat tissues following subcutaneous administration.

    PubMed

    Noll, Bernhard O; McCluskie, Michael J; Sniatala, Tanja; Lohner, Angela; Yuill, Stephanie; Krieg, Arthur M; Schetter, Christian; Davis, Heather L; Uhlmann, Eugen

    2005-03-15

    To evaluate pharmacokinetics (PK) and biodistribution, CPG 7909, a 24-mer immunostimulatory fully phosphorothioated oligodeoxynucleotide (PS-ODN), was administered by subcutaneous injection at 2, 5 and 12.5mg/kg to mice and at 9mg/kg to rats. Parent compound and metabolites were isolated from plasma and tissues and quantified by capillary gel electrophoresis with UV detection (CGE-UV) and molecular masses were determined by matrix-assisted-laser-desorption-ionization time of flight detection (MALDI-TOF). An established method for PS-ODN isolation from plasma and tissue was modified to prevent oxidation of the phosphorothioate bonds during the extraction process, significantly increasing sensitivity in the subsequent MALDI-TOF analysis. Concentrations of CPG 7909 and metabolites were highest at the injection site (>600mg/kg at 4h). Maximal concentrations in local (draining) lymph nodes (LLN), kidney and liver were 10-15% of that at the injection site. The highest total amount of PS-ODN (percentage of administered dose) was found in the liver (32% at 4h), followed closely by the injection site (23% at 4h). Only very low levels of CPG 7909 and metabolites were found in plasma and only during the first hours. Metabolites identified by MALDI-TOF were similar for both species and all analyzed tissues, although the relative amounts of the different metabolites varied with tissue and over time. Degradation of CPG 7909 in vivo occurred predominantly by 3'exonucleases with additional cleavage by endonucleases.

  14. Biodistribution and Trafficking of Hydrogel Nanoparticles in Adult Mosquitoes

    PubMed Central

    Paquette, Cynthia C. H.; Phanse, Yashdeep; Perry, Jillian L.; Sanchez-Vargas, Irma; Airs, Paul M.; Dunphy, Brendan M.; Xu, Jing; Carlson, Jonathan O.; Luft, J. Christopher; DeSimone, Joseph M.; Bartholomay, Lyric C.; Beaty, Barry J.

    2015-01-01

    Background Nanotechnology offers great potential for molecular genetic investigations and potential control of medically important arthropods. Major advances have been made in mammalian systems to define nanoparticle (NP) characteristics that condition trafficking and biodistribution of NPs in the host. Such information is critical for effective delivery of therapeutics and molecules to cells and organs, but little is known about biodistribution of NPs in mosquitoes. Methodology/Principal Findings PRINT technology was used to construct a library of fluorescently labeled hydrogel NPs of defined size, shape, and surface charge. The biodistribution (organ, tissue, and cell tropisms and trafficking kinetics) of positively and negatively charged 200 nm x 200 nm, 80 nm x 320 nm, and 80 nm x 5000 nm NPs was determined in adult Anopheles gambiae mosquitoes as a function of the route of challenge (ingestion, injection or contact) using whole body imaging and fluorescence microscopy. Mosquitoes readily ingested NPs in sugar solution. Whole body fluorescence imaging revealed substantial NP accumulation (load) in the alimentary tracts of the adult mosquitoes, with the greatest loads in the diverticula, cardia and foregut. Positively and negatively charged NPs differed in their biodistribution and trafficking. Following oral challenge, negatively charged NPs transited the alimentary tract more rapidly than positively charged NPs. Following contact challenge, negatively charged NPs trafficked more efficiently in alimentary tract tissues. Following parenteral challenge, positively and negatively charged NPs differed in tissue tropisms and trafficking in the hemocoel. Injected NPs were also detected in cardia/foregut, suggesting trafficking of NPs from the hemocoel into the alimentary tract. Conclusions/Significance Herein we have developed a tool box of NPs with the biodistribution and tissue tropism characteristics for gene structure/function studies and for delivery of vector

  15. Functionalized Single-Walled Carbon Nanotubes: Cellular Uptake, Biodistribution and Applications in Drug Delivery.

    PubMed

    Li, Zixian; de Barros, Andre Luis Branco; Soares, Daniel Cristian Ferreira; Moss, Sara Nicole; Alisaraie, Laleh

    2017-03-11

    The unique properties of single-walled carbon nanotubes (SWNTs) enable them to play important roles in many fields. One of their functional roles is to transport cargo into the cell. SWNTs are able to traverse amphipathic cell membranes due to their large surface area, flexible interactions with cargo, customizable dimensions, and surface chemistry. The cargoes delivered by SWNTs include peptides, proteins, nucleic acids, as well as drug molecules for therapeutic purpose. The drug delivery functions of SWNTs have been explored over the past decade. Many breakthrough studies have shown the high specificity and potency of functionalized SWNT-based drug delivery systems for the treatment of cancers and other diseases. In this review, we discuss different aspects of drug delivery by functionalized SWNT carriers, diving into the cellular uptake mechanisms, biodistribution of the delivery system, and safety concerns on degradation of the carriers. We emphasize the delivery of several common drugs to highlight the recent achievements of SWNT-based drug delivery.

  16. Biodistribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure in mice, rats and dogs

    SciTech Connect

    Turowska, Agnieszka; Librizzi, Damiano; Baumgartl, Nadja; Kuhlmann, Jens; Dicke, Tanja; Merkel, Olivia; Homburg, Ursula; Höffken, Helmut; Renz, Harald; Garn, Holger

    2013-10-15

    The DNAzyme hgd40 was shown to effectively reduce expression of the transcription factor GATA-3 RNA which plays an important role in the regulation of Th2-mediated immune mechanisms such as in allergic bronchial asthma. However, uptake, biodistribution and pharmacokinetics of hgd40 have not been investigated yet. We examined local and systemic distribution of hgd40 in naive mice and mice suffering from experimental asthma. Furthermore, we evaluated the pharmacokinetics as a function of dose following single and repeated administration in rats and dogs. Using intranasal administration of fluorescently labeled hgd40 we demonstrated that the DNAzyme was evenly distributed in inflamed asthmatic mouse lungs within minutes after single dose application. Systemic distribution was investigated in mice using radioactive labeled hgd40. After intratracheal application, highest amounts of hgd40 were detected in the lungs. High amounts were also detected in the bladder indicating urinary excretion as a major elimination pathway. In serum, low systemic hgd40 levels were detected already at 5 min post application (p.a.), subsequently decreasing over time to non-detectable levels at 2 h p.a. As revealed by Single Photon Emission Computed Tomography, trace amounts of hgd40 were detectable in lungs up to 7 days p.a. Also in the toxicologically relevant rats and dogs, hgd40 was detectable in blood only shortly after inhalative application. The plasma pharmacokinetic profile was dose and time dependent. Repeated administration did not lead to drug accumulation in plasma of dogs and rats. These pharmacokinetic of hgd40 provide guidance for clinical development, and support an infrequent and convenient dose administration regimen. - Highlights: • Local and systemic distribution of GATA-3-specific DNAzyme hgd40 was investigated. • Pharmacokinetics of hgd40 was tested in rats and dogs. • hgd40 dissolved in PBS was easily taken up into the lungs after local application. • No

  17. Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML).

    PubMed

    Erba, Harry P; Sayar, Hamid; Juckett, Mark; Lahn, Michael; Andre, Valerie; Callies, Sophie; Schmidt, Shelly; Kadam, Sunil; Brandt, John T; Van Bockstaele, Dirk; Andreeff, Michael

    2013-08-01

    Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n = 8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n = 16). LY2181308 was administered with a loading dosage of three consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m(2) was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m(2) was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.

  18. Safety, Pharmacokinetics, and Antiretroviral Activity of Multiple Doses of Ibalizumab (formerly TNX-355), an Anti-CD4 Monoclonal Antibody, in Human Immunodeficiency Virus Type 1-Infected Adults ▿

    PubMed Central

    Jacobson, Jeffrey M.; Kuritzkes, Daniel R.; Godofsky, Eliot; DeJesus, Edwin; Larson, Jeffrey A.; Weinheimer, Steven P.; Lewis, Stanley T.

    2009-01-01

    Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log10) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4+ T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4+ T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted. PMID:19015347

  19. Paediatric pharmacokinetics: key considerations

    PubMed Central

    Batchelor, Hannah Katharine; Marriott, John Francis

    2015-01-01

    A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials. PMID:25855821

  20. Paediatric pharmacokinetics: key considerations.

    PubMed

    Batchelor, Hannah Katharine; Marriott, John Francis

    2015-03-01

    A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials.

  1. The biodistribution of gold nanoparticles designed for renal clearance

    NASA Astrophysics Data System (ADS)

    Alric, Christophe; Miladi, Imen; Kryza, David; Taleb, Jacqueline; Lux, François; Bazzi, Rana; Billotey, Claire; Janier, Marc; Perriat, Pascal; Roux, Stéphane; Tillement, Olivier

    2013-06-01

    Owing to their tunable optical properties and their high absorption cross-section of X- and γ-ray, gold nanostructures appear as promising agents for remotely controlled therapy. Since the efficiency of cancer therapy is not limited to the eradication of the tumour but rests also on the sparing of healthy tissue, a biodistribution study is required in order to determine whether the behaviour of the nanoparticles after intravenous injection is safe (no accumulation in healthy tissue, no uptake by phagocytic cell-rich organs (liver, spleen) and renal clearance). The biodistribution of Au@DTDTPA nanoparticles which are composed of a gold core and a DTDTPA (dithiolated polyaminocarboxylate) shell can be established by X-ray imaging (owing to the X-ray absorption of the gold core) and by magnetic resonance imaging (MRI) since the DTDTPA shell was designed for the immobilization of paramagnetic gadolinium ions. However scintigraphy appears better suited for a biodistribution study owing to a great sensitivity. The successful immobilization of radioelements (99mTc, 111In) in the DTDTPA shell, instead of gadolinium ions, renders possible the follow up of Au@DTDTPA by scintigraphy which showed that Au@DTDTPA nanoparticles exhibit a safe behaviour after intravenous injection to healthy rats.Owing to their tunable optical properties and their high absorption cross-section of X- and γ-ray, gold nanostructures appear as promising agents for remotely controlled therapy. Since the efficiency of cancer therapy is not limited to the eradication of the tumour but rests also on the sparing of healthy tissue, a biodistribution study is required in order to determine whether the behaviour of the nanoparticles after intravenous injection is safe (no accumulation in healthy tissue, no uptake by phagocytic cell-rich organs (liver, spleen) and renal clearance). The biodistribution of Au@DTDTPA nanoparticles which are composed of a gold core and a DTDTPA (dithiolated polyaminocarboxylate

  2. Comprehensive characterizations of nanoparticle biodistribution following systemic injection in mice

    NASA Astrophysics Data System (ADS)

    Liao, Wei-Yin; Li, Hui-Jing; Chang, Ming-Yao; Tang, Alan C. L.; Hoffman, Allan S.; Hsieh, Patrick C. H.

    2013-10-01

    Various nanoparticle (NP) properties such as shape and surface charge have been studied in an attempt to enhance the efficacy of NPs in biomedical applications. When trying to undermine the precise biodistribution of NPs within the target organs, the analytical method becomes the determining factor in measuring the precise quantity of distributed NPs. High performance liquid chromatography (HPLC) represents a more powerful tool in quantifying NP biodistribution compared to conventional analytical methods such as an in vivo imaging system (IVIS). This, in part, is due to better curve linearity offered by HPLC than IVIS. Furthermore, HPLC enables us to fully analyze each gram of NPs present in the organs without compromising the signals and the depth-related sensitivity as is the case in IVIS measurements. In addition, we found that changing physiological conditions improved large NP (200-500 nm) distribution in brain tissue. These results reveal the importance of selecting analytic tools and physiological environment when characterizing NP biodistribution for future nanoscale toxicology, therapeutics and diagnostics.Various nanoparticle (NP) properties such as shape and surface charge have been studied in an attempt to enhance the efficacy of NPs in biomedical applications. When trying to undermine the precise biodistribution of NPs within the target organs, the analytical method becomes the determining factor in measuring the precise quantity of distributed NPs. High performance liquid chromatography (HPLC) represents a more powerful tool in quantifying NP biodistribution compared to conventional analytical methods such as an in vivo imaging system (IVIS). This, in part, is due to better curve linearity offered by HPLC than IVIS. Furthermore, HPLC enables us to fully analyze each gram of NPs present in the organs without compromising the signals and the depth-related sensitivity as is the case in IVIS measurements. In addition, we found that changing physiological

  3. Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults

    PubMed Central

    Khan, Anis A.; Esser, Mark T.; Jensen, Kathryn; Takas, Therese; Kankam, Martin K.; Villafana, Tonya; Dubovsky, Filip

    2016-01-01

    ABSTRACT Prevention of respiratory syncytial virus (RSV) illness in infants is a major public health priority, but there is no approved vaccine. Palivizumab is a monoclonal antibody that provides RSV prophylaxis but requires 5 monthly injections and is approved only for infants who experience the greatest morbidity and mortality from RSV. Thus, there remains a significant unmet medical need for prevention of RSV disease in healthy infants. MEDI8897 is a recombinant human RSV monoclonal antibody with a modified Fc region that extends its half-life and is being developed as RSV prophylaxis for all infants. In this phase 1, first-in-human, placebo-controlled study, 136 healthy adults were randomized to receive a single dose of MEDI8897 (n = 102) or placebo (n = 34) in 1 of 5 cohorts (300, 1,000, or 3,000 mg intravenously or 100 or 300 mg intramuscularly [i.m.]) and were monitored for 360 days. The mean half-life of MEDI8897 was 85 to 117 days across dose groups, and bioavailability after 300-mg i.m. dose administration was 77%. Time to maximum concentration following i.m. dosing was 5 to 9 days. Antidrug antibody (ADA) responses were detected in a similar proportion of placebo (15.2%) and MEDI8897 (13.7%) recipients. The safety profile of MEDI8897 was similar to that of the placebo. These results support clinical studies of the i.m. administration of a single dose of MEDI8897 in the target population of infants to provide protection for the duration of the RSV season. (This study has been registered at ClinicalTrials.gov under identifier NCT02114268.) PMID:27956428

  4. Pharmacokinetic characterization of amrubicin cardiac safety in an ex vivo human myocardial strip model. II. Amrubicin shows metabolic advantages over doxorubicin and epirubicin.

    PubMed

    Salvatorelli, Emanuela; Menna, Pierantonio; Gonzalez Paz, Odalys; Surapaneni, Sekhar; Aukerman, Sharon L; Chello, Massimo; Covino, Elvio; Sung, Victoria; Minotti, Giorgio

    2012-05-01

    metabolic advantages over doxorubicin and epirubicin, which may correlate with amrubicin cardiac safety in preclinical or clinical settings.

  5. Altered biodistribution of Ga-67 by intramuscular gold salts

    SciTech Connect

    Moult, R.G.; Bekerman, C. )

    1989-11-01

    The authors observed a deviation from the normal scintigraphic pattern of Ga-67 citrate biodistribution. An 8-year-old black girl with juvenile rheumatoid arthritis, who had been treated with intramuscular injections of gold salts, had a Ga-67 study as part of her workup. The study demonstrated no hepatic uptake, but showed elevated skeletal and renal activity. This characteristic biodistribution of Ga-67 may be due to inhibition of lysosomal enzymes by gold and/or to accumulation of gold in lysosomes. To study these possibilities, the authors reviewed the mechanisms of Ga-67 localization and gold metabolism. Alteration of the Ga-67 citrate scintigraphic pattern due to earlier treatment with gold salts has not been reported previously.

  6. Biodistribution of quantum dots in the kidney after intravenous injection.

    PubMed

    Pollinger, K; Hennig, R; Bauer, S; Breunig, M; Tessmar, J; Buschauer, A; Witzgall, R; Goepferich, A

    2014-05-01

    The biodistribution of nanoparticles is a major subject of current nanomedical research. To date, however, the exact investigation of nanoparticle fate in the microenvironment of a main excretory organ, the kidney has largely been neglected. In this study, the biodistribution of polyethylene glycol-coated quantum dots (Qdots) with special focus on their interaction with the kidney is investigated. Upon intravenous injection, nanoparticles showed effective blood circulation in mice and significant renal accumulation after two hours. Histological analysis of the kidney revealed that Qdots were strongly associated to the intraglomerular mesangial cells. This preferential deposition of nanoparticles in the kidney mesangium is highly promising, since it could be of utmost value for site-specific treatment of severe kidney diseases like diabetic nephropathy in the future.

  7. Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles

    PubMed Central

    2008-01-01

    Nanoparticle (NP) drug delivery systems (5−250 nm) have the potential to improve current disease therapies because of their ability to overcome multiple biological barriers and releasing a therapeutic load in the optimal dosage range. Rapid clearance of circulating nanoparticles during systemic delivery is a critical issue for these systems and has made it necessary to understand the factors affecting particle biodistribution and blood circulation half-life. In this review, we discuss the factors which can influence nanoparticle blood residence time and organ specific accumulation. These factors include interactions with biological barriers and tunable nanoparticle parameters, such as composition, size, core properties, surface modifications (pegylation and surface charge), and finally, targeting ligand functionalization. All these factors have been shown to substantially affect the biodistribution and blood circulation half-life of circulating nanoparticles by reducing the level of nonspecific uptake, delaying opsonization, and increasing the extent of tissue specific accumulation. PMID:18672949

  8. Biodistribution of Amikacin Solid Lipid Nanoparticles after Pulmonary Delivery

    PubMed Central

    Varshosaz, J.; Ghaffari, S.; Mirshojaei, S. F.; Jafarian, A.; Atyabi, F.; Kobarfard, F.; Azarmi, S.

    2013-01-01

    The main purpose of the present work was studying the biodistribution of amikacin solid lipid nanoparticles (SLNs) after pulmonary delivery to increase its concentration in the lungs for treatment of cystic fibrosis lung infections and also providing a new method for clinical application of amikacin. To achieve this aim, 99mTc labelled amikacin was loaded in cholesterol SLNs and after in vitro optimization, the desired SLNs and free drug were administered through pulmonary and i.v. routes to male rats and qualitative and biodistribution studies were done. Results showed that pulmonary delivery of SLNs of amikacin by microsprayer caused higher drug concentration in lungs than kidneys while i.v. administration of free drug caused reverse conditions. It seems that pulmonary delivery of SLNs may improve patients' compliance due to reduction of drug side effects in kidneys and elongation of drug dosing intervals due to the sustained drug release from SLNs. PMID:23984315

  9. Ac magnetic susceptibility study of in vivo nanoparticle biodistribution

    NASA Astrophysics Data System (ADS)

    Gutiérrez, L.; Mejías, R.; Barber, D. F.; Veintemillas-Verdaguer, S.; Serna, C. J.; Lázaro, F. J.; Morales, M. P.

    2011-06-01

    We analysed magnetic nanoparticle biodistribution, before and after cytokine conjugation, in a mouse model by ac susceptibility measurements of the corresponding resected tissues. Mice received repeated intravenous injections of nanoparticle suspension for two weeks and they were euthanized 1 h after the last injection. In general, only 10% of the total injected nanoparticles after multiple exposures were found in tissues. The rest of the particles may probably be metabolized or excreted by the organism. Our findings indicate that the adsorption of interferon to DMSA-coated magnetic nanoparticles changes their biodistribution, reducing the presence of nanoparticles in lungs and therefore their possible toxicity. The specific targeting of the particles to tumour tissues by the use of an external magnetic field has also been studied. Magnetic nanoparticles were observed by transmission electron microscopy in the targeted tissue and quantified by ac magnetic susceptibility.

  10. Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies.

    PubMed

    Hillaireau, Hervé; Dereuddre-Bosquet, Nathalie; Skanji, Rym; Bekkara-Aounallah, Fawzia; Caron, Joachim; Lepêtre, Sinda; Argote, Sébastien; Bauduin, Laurent; Yousfi, Rahima; Rogez-Kreuz, Christine; Desmaële, Didier; Rousseau, Bernard; Gref, Ruxandra; Andrieux, Karine; Clayette, Pascal; Couvreur, Patrick

    2013-07-01

    Due to their hydrophilic nature, most nucleoside reverse transcriptase inhibitors (NRTIs) display a variable bioavailability after oral administration and a poor control over their biodistribution, thus hampering their access to HIV sanctuaries. The limited cellular uptake and activation in the triphosphate form of NRTIs further restrict their efficacy and favour the emergence of viral resistance. We have shown that the conjugation of squalene (sq) to the nucleoside analogues dideoxycytidine (ddC) and didanosine (ddI) leads to amphiphilic prodrugs (ddC-sq and ddI-sq) that spontaneously self-organize in water as stable nanoassemblies of 100-300 nm. These nanoassemblies can also be formulated with polyethylene glycol coupled to either cholesterol (Chol-PEG) or squalene (sq-PEG). When incubated with peripheral blood mononuclear cells (PBMCs) in vitro infected with HIV, the NRTI-sq prodrugs enhanced the antiviral efficacy of the parent NRTIs, with a 2- to 3-fold decrease of the 50% effective doses and a nearly 2-fold increase of the selectivity index. This was also the case with HIV-1 strains resistant to ddC and/or ddI. The enhanced antiviral activity of ddI-sq was correlated with an up to 5-fold increase in the intracellular concentration of the corresponding pharmacologically active metabolite ddA-TP. The ddI-sq prodrug was further investigated in vivo by the oral route, the preferred route of administration of NRTIs. Pharmacokinetics studies performed on rats showed that the prodrug maintained low amounts of free ddI in the plasma. Administration of (3)H-ddI-sq led to radioactivity levels higher in the plasma and relevant organs in HIV infection as compared to administration of free (3)H-ddI. Taken together, these results show the potential of the squalenoylated prodrugs of NRTIs to enhance their absorption and improve their biodistribution, but also to enhance their intracellular delivery and antiviral efficacy towards HIV-infected cells.

  11. Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

    PubMed

    Blesch, Karen S; Gieschke, Ronald; Tsukamoto, Yuko; Reigner, Bruno G; Burger, Hans U; Steimer, Jean-Louis

    2003-05-01

    Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors. Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety. It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans. Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes. The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU. This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes.

  12. Pharmacokinetics of biotech drugs: peptides, proteins and monoclonal antibodies.

    PubMed

    Lin, Jiunn H

    2009-09-01

    With the advances in recombinant DNA biotechnology, molecular biology and immunology, the number of biotech drugs, including peptides, proteins and monoclonal antibodies, available for clinical use has dramatically increased in recent years. Although pharmacokinetic principles are equally applicable to the large molecule drugs and conventional small molecule drugs, the underlying mechanisms for the processes of absorption, distribution, metabolism and excretion (ADME) of large molecule drugs are often very different from that of small molecule drugs. Therefore, a good understanding of the ADME processes of large molecule drugs is essential in support of the development of therapeutic biologics. The purpose of this article is to review the current knowledge of the ADME processes that govern the pharmacokinetics of biotech drugs. The challenges encountered by orally administered peptide and protein drugs, and the nature of lymphatic absorption after subcutaneous administration will be discussed. In addition, molecular mechanisms of biodistribution, metabolism and renal excretion of biotech drugs will also be discussed. Finally, approaches used for prediction of human pharmacokinetics of protein drugs will be briefly discussed.

  13. Lisdexamfetamine: A pharmacokinetic review.

    PubMed

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice.

  14. In Vivo Imaging of Glycol Chitosan-Based Nanogel Biodistribution.

    PubMed

    Pereira, Paula; Correia, Alexandra; Gama, Francisco M

    2016-03-01

    The preclinical development of nanomedicines raises several challenges and requires a comprehensive characterization. Among them is the evaluation of the biodistribution following systemic administration. In previous work, the biocompatibility and in vitro targeting ability of a glycol chitosan (GC) based nanogel have been validated. In the present study, its biodistribution in the mice is assessed, using near-infrared (NIR) fluorescence imaging as a tool to track the nanogel over time, after intravenous administration. Rapid whole body biodistribution of both Cy5.5 labeled GC nanogel and free polymer is found at early times. It remains widespreadly distributed in the body at least up to 6 h postinjection and its concentration then decreases drastically after 24 h. Nanogel blood circulation half-life lies around 2 h with the free linear GC polymer presenting lower blood clearance rate. After 24 h, the blood NIR fluorescence intensity associated with both samples decreases to insignificant values. NIR imaging of the organs shows that the nanogel had a body clearance time of ≈48 h, because at this time point a weak signal of NIR fluorescence is observed only in the kidneys. Hereupon it can be concluded that the engineered GC nanogel has a fairly long blood circulation time, suitable for biomedical applications, namely, drug delivery, simultaneously allowing efficient and quick body clearance.

  15. A mechanistic pharmacokinetic/pharmacodynamic model of factor D inhibition in cynomolgus monkeys by lampalizumab for the treatment of geographic atrophy.

    PubMed

    Le, Kha N; Gibiansky, Leonid; Good, Jeremy; Davancaze, Teresa; van Lookeren Campagne, Menno; Loyet, Kelly M; Morimoto, Alyssa; Jin, Jin; Damico-Beyer, Lisa A; Hanley, William D

    2015-11-01

    Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody against complement factor D (CFD), a rate-limiting enzyme in the activation and amplification of the alternative complement pathway (ACP), which is in phase III clinical trials for the treatment of geographic atrophy. Understanding of the pharmacokinetics, pharmacodynamics, and biodistribution of lampalizumab following intravitreal administration in the ocular compartments and systemic circulation is limited but crucial for selecting doses that provide optimal efficacy and safety. Here, we sought to construct a semimechanistic and integrated ocular-systemic pharmacokinetic-pharmacodynamic model of lampalizumab in the cynomolgus monkey to provide a quantitative understanding of the ocular and systemic disposition of lampalizumab and CFD inhibition. The model takes into account target-mediated drug disposition, target turnover, and drug distribution across ocular tissues and systemic circulation. Following intravitreal administration, lampalizumab achieves rapid equilibration across ocular tissues. Lampalizumab ocular elimination is relatively slow, with a τ1/2 of approximately 3 days, whereas systemic elimination is rapid, with a τ1/2 of 0.8 hours. Target-independent linear clearance is predominant in the eye, whereas target-mediated clearance is predominant in the systemic circulation. Systemic CFD synthesis was estimated to be high (7.8 mg/day); however, the amount of CFD entering the eye due to influx from the systemic circulation was small (<10%) compared with the lampalizumab dose and is thus expected to have an insignificant impact on the clinical dose-regimen decision. Our findings support the clinical use of intravitreal lampalizumab to achieve significant ocular ACP inhibition while maintaining low systemic exposure and minimal systemic ACP inhibition.

  16. Nanobarcoding for improved nanoparticle detection in nanomedical biodistribution studies

    NASA Astrophysics Data System (ADS)

    Eustaquio, Trisha

    Determination of the fate of nanoparticles (NPs) in a biological system, or NP biodistribution, is critical in evaluating a NP formulation for nanomedicine. Unlike small-molecule drugs, NPs impose unique challenges in the design of appropriate biodistribution studies due to their small size and subsequent detection signal. Current methods to determine NP biodistribution are greatly inadequate due to their limited detection thresholds. There is an overwhelming need for a sensitive and efficient imaging-based method that can (1) detect and measure small numbers of NPs of various types, ideally single NPs, (2) associate preferential NP uptake with histological cell type by preserving spatial information in samples, and (3) allow for relatively quick and accurate NP detection in in vitro (and possibly ex vivo) samples for comprehensive NP biodistribution studies. Herein, a novel method for improved NP detection is proposed, coined "nanobarcoding." Nanobarcoding utilizes a non-endogenous oligonucleotide, or "nanobarcode" (NB), conjugated to the NP surface to amplify the detection signal from a single NP via in situ polymerase chain reaction (ISPCR), and this signal amplification will facilitate rapid and precise detection of single NPs inside cells over large areas of sample such that more sophisticated studies can be performed on the NP-positive subpopulation. Moreover, nanobarcoding has the potential to be applied to the detection of more than one NP type to study the effects of physicochemical properties, targeting mechanisms, and route of entry on NP biodistribution. The nanobarcoding method was validated in vitro using NB-functionalized superparamagnetic iron oxide NPs (NB-SPIONs) as the model NP type for improved NP detection inside HeLa human cervical cancer cells, a cell line commonly used for ISPCR-mediated detection of human papilloma virus (HPV). Nanotoxicity effects of NB-SPIONs were also evaluated at the single-cell level using LEAP (Laser-Enabled Analysis

  17. Organophosphorus Insecticide Pharmacokinetics

    SciTech Connect

    Timchalk, Charles

    2010-01-01

    This chapter highlights a number of current and future applications of pharmacokinetics to assess organophosphate (OP) insecticide dosimetry, biological response and risk in humans exposed to these agents. Organophosphates represent a large family of pesticides where insecticidal as well as toxicological mode of action is associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetics entails the quantitative integration of physiological and metabolic processes associated with the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics. Pharmacokinetic studies provide important data on the amount of toxicant delivered to a target site as well as species-, age-, gender-specific and dose-dependent differences in biological response. These studies have been conducted with organophosphorus insecticides in multiple species, at various dose levels, and across different routes of exposure to understand their in vivo pharmacokinetics and how they contribute to the observed toxicological response. To access human exposure to organophosphorus insecticides, human pharmacokinetic studies have been conducted and used to develop biological monitoring strategies based on the quantitation of key metabolites in biological fluids. Pharmacokinetic studies with these insecticides are also useful to facilitate extrapolation of dosimetry and biological response from animals to humans and for the assessment of human health risk. In this regard, physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models are being utilized to assess risk and understand the toxicological implications of known or suspected exposures to various insecticides. In this chapter a number of examples are presented that illustrate the utility and limitation of pharmacokinetic studies to address human health concerns associated with organophosphorus insecticides.

  18. Efficacy, safety and pharmacokinetic of once-daily boosted saquinavir (1500/100 mg) together with 2 nucleos(t)ide reverse transcriptase inhibitors in real life: a multicentre prospective study

    PubMed Central

    2010-01-01

    Background Ritonavir-boosted saquinavir (SQVr) is nowadays regarded as an alternative antiretroviral drug probably due to several drawbacks, such as its high pill burden, twice daily dosing and the requirement of 200 mg ritonavir when given at the current standard 1000/100 mg bid dosing. Several once-daily SQVr dosing schemes have been studied with the 200 mg SQV old formulations, trying to overcome some of these disadvantages. SQV 500 mg strength tablets became available at the end of 2005, thus facilitating a once-daily regimen with fewer pills, although there is very limited experience with this formulation yet. Methods Prospective, multicentre study in which efficacy, safety and pharmacokinetics of a regimen of once-daily SQVr 1500/100 mg plus 2 NRTIs were evaluated under routine clinical care conditions in either antiretroviral-naïve patients or in those with no previous history of antiretroviral treatments and/or genotypic resistance tests suggesting SQV resistance. Plasma SQV trough levels were measured by HPLV-UV. Results Five hundred and fourteen caucasian patients were included (47.2% coinfected with hepatitis C and/or B virus; 7.8% with cirrhosis). Efficacy at 52 weeks (plasma RNA-HIV <50 copies/ml) was 67.7% (CI95: 63.6 - 71.7%) by intention-to-treat, and 92.2% (CI95: 89.8 - 94.6%) by on-treatment analysis. The reasons for failure were: dropout or loss to follow-up (18.4%), virological failure (7.8%), adverse events (3.1%), and other reasons (4.6%). The high rate of dropout may be explained by an enrollement and follow-up under routine clinical care condition, and a population with a significant number of drug users. The median SQV Cmin (n = 49) was 295 ng/ml (range, 53-2172). The only variable associated with virological failure in the multivariate analysis was adherence (OR: 3.36; CI95, 1.51-7.46, p = 0.003). Conclusions Our results suggests that SQVr (1500/100 mg) once-daily plus 2 NRTIs is an effective regimen, without severe clinical adverse

  19. Biodistribution of Small Interfering RNA at the Organ and Cellular Levels after Lipid Nanoparticle-mediated Delivery

    PubMed Central

    Shi, Bin; Keough, Ed; Matter, Andrea; Leander, Karen; Young, Stephanie; Carlini, Ed; Sachs, Alan B.; Tao, Weikang; Abrams, Marc; Howell, Bonnie; Sepp-Lorenzino, Laura

    2011-01-01

    Chemically stabilized small interfering RNA (siRNA) can be delivered systemically by intravenous injection of lipid nanoparticles (LNPs) in rodents and primates. The biodistribution and kinetics of LNP–siRNA delivery in mice at organ and cellular resolution have been studied using immunofluorescence (IF) staining and quantitative polymerase chain reaction (qPCR). At 0.5 and 2 hr post tail vein injection of Cy5-labeled siRNA encapsulated in LNP, the organ rank-order of siRNA levels is liver > spleen > kidney, with only negligible accumulation in duodenum, lung, heart, and brain. Similar conclusions were drawn by using qPCR to measure tissue siRNA levels as a secondary end point. siRNA levels in these tissues decreased by more than 10-fold after 24 hr. Within the liver, LNPs delivered siRNA to hepatocytes, Kupffer cells, and sinusoids in a time-dependent manner, as revealed by IF staining and signal quantitation methods established using OPERA/Columbus software. siRNA first accumulated in liver sinusoids and trafficked to hepatocytes by 2 hr post dose, corresponding to the onset of target mRNA silencing. Fluorescence in situ hybridization methods were used to detect both strands of siRNA in fixed tissues. Collectively, the authors have implemented a platform to evaluate biodistribution of siRNA across cell types and across tissues in vivo, with the objective of elucidating the pharmacokinetic and pharmacodynamic relationship to guide optimization of delivery vehicles. PMID:21804077

  20. Biodistribution of sodium borocaptate (BSH) for boron neutron capture therapy (BNCT) in an oral cancer model.

    PubMed

    Garabalino, Marcela A; Heber, Elisa M; Monti Hughes, Andrea; González, Sara J; Molinari, Ana J; Pozzi, Emiliano C C; Nievas, Susana; Itoiz, Maria E; Aromando, Romina F; Nigg, David W; Bauer, William; Trivillin, Verónica A; Schwint, Amanda E

    2013-08-01

    Boron neutron capture therapy (BNCT) is based on selective accumulation of ¹⁰B carriers in tumor followed by neutron irradiation. We previously proved the therapeutic success of BNCT mediated by the boron compounds boronophenylalanine and sodium decahydrodecaborate (GB-10) in the hamster cheek pouch oral cancer model. Based on the clinical relevance of the boron carrier sodium borocaptate (BSH) and the knowledge that the most effective way to optimize BNCT is to improve tumor boron targeting, the specific aim of this study was to perform biodistribution studies of BSH in the hamster cheek pouch oral cancer model and evaluate the feasibility of BNCT mediated by BSH at nuclear reactor RA-3. The general aim of these studies is to contribute to the knowledge of BNCT radiobiology and optimize BNCT for head and neck cancer. Sodium borocaptate (50 mg ¹⁰B/kg) was administered to tumor-bearing hamsters. Groups of 3-5 animals were killed humanely at nine time-points, 3-12 h post-administration. Samples of blood, tumor, precancerous pouch tissue, normal pouch tissue and other clinically relevant normal tissues were processed for boron measurement by optic emission spectroscopy. Tumor boron concentration peaked to therapeutically useful boron concentration values of 24-35 ppm. The boron concentration ratio tumor/normal pouch tissue ranged from 1.1 to 1.8. Pharmacokinetic curves showed that the optimum interval between BSH administration and neutron irradiation was 7-11 h. It is concluded that BNCT mediated by BSH at nuclear reactor RA-3 would be feasible.

  1. IN VITRO BIODISTRIBUTION OF SILVER NANOPARTICLES IN ISOLATED PERFUSED PORCINE SKIN FLAPS

    PubMed Central

    Leavens, Teresa L.; Monteiro-Riviere, Nancy A.; Inman, Alfred O.; Brooks, James D.; Oldenburg, Steven J.; Riviere, Jim E.

    2012-01-01

    Nanomaterials increasingly are playing a role in society for uses ranging from biomedicine to microelectronics; however pharmacokinetic studies, which will be necessary for human health risk assessments, are limited. Currently the most widely used nanoparticle in consumer products is silver (Ag). The objective of this study was to quantify the local biodistribution of two types of Ag nanoparticles, Ag-citrate and Ag-silica, in the isolated perfused porcine skin flap (IPPSF). IPPSFs were perfused for 4 h with 0.84 μg/ml Ag-citrate or 0.48 μg/ml Ag-silica followed by a 4-h perfusion with media only during a washout phase. Arterial and venous concentrations of Ag were measured in the media by ICP-OES. Venous concentrations of Ag for both types of nanoparticles were best fit with a two compartment model. The normalized volumes of distribution estimated from the noncompartmental analysis of the venous concentrations indicated distribution of Ag greater than the vascular space, however, because total Ag was measured, the extravascular distribution could be attributed to diffusion of Ag ions. The estimated clearance for both types of Ag nanoparticles was 1 ml/min, which was equal to the flap perfusion rate, indicating no detectable elimination of Ag from the system. By 4 hrs following infusion of the Ag nanoparticles, the recovery of Ag in the venous effluent was 90 ± 5.0% and 87 ± 22 % of the infused Ag for Ag-citrate and Ag-silica, respectively. PMID:22760951

  2. Uptake and biodistribution of rizatriptan to blood and brain following different routes of administration in rats.

    PubMed

    Wang, Chun; Quan, Li-Hui; Guo, Yi; Liu, Chun-Yu; Liao, Yong-Hong

    2007-06-07

    The objective of the present study was to investigate the biodistribution profiles of rizatriptan in the blood and brain of Wistar rats after peroral, subcutaneous, intranasal and intratracheal administration with a particular view to determining the applicability of inhalation delivery to achieve rapid and high availability of the drug in both blood and the brain. Following the intratracheal administration of the drug (4.0mg/kg) to the rats, the absolute bioavailability was found to be 91.2%, significantly higher than those from intranasal or peroral routes, and T(max) in plasma and brain was attained within 2 min, significantly shorter than the T(max) of intranasal ( approximately 10 min in both plasma and brain), subcutaneous (16.7 min in plasma and 22.5 min in brain) and peroral (30.0 min in plasma and 45.0 min in brain) administration. In addition, other pharmacokinetic parameters associated with rapid onset of action including AUC(plasma/brain) and C(max), of intratracheal instillated rizatriptan appeared also to be comparable or superior to those of other delivered routes. Although AUC(brain)/AUC(plasma) ratios after intranasal delivery (43.4%) differed significantly from the ratios shown after intratracheal instillation (23.2%), the AUC(brain 0-120 min) via the latter routes was slightly but not significantly higher than that from the former routes. The results in the present study indicated that pulmonary delivery of rizatriptan may achieve maximum plasma and brain concentrations significantly more rapidly compared with intranasal, subcutaneous and peroral administration and be a promising delivery method with extremely rapid onset of action in the pain relief of migraine.

  3. Synthesis, bioanalysis and biodistribution of photosensitizer conjugates for photodynamic therapy

    PubMed Central

    Denis, Tyler GSt; Hamblin, Michael R

    2013-01-01

    Photodynamic therapy (PDT) was discovered in 1900 by Raab, and has since emerged as a promising tool for treating diseases characterized by unwanted cells or hyperproliferating tissue (e.g., cancer or infectious disease). PDT consists of the light excitation of a photosensitizer (PS) in the presence of O2 to yield highly reactive oxygen species. In recent years, PDT has been improved by the synthesis of targeted bioconjugates between monoclonal antibodies and PS, and by investigating PS biodistribution and PD. Here, we provide a comprehensive review of major developments in PS-immunoconjugate-based PDT and the bioanalysis of these agents, with a specific emphasis on anticancer and antimicrobial PDT. PMID:23641699

  4. PET Imaging and Biodistribution of Silicon Quantum Dots in Mice

    PubMed Central

    2011-01-01

    Investigation of nanomaterial disposition and fate in the body is critical before such material can be translated into clinical application. Herein a new macrocyclic ligand−64Cu2+ complex was synthesized and used to label dextran-coated silicon quantum dots (QD), with an average hydrodynamic diameter of 15.1 ± 7.6 nm. The chelate showed exceptional stability, demonstrated by no loss radiolabel under a ligand competition reaction with EDTA. The QDs’ biodistribution in mice was quantitatively evaluated by in vivo positron emission tomography (PET) imaging and ex vivo gamma counting. Results showed that they were excreted via renal filtration shortly postinjection and also accumulated in the liver. PMID:21546997

  5. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    EPA Science Inventory

    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  6. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonyl-propylene carbonate) micelles for rapamycin delivery: in vitro characterization and biodistribution.

    PubMed

    Lu, Wenli; Li, Feng; Mahato, Ram I

    2011-06-01

    Our objective was to synthesize an amphiphilic diblock copolymer for micellar delivery of rapamycin. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonyl-propylene carbonate) (PEG-b-PBC) with different hydrophobic core lengths were synthesized from methoxy poly(ethylene glycol) and 2-methyl-2-benzoxycarbonyl-propylene carbonate through ring-opening polymerization using 1,8-diazabicycloundec-7-ene as a catalyst. The critical micelle concentration of PEG-b-PBC was around 10(-8) M and depends on the hydrophobic core length. Rapamycin was effectively incorporated into micelles and drug loading increased with increasing hydrophobic core length, with maximal drug loading of 10% (w/w, drug/polymer), drug loading efficiency of about 85%, and mean particle size of around 70 nm. The drug release profile was also dependent on the hydrophobic core length and the drug release from PEG(114) -b-PBC(30) micelles was the slowest. We also determined the toxicity of rapamycin micelles on insulinoma (INS-1E) β-cells and human islets. Encapsulation of rapamycin into PEG-b-PBC micelles reduced its toxicity. Biodistribution of rapamycin-loaded PEG-b-PBC micelles was determined after systemic administration into mice. Rapamycin-loaded PEG-b-PBC micelles showed little difference in pharmacokinetics and biodistribution characteristics in mice compared with rapamycin carrying nanosuspension. In conclusion, rapamycin formulated with PEG-b-PBC micelles showed significantly reduced toxicity on INS-1E β-cells and human islets, but had similar biodistribution profiles as those of nanosuspensions.

  7. Preparation and biodistribution of F-18 labeled FQNPe

    SciTech Connect

    Luo, H.; Beets, K.; McPherson, D.W.; Knapp, F.F. Jr.

    1996-05-01

    1-Azabicyclo[2.2.2]oct-3-yl {alpha}-(1-fluoropentan-5-yl)-{alpha}-hydroxy-{alpha}-phenylacetate (FQNPe) is an attractive candidate for the in vivo imaging of muscarinic receptors (mAChR) by PET. Initial studies with this new agent demonstrated a high binding affinity and ability to bind to regions of the brain containing mAChR. Fluorine-18 (F-18) labeling of racemic 1 was performed using X = tosyl, triflate, or mesylate group and a decay corrected radiolabeling yields of 2.6, 33, 75%, respectively, were obtained. F-18-3 in 11 % yield (decay corrected to beginning of synthesis). Initial biodistribution studies in rats (n=5) showed F-18-3 had high cerebral uptake of 0.72 ({plus_minus}0.26) and 0.83 ({plus_minus} 0.12) injected dose/gram at 15 and 30 minutes, respectively. The F-18 labeling and biodistribution study of the (-)-quinuclidinyl (-)-acetate and (-)-quinuclidinyl (+)-acetate isomers of FQNPe are currently being pursued.

  8. Macroscopic and microscopic biodistribution of intravenously administered iron oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Misra, Adwiteeya; Petryk, Alicia A.; Strawbridge, Rendall R.; Hoopes, P. Jack

    2015-03-01

    Iron oxide nanoparticles (IONP) are being developed for use as a cancer treatment. They have demonstrated efficacy when used either as a monotherapy or in conjunction with conventional chemotherapy and radiation. The success of IONP as a therapeutic tool depends on the delivery of a safe and controlled cytotoxic thermal dose to tumor tissue following activation with an alternating magnetic field (AMF). Prior to clinical approval, knowledge of IONP toxicity, biodistribution and physiological clearance is essential. This preliminary time-course study determines the acute toxicity and biodistribution of 110 nm dextran-coated IONP (iron) in mice, 7 days post systemic, at doses of 0.4, 0.6, and 1.0 mg Fe/ g mouse bodyweight. Acute toxicity, manifested as changes in the behavior of mice, was only observed temporarily at 1.0 mg Fe/ g mouse bodyweight, the highest dose administered. Regardless of dose, mass spectrometry and histological analysis demonstrated over 3 mg Fe/g tissue in organs within the reticuloendotheilial system (i.e. liver, spleen, and lymph nodes). Other organs (brain, heart, lungs, and kidney) had less than 0.5 mg Fe/g tissue with iron predominantly confined to the organ vasculature.

  9. Preparation and biodistribution of radiolabeled fullerene C60 nanocrystals

    NASA Astrophysics Data System (ADS)

    Nikolić, Nadežda; Vranješ-Ðurić, Sanja; Janković, Drina; Ðokić, Divna; Mirković, Marija; Bibić, Nataša; Trajković, Vladimir

    2009-09-01

    The present study describes for the first time a procedure for the radiolabeling of fullerene (C60) nanocrystals (nanoC60) with Na 125I, as well as the biodistribution of radiolabeled nanoC60 (125I-nanoC60). The solvent exchange method with tetrahydrofuran was used to make colloidal water suspensions of radiolabeled nanoC60 particles. The radiolabeling procedure with the addition of Na 125I to tetrahydrofuran during dissolution of C60 gave a higher radiochemical yield of radiolabeled nanoC60 particles in comparison to the second option, in which Na 125I was added after C60 was dissolved. Using photon correlation spectroscopy and transmission electron microscopy, 125I-nanoC60 particles were found to have a crystalline structure and a mean diameter of 200-250 nm. The 125I-nanoC60 had a particularly high affinity for human serum albumin, displaying 95% binding efficiency after 1 h. Biodistribution studies of 125I-nanoC60 in rats indicated significant differences in tissue accumulation of 125I-nanoC60 and the radioactive tracer Na 125I. The higher accumulation of radiolabeled nanoC60 was observed in liver and spleen, while accumulation in thyroid, stomach, lungs and intestines was significantly lower in comparison to Na 125I. In addition to being useful for testing the biological distribution of nanoC60, the described radiolabeling procedure might have possible applications in cancer radiotherapy.

  10. Radiosynthesis and pharmacokinetics of [18F]fluoroethyl bufalin in hepatocellular carcinoma-bearing mice

    PubMed Central

    Yang, Zhaoshuo; Liu, Jianhua; Huang, Qingqing; Zhang, Zhouji; Zhang, Jiawei; Pan, Yanjia; Yang, Yunke; Cheng, Dengfeng

    2017-01-01

    Purpose Bufalin, the main component of a Chinese traditional medicine chansu, shows convincing anticancer effects in a lot of tumor cell lines. However, its in vivo behavior is still unclear. This research aimed to evaluate how bufalin was dynamically absorbed after intravenous injection in animal models. We developed a radiosynthesis method of [18F]fluoroethyl bufalin to noninvasively evaluate the tissue biodistribution and pharmacokinetics in hepatocellular carcinoma-bearing mice. Methods [18F]fluoroethyl bufalin was synthesized with conjugation of 18F-CH2CH2OTs and bufalin. The radiochemical purity was proved by the radio-high-performance liquid chromatography (HPLC). The pharmacokinetic studies of [18F]fluoroethyl bufalin were then performed in Institute of Cancer Research (ICR) mice. Furthermore, the biodistribution and metabolism of [18F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing nude mice were studied in vivo by micro-positron emission tomography (micro-PET). Results The radiochemical purity (RCP) of [18F]fluoroethyl bufalin confirmed by radio-HPLC was 99%±0.18%, and [18F]fluoroethyl bufalin showed good in vitro and in vivo stabilities. Blood dynamics of [18F]fluoroethyl bufalin conformed to the two compartments in the ICR mice model. The pharmacokinetic parameters of [18F]fluoroethyl bufalin were calculated by DAS 2.0 software. The area under concentration–time curve (AUC0–t) and the values of clearance (CL) were 540.137 μg/L·min and 0.001 L/min/kg, respectively. The half-life of distribution (t1/2α) and half-life of elimination (t1/2β) were 0.693 and 510.223 min, respectively. Micro-PET imaging showed that [18F]fluoroethyl bufalin was quickly distributed via the blood circulation; the major tissue biodistribution of [18F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing mice was liver and bladder. Conclusion [18F]fluoroethyl bufalin was accumulated rapidly in the liver at an early time point (5 min) post injection (pi) and

  11. Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

    PubMed Central

    Smith, Alison; Manoli, Hugh; Jaw, Stacey; Frutoz, Kimberley; Epstein, Alan L.

    2016-01-01

    Biologics have emerged as a powerful and diverse class of molecular and cell-based therapies that are capable of replacing enzymes, editing genomes, targeting tumors, and more. As this complex array of tools arises a distinct set of challenges is rarely encountered in the development of small molecule therapies. Biotherapeutics tend to be big, bulky, polar molecules comprised of protein and/or nucleic acids. Compared to their small molecule counterparts, they are fragile, labile, and heterogeneous. Their biodistribution is often limited by hydrophobic barriers which often restrict their administration to either intravenous or subcutaneous entry routes. Additionally, their potential for immunogenicity has proven to be a challenge to developing safe and reliably efficacious drugs. Our discussion will emphasize immunogenicity in the context of therapeutic proteins, a well-known class of biologics. We set out to describe what is known and unknown about the mechanisms underlying the interplay between antigenicity and immune response and their effect on the safety, efficacy, pharmacokinetics, and pharmacodynamics of these therapeutic agents. PMID:27579329

  12. Computational approaches and metrics required for formulating biologically realistic nanomaterial pharmacokinetic models

    NASA Astrophysics Data System (ADS)

    Riviere, Jim E.; Scoglio, Caterina; Sahneh, Faryad D.; Monteiro-Riviere, Nancy A.

    2013-01-01

    The field of nanomaterial pharmacokinetics is in its infancy, with major advances largely restricted by a lack of biologically relevant metrics, fundamental differences between particles and small molecules of organic chemicals and drugs relative to biological processes involved in disposition, a scarcity of sufficiently rich and characterized in vivo data and a lack of computational approaches to integrating nanomaterial properties to biological endpoints. A central concept that links nanomaterial properties to biological disposition, in addition to their colloidal properties, is the tendency to form a biocorona which modulates biological interactions including cellular uptake and biodistribution. Pharmacokinetic models must take this crucial process into consideration to accurately predict in vivo disposition, especially when extrapolating from laboratory animals to humans since allometric principles may not be applicable. The dynamics of corona formation, which modulates biological interactions including cellular uptake and biodistribution, is thereby a crucial process involved in the rate and extent of biodisposition. The challenge will be to develop a quantitative metric that characterizes a nanoparticle's surface adsorption forces that are important for predicting biocorona dynamics. These types of integrative quantitative approaches discussed in this paper for the dynamics of corona formation must be developed before realistic engineered nanomaterial risk assessment can be accomplished.

  13. SYMBOLS IN PHARMACOKINETICS1

    PubMed Central

    Rowland, Malcolm; Tucker, Geoffrey

    1982-01-01

    To encourage uniformity in the presentation of pharmacokinetic data, a general nomenclature has been developed. The system has wide application. Flexibility is achieved through the use of general variables, constants, qualifying terms and subscripts. Yet, through the use of implied terms, the symbols describing many common variables and constants are simple.

  14. Lumping in pharmacokinetics.

    PubMed

    Brochot, Céline; Tóth, János; Bois, Frédéric Y

    2005-12-01

    Pharmacokinetic (PK) models simplify biological complexity by dividing the body into interconnected compartments. The time course of the chemical's amount (or concentration) in each compartment is then expressed as a system of ordinary differential equations. The complexity of the resulting system of equations can rapidly increase if a precise description of the organism is needed. However, difficulties arise when the PK model contains more variables and parameters than comfortable for mathematical and computational treatment. To overcome such difficulties, mathematical lumping methods are new and powerful tools. Such methods aim at reducing a differential system by aggregating several variables into one. Typically, the lumped model is still a differential equation system, whose variables are interpretable in terms of variables of the original system. In practice, the reduced model is usually required to satisfy some constraints. For example, it may be necessary to keep state variables of interest for prediction unlumped. To accommodate such constraints, constrained lumping methods have are also available. After presenting the theory, we study, here, through practical examples, the potential of such methods in toxico/pharmacokinetics. As a tutorial, we first simplify a 2-compartment pharmacokinetic model by symbolic lumping. We then explore the reduction of a 6-compartment physiologically based pharmacokinetic model for 1,3-butadiene with numerical constrained lumping. The lumping methods presented here can be easily automated, and are applicable to first-order ordinary differential equation systems.

  15. Liquid chromatography-tandem mass spectrometry evaluation of the pharmacokinetics of a diacid metabolite of norcantharidin loaded in folic acid-targeted liposomes in mice.

    PubMed

    Liu, Min-Chen; Ma, Xiao-Qiong; Xu, Yong; Peng, Li-Hua; Han, Min; Gao, Jian-Qing

    2016-02-05

    A previous study has reported diacid metabolite (DM) as the stable form of norcantharidin (NCTD), which is almost 100% metabolized to DM-NCTD. However, the unreliable pharmacokinetic characteristics of DM-NCTD could result in low bioavailability, hindering the clinical use of DM-NCTD in the treatment of diseases. A liposomal drug delivery system could overcome the shortcomings of DM-NCTD by improving the relative bioavailability (Fr), reducing drug toxicity, and increasing the therapeutic efficacy. However, there are no data concerning the pharmacokinetics of a DM-NCTD-loaded liposomal drug delivery system in animals, which is required for assessing its safety profile. Therefore, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of DM-NCTD in mouse plasma. Standard curves were linear (r=0.9966) over the range 10.0-1.00×10(4)ng/ml in mouse plasma with a lower limit of quantification (LLOQ) of 10ng/ml. This study successfully investigated the pharmacokinetics of DM-NCTD and DM-NCTD encapsulated in polyethylene glycol (PEG)-Liposomes (DM-NCTD/PEG-Liposome) or folic acid (FA)-PEG-Liposomes (DM-NCTD/FA-PEG-Liposome) in Kunming mice after a single intravenous dose of 2mg/kg. The plasma profile data of the three groups adhered to a two-compartment model. Compared with the DM-NCTD group, the Liposome groups had longer circulation times following intravenous administration in mice, and the Fr of DM-NCTD increased significantly (P<0.05). Furthermore, the area under the concentration-time curve (AUC) declined with an increase in the volume of distribution (Vd) from the PEG-Liposome to the FA-PEG-Liposome groups, which indicates a more efficient removal of the drug from the plasma of the FA-PEG-Liposome group. This result suggests a possible increased risk of DM-NCTD intoxication in normal tissues with FA-PEG-Liposomes. Based on this study, further investigation of the biodistribution of DM

  16. Amsacrine analog-loaded solid lipid nanoparticle to resolve insolubility for injection delivery: characterization and pharmacokinetics

    PubMed Central

    Fang, Yi-Ping; Chuang, Chih-Hung; Wu, Pao-Chu; Huang, Yaw-Bin; Tzeng, Cherng-Chyi; Chen, Yeh-Long; Liu, Ya-Ting; Tsai, Yi-Hung; Tsai, Ming-Jun

    2016-01-01

    Amsacrine analog is a novel chemotherapeutic agent that provides potentially broad antitumor activity when compared to traditional amsacrine. However, the major limitation of amsacrine analog is that it is highly lipophilic, making it nonconductive to intravenous administration. The aim of this study was to utilize solid lipid nanoparticles (SLN) to resolve the delivery problem and to investigate the biodistribution of amsacrine analog-loaded SLN. Physicochemical characterizations of SLN, including particle size, zeta potential, entrapment efficiency, and stability, were evaluated. In vitro release behavior was also measured by the dialysis method. In vivo pharmacokinetics and biodistribution behavior of amsacrine analog were investigated and incorporated with a non invasion in vivo imaging system to confirm the localization of SLN. The results showed that amsacrine analog-loaded SLN was 36.7 nm in particle size, 0.37 in polydispersity index, and 34.5±0.047 mV in zeta potential. More than 99% of amsacrine analog was successfully entrapped in the SLN. There were no significant differences in the physicochemical properties after storage at room temperature (25°C) for 1 month. Amsacrine analog-loaded SLN maintained good stability. An in vitro release study showed that amsacrine analog-loaded SLN sustained a release pattern and followed the zero equation. An in vivo pharmacokinetics study showed that amsacrine analog was rapidly distributed from the central compartment to the tissue compartments after intravenous delivery of amsacrine analog-loaded SLN. The biodistribution behavior demonstrated that amsacrine analog mainly accumulated in the lungs. Noninvasion in vivo imaging system images also confirmed that the drug distribution was predominantly localized in the lungs when IR-780-loaded SLN was used. PMID:27019595

  17. Toxicokinetics and biodistribution of dextran stabilized iron oxide nanoparticles in rats

    NASA Astrophysics Data System (ADS)

    Easo, S. L.; Neelima, R.; Mohanan, P. V.

    2015-07-01

    Dextran stabilized iron oxide nanoparticles (DIONPs) synthesized and characterized for hyperthermia application were tested for toxicokinetics and biodistribution in order to analyze the prospect of safety and biocompatibility of these particles for advanced use. Rats were administered a single dose of DIONPs at a concentration of 10 mg kg-1 by intravenous injection with a post-exposure period of 1, 7, 14 and 28 days. Liver, spleen, kidney, blood, urine and feces were examined for iron content by inductively coupled plasma atomic emission spectroscopy. At 24 h, greater amounts of nanoparticles were deposited in liver and spleen. Maximum absorption of iron in blood occurred at day 7 and excess iron appeared to be eliminated by liver, seemingly via biliary excretion. Serum hematology and biochemistry analysis revealed an overall lack of systemic toxicity due to metabolism of DIONPs. Additionally, pathological changes associated with repeated exposure to DIONPs with a post exposure period of 28 days were also assessed. Although no significant pathological alterations were seen in spleen or kidney, slight morphological deviations from normal were observed in liver. Further progression in the analysis of biological response towards DIONPs will be determined in long-term studies in the presence of an alternating magnetic field in the context of hyperthermia application.

  18. Testicular biodistribution of silica-gold nanoparticles after intramuscular injection in mice.

    PubMed

    Leclerc, Lara; Klein, Jean-Philippe; Forest, Valérie; Boudard, Delphine; Martini, Matteo; Pourchez, Jérémie; Blanchin, Marie-Geneviève; Cottier, Michèle

    2015-08-01

    With the continuing development of nanomaterials, the assessment of their potential impact on human health, and especially human reproductive toxicity, is a major issue. The testicular biodistribution of nanoparticles remains poorly studied. This study investigated whether gold-silica nanoparticles could be detected in mouse testes after intramuscular injection, with a particular focus on their ability to cross the blood-testis barrier. To that purpose, well-characterized 70-nm gold core-silica shell nanoparticles were used to ensure sensitive detection using high-resolution techniques. Testes were collected at different time points corresponding to spermatogenesis stages in mice. Transmission electron microscopy and confocal microscopy were used for nanoparticle detection, and nanoparticle quantification was performed by atomic emission spectroscopy. All these techniques showed that no particles were able to reach the testes. Results accorded with the normal histological appearance of testes even at 45 days post sacrifice. High-resolution techniques did not detect 70-nm silica-gold nanoparticles in mouse testes after intramuscular injection. These results are reassuring about the safety of nanoparticles with regard to male human reproduction, especially in the context of nanomedicine.

  19. The pharmacokinetics of meloxicam in vultures.

    PubMed

    Naidoo, V; Wolter, K; Cromarty, A D; Bartels, P; Bekker, L; McGaw, L; Taggart, M A; Cuthbert, R; Swan, G E

    2008-04-01

    Vulture populations across the Asian subcontinent have declined dramatically in the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian, Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based on extensive acute safety studies in the African White-backed vulture (Gyps africanus), which evaluated worst case scenarios of maximum intake based on a once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further support for the safety of meloxicam in this animal species. This article discusses the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combination with a short duration of effect in the studied species Gyps vultures shown in this study makes it unlikely that the drug could accumulate. This confirms the safety of repeated exposure to meloxicam in vultures of this genus.

  20. Altered biodistribution of radiopharmaceuticals used in bone scintigraphy.

    PubMed

    Zuckier, Lionel S; Martineau, Patrick

    2015-01-01

    Bone scintigraphy has remained a mainstay of clinical nuclear medicine for more than 4 decades. Extensive medical literature has developed surrounding the etiology and significance of alterations in distribution of bone radiopharmaceuticals. Altered biodistribution may be of a global nature, reflecting altered partition of radiopharmaceutical between bone and soft tissues, or more focal, reflecting regional abnormalities, including those related to bone or soft tissues. A third category of alterations in the distribution of bone radiopharmaceuticals is those due to errors and blunders, colloquially termed "artifactual" in the medical imaging literature. Being cognizant of these unexpected abnormalities, and understanding their etiology, will prepare the reader to more readily appreciate the significance of these findings when encountered in clinical practice.

  1. Ethanol Pharmacokinetics in Neonates and Infants

    PubMed Central

    Marek, Elizabeth; Kraft, Walter K.

    2014-01-01

    Introduction Ethanol has been used for years in neonatal and infant liquid medications, yet the pharmacokinetics, pharmacodynamics, and safety of ethanol in this vulnerable population have not been well characterized. The purpose of this review is to raise awareness of ethanol use as an excipient in neonatal and infant medications and to provide insight, based on the available evidence, into clearance rates of ethanol in babies. We also discuss ethanol pharmacokinetics in adults, theoretical pharmacokinetic changes in neonates and infants as it may apply to ethanol disposition, and case reports involving ethanol exposure in neonates and infants. Materials and methods This study was a narrative review in which relevant papers were selected using databases and scientific search engines such as PubMed with the key words ethanol, infant, and newborninfant. Results It remains unclear what ethanol exposure is safe for neonates and infants. The Food and Drug Administration and American Academy of Pediatrics have both taken action, by either setting limits of ethanol content in over-the-counter medications or by recommending restricted exposure to ethanol-containing pediatric formulations. Conclusions Until the short- and long-term health effects of chronic ethanol administration can be further characterized, ethanol-containing medications should be used with caution. PMID:25379066

  2. Pharmacokinetics of an Elevated Dosage of Micafungin in Premature Neonates

    PubMed Central

    Smith, P Brian; Walsh, Thomas J; Hope, William; Arrieta, Antonio; Takada, Akitsugu; Kovanda, Laura L; Kearns, Gregory L; Kaufman, David; Sawamoto, T; Buell, Donald N; Benjamin, Daniel K

    2009-01-01

    Background Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma micafungin concentrations than in older patients because of increased apparent plasma clearance of micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/day) dose of micafungin. Methods A repeated dose, open-label pharmacokinetic and safety trial of intravenous micafungin in 12 preterm neonates > 48 hours of life with suspected systemic infections. Neonates received 15 mg/kg/day of micafungin for 5 days. Blood samples were drawn relative to either the fourth or fifth dose. Systemic exposure was assessed by examination of the plasma area under the curve. Results The median birth weight and gestational age of the neonates were 775 g and 27 weeks, respectively. No adverse events related to micafungin were detected. The mean area under the curve and clearance for the cohort was 437.5 μg · h/mL and 0.575 mL/min/kg, respectively. The calculated clearance and volume of distribution for neonates was greater than that observed in older children and adults. Conclusions These data suggest that 15 mg/kg dosing in premature neonates corresponds to an exposure of approximately 5 mg/kg in adults. No adverse events related to micafungin were observed. PMID:19319022

  3. Modulation of the pharmacokinetics of zinc oxide nanoparticles and their fates in vivo

    NASA Astrophysics Data System (ADS)

    Paek, Hee-Jeong; Lee, Youn-Joung; Chung, Hea-Eun; Yoo, Nan-Hui; Lee, Jeong-A.; Kim, Mi-Kyung; Lee, Jong Kwon; Jeong, Jayoung; Choi, Soo-Jin

    2013-11-01

    In the present study, the effects of particle size (20 nm or 70 nm) and surface charge (negative or positive) on the pharmacokinetics, tissue distributions, and excretion of ZnO nanoparticles were examined following the administration of a single oral dose to rats. Pharmacokinetic profiles and biodistributions were not affected by particle size or gender. However, ZnO (-) particles were markedly more absorbed by the systemic circulation than ZnO (+) particles. Furthermore, the kinetic behaviors of ZnO nanoparticles differed from those of zinc ions, as evidenced by the low dissolution (13-14%) of ZnO nanoparticles under gastric conditions. The kidneys, liver, and lungs were found to be target organs. However, the major biological fate of ZnO nanoparticles in tissues was the ionic form, not the particulate form, and this was independent of exposure routes (oral and intravenous). Particle size was only found to affect excretion kinetics, and 20 nm particles were more rapidly eliminated. Most nanoparticles were excreted via the biliary and fecal routes, but a small amount of the nanoparticles was excreted via urine. The study shows that surface charge, rather than particle size or gender, is the critical modulator of the pharmacokinetic behavior of ZnO nanoparticles.In the present study, the effects of particle size (20 nm or 70 nm) and surface charge (negative or positive) on the pharmacokinetics, tissue distributions, and excretion of ZnO nanoparticles were examined following the administration of a single oral dose to rats. Pharmacokinetic profiles and biodistributions were not affected by particle size or gender. However, ZnO (-) particles were markedly more absorbed by the systemic circulation than ZnO (+) particles. Furthermore, the kinetic behaviors of ZnO nanoparticles differed from those of zinc ions, as evidenced by the low dissolution (13-14%) of ZnO nanoparticles under gastric conditions. The kidneys, liver, and lungs were found to be target organs. However

  4. Pharmacokinetic consequences of spaceflight

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Cintron, N. M.

    1991-01-01

    Spaceflight induces a wide range of physiological and biochemical changes, including disruption of gastrointestinal (GI) function, fluid and electrolyte balance, circulatory dynamics, and organ blood flow, as well as hormonal and metabolic perturbations. Any of these changes can influence the pharmacokinetics and pharmacodynamics of in-flight medication. That spaceflight may alter bioavailability was proposed when drugs prescribed to alleviate space motion sickness (SMS) had little therapeutic effect. Characterization of the pharmacokinetic and/or pharmacodynamic behavior of operationally critical medications is crucial for their effective use in flight; as a first step, we sought to determine whether drugs administered in space actually reach the site of action at concentrations sufficient to elicit the therapeutic response.

  5. Antifungal pharmacokinetics and pharmacodynamics.

    PubMed

    Lepak, Alexander J; Andes, David R

    2014-11-10

    Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class (polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy.

  6. Pharmacokinetics of levodopa.

    PubMed

    Contin, Manuela; Martinelli, Paolo

    2010-11-01

    This paper reviews the clinically relevant determinants of levodopa peripheral pharmacokinetics and main observed changes in the levodopa concentration-effect relationship with Parkinson's disease (PD) progression. Available clinically practical strategies to optimise levodopa pharmacokinetics and pharmacodynamics are briefly discussed. Levodopa shows particular pharmacokinetics including an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme L: -amino acid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both intestinal absorption and delivery to the brain, and the clinical effect include standardization of levodopa dosing with respect to meal times and a controlled dietary protein intake. Levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, to swings in the therapeutic response ("wearing-off" phenomena). "Wearing-off" phenomena can also be associated, at the more advanced disease stages, with a "negative", both parkinsonism-exacerbating and dyskinetic effect of levodopa at low, subtherapeutic plasma concentrations. Dyskinesias may also be related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone and simultaneous monitoring of the levodopa concentration-effect relationship may prove useful to disclose the underlying mechanism and in planning the correct management. Clinically practical strategies to optimise levodopa pharmacokinetics, and possibly its therapeutic response, include liquid drug solutions, controlled release formulations and the use of inhibitors

  7. Population pharmacokinetics of exenatide

    PubMed Central

    Mager, Donald E.

    2016-01-01

    Aim The aim of the present analysis was to develop a core population pharmacokinetic model for the pharmacokinetic properties of immediate‐release (IR) exenatide, which can be used in subsequent analyses of novel sustained‐release formulations. Methods Data from eight clinical trials, evaluating a wide range of doses and different administration routes, were available for analysis. All modelling and simulations were conducted using the nonlinear mixed‐effect modelling program NONMEM. External model validation was performed using data from the phase III clinical trials programme through standard visual predictive checks. Results The pharmacokinetics of IR exenatide was described by a two‐compartment model, and the absorption of subcutaneous exenatide was described with a sequential zero‐order rate constant followed by a saturable nonlinear absorption process. Drug elimination was characterized by two parallel routes (linear and nonlinear), with significant relationships between renal function and the linear elimination route, and between body weight and volume of distribution. For a subject with normal renal function, the linear clearance was estimated to be 5.06 l hr−1. The nonlinear elimination was quantified with a Michaelis–Menten constant (K m) of 567 pg ml−1 and a maximum rate of metabolism (V max) of 1.6 μg h−1. For subcutaneous administration, 37% of the subcutaneous dose is absorbed via the zero‐order process, and the remaining 63% via the nonlinear pathway. Conclusions The present analysis provides a comprehensive population pharmacokinetic model for exenatide, expanding the elimination process to include both linear and nonlinear components, providing a suitable platform for a broad range of concentrations and patient conditions that can be leveraged in future modelling efforts of sustained‐release exenatide formulations. PMID:27650681

  8. [Delta-9-tetrahydrocannabinol pharmacokinetics].

    PubMed

    Goullé, J-P; Saussereau, E; Lacroix, C

    2008-08-01

    Delta-9-tetrahydrocannabinol (Delta-9-THC) is the main psychoactive ingredient of cannabis. Smoking is currently most common use of cannabis. The present review focuses on the pharmacokinetics of THC. The variability of THC in plant material which has significantly increased in recent years leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. This variability of THC content has an important impact on drug pharmacokinetics and pharmacology. After smoking THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level near 160 ng/mL occurs approximately 10 min after inhalation. THC is eliminated quickly from plasma in a multiphasic manner and is widely distributed to tissues, which is responsible for its pharmacologic effects. Body fat then serves as a long-term storage site. This particular pharmacokinetics explains the noncorrelation between THC blood level and clinical effects as is observed for ethanol. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20 and 100% of parent, respectively). The elimination of THC and its many metabolites, mainly THC-COOH, occurs via the feces and urine for several weeks. Thus, to confirm abstinence, urine THC-COOH analysis would be a useful tool. A positive result could be checked by gas chromatography-mass spectrometry THC blood analysis, indicative of a recent cannabis exposure.

  9. Pharmacokinetics of grepafloxacin.

    PubMed

    Efthymiopoulos, C

    1997-12-01

    Grepafloxacin is a fluoroquinolone antibiotic which is rapidly absorbed in healthy volunteers following oral dosing. It reaches peak plasma levels around 2 h after administration, then declines bi-exponentially, with an extended half-life of around 12 h. Grepafloxacin is eliminated primarily through metabolism and is excreted mainly in the faeces. Renal clearance accounts for only 10-15% of the administered dose. Grepafloxacin plasma concentrations increase disproportionately with increasing doses, but this is unlikely to be of clinical significance over the range of therapeutic doses. The rate and extent of absorption are not affected by food or elevated intragastric pH. The pharmacokinetics of grepafloxacin are affected by gender, with these differences relating to variations in body weight. No effect of age on the pharmacokinetics of grepafloxacin was found. Renal impairment does not affect grepafloxacin pharmacokinetics, whereas peak plasma concentrations, areas under plasma concentration-time curves and renal excretion are increased in patients with hepatic impairment. Grepafloxacin can be co-administered with warfarin and theophylline, though reduction of the theophylline dose is necessary. Following oral administration, higher grepafloxacin concentrations are achieved in lung and genital tissues than in serum, indicating its potential in the treatment of respiratory and sexually transmitted diseases. In addition, it exceeds therapeutically effective levels in bile and gall-bladder tissues, and accumulates in polymorphonuclear leucocytes such that it may be useful against intracellular pathogens.

  10. Hand Safety

    MedlinePlus

    ... Hand Safety Fireworks Safety Lawnmower Safety Snowblower safety Pumpkin Carving Gardening Safety Turkey Carving Removing a Ring ... Hand Safety Fireworks Safety Lawnmower Safety Snowblower safety Pumpkin Carving Gardening Safety Turkey Carving Removing a Ring ...

  11. Computational Opioid Prescribing: A Novel Application of Clinical Pharmacokinetics

    PubMed Central

    Linares, Oscar A; Linares, Annemarie L

    2011-01-01

    We implemented a pharmacokinetics-based mathematical modeling technique using algebra to assist pre-scribers with point-of-care opioid dosing. We call this technique computational opioid prescribing (COP). Because population pharmacokinetic parameter values are needed to estimate drug dosing regimen designs for individual patients using COP, and those values are not readily available to prescribers because they exist scattered in the vast pharmacology literature, we estimated the population pharmacokinetic parameter values for 12 commonly prescribed opioids from various sources using the bootstrap resampling technique. Our results show that opioid dosing regimen design, evaluation, and modification is feasible using COP. We conclude that COP is a new technique for the quantitative assessment of opioid dosing regimen design evaluation and adjustment, which may help prescribers to manage acute and chronic pain at the point-of-care. Potential benefits include opioid dose optimization and minimization of adverse opioid drug events, leading to potential improvement in patient treatment outcomes and safety. PMID:21657860

  12. Biodistribution and acute toxicity of a nanofluid containing manganese iron oxide nanoparticles produced by a mechanochemical process

    PubMed Central

    Bellusci, Mariangela; La Barbera, Aurelio; Padella, Franco; Mancuso, Mariateresa; Pasquo, Alessandra; Grollino, Maria Giuseppa; Leter, Giorgio; Nardi, Elisa; Cremisini, Carlo; Giardullo, Paola; Pacchierotti, Francesca

    2014-01-01

    Superparamagnetic iron oxide nanoparticles are candidate contrast agents for magnetic resonance imaging and targeted drug delivery. Biodistribution and toxicity assessment are critical for the development of nanoparticle-based drugs, because of nanoparticle-enhanced biological reactivity. Here, we investigated the uptake, in vivo biodistribution, and in vitro and in vivo potential toxicity of manganese ferrite (MnFe2O4) nanoparticles, synthesized by an original high-yield, low-cost mechanochemical process. Cultures of murine Balb/3T3 fibroblasts were exposed for 24, 48, or 72 hours to increasing ferrofluid concentrations. Nanoparticle cellular uptake was assessed by flow-cytometry scatter-light measurements and microscopy imaging after Prussian blue staining; cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony-forming assays. After a single intravenous injection, in vivo nanoparticle biodistribution and clearance were evaluated in mice by Mn spectrophotometric determination and Prussian blue staining in the liver, kidneys, spleen, and brain at different posttreatment times up to 21 days. The same organs were analyzed for any possible histopathological change. The in vitro study demonstrated dose-dependent nanoparticle uptake and statistically significant cytotoxic effects from a concentration of 50 μg/mL for the MTT assay and 20 μg/mL for the colony-forming assay. Significant increases in Mn concentrations were detected in all analyzed organs, peaking at 6 hours after injection and then gradually declining. Clearance appeared complete at 7 days in the kidneys, spleen, and brain, whereas in the liver Mn levels remained statistically higher than in vehicle-treated mice up to 3 weeks postinjection. No evidence of irreversible histopathological damage to any of the tested organs was observed. A comparison of the lowest in vitro toxic concentration with the intravenously injected dose and the administered dose of

  13. Potentials of polymeric nanoparticle as drug carrier for cancer therapy: with a special reference to pharmacokinetic parameters.

    PubMed

    Mukherjee, Biswajit; Das, Surajit; Chakraborty, Samrat; Satapathy, Bhabani Sankar; Das, Pranab Jyoti; Mondal, Laboni; Hossain, Chowdhury Mobaswar; Dey, Niladri Shekhar; Chaudhury, Anumita

    2014-01-01

    Nanomaterials have made a significant impact on cancer therapeutics and an emergence of polymeric nanoparticle provides a unique platform for delivery of drug molecules of diverse nature. Nanoparticles can be targeted at the tumor cells due to enhanced permeability and retention effect. Moreover, nanoparticles can be grafted by various ligands on their surface to target the specific receptors overexpressed by cancer cells or angiogenic endothelial cells. These approaches ultimately result in longer circulation half-lives, improved drug pharmacokinetics, reduced side effects of therapeutically active substances and overcoming cancer chemo-resistance thereby enhancing the therapeutic efficacy of the treatment. This review article summarizes the recent efforts in cancer nanochemotherapeutics using polymeric nanoparticles with a special reference to their pharmacokinetic and biodistribution profiles, their role in reversing multidrug resistance in cancer and strategies of tumor targeting with them, along with the challenges in the field.

  14. Facile synthesis, silanization, and biodistribution of biocompatible quantum dots.

    PubMed

    Ma, Nan; Marshall, Ann F; Gambhir, Sanjiv S; Rao, Jianghong

    2010-07-19

    A facile strategy for the synthesis of silica-coated quantum dots (QDs) for in vivo imaging is reported. All the QD synthesis and silanization steps are conducted in water and methanol under mild conditions without involving any organometallic precursors or high-temperature, oxygen-free environments. The as-prepared silica-coated QDs possess high quantum yields and are extremely stable in mouse serum. In addition, the silanization method developed here produces nanoparticles with small sizes that are difficult to achieve via conventional silanization methods. The silica coating helps to prevent the exposure of the QD surface to the biological milieu and therefore increases the biocompatibility of QDs for in vivo applications. Interestingly, the silica-coated QDs exhibit a different biodistribution pattern from that of commercially available Invitrogen QD605 (carboxylate) with a similar size and emission wavelength. The Invitrogen QD605 exhibits predominant liver (57.2% injected dose (ID) g(-1)) and spleen (46.1% ID g(-1)) uptakes 30 min after intravenous injection, whereas the silica-coated QDs exhibit much lower liver (16.2% ID g(-1)) and spleen (3.67% ID g(-1)) uptakes but higher kidney uptake (8.82% ID g(-1)), blood retention (15.0% ID g(-1)), and partial renal clearance. Overall, this straightforward synthetic strategy paves the way for routine and customized synthesis of silica-coated QDs for biological use.

  15. EGFR-specific nanoprobe biodistribution in mouse models

    NASA Astrophysics Data System (ADS)

    Fashir, Samia A.; Castilho, Maiara L.; Hupman, Michael A.; Lee, Christopher L. D.; Raniero, Leandro J.; Alwayn, Ian; Hewitt, Kevin C.

    2015-06-01

    Nanotechnology offers a targeted approach to both imaging and treatment of cancer, the leading cause of death worldwide. Previous studies have found nanoparticles with a wide variety of coatings initiate an immune response leading to sequestration in the liver and spleen. In an effort to find a nanoparticle platform which does not elicit an immune response we created 43/44 nm gold or silver nanoparticles coated with biomolecules normally produced by the body, α-lipoic acid and the Epidermal Growth Factor (EGF), and have used mass spectroscopy to determine their biodistribution in mouse models, 24 hours following tail vein injection. Relative to controls, mouse EGF (mEGF) coated silver and gold nanoprobes are found at reduced levels in the liver and spleen. mEGF coated gold nanoprobes on the other hand do not appear to elicit any immune response, as they are found at background levels in these organs. As a result they should remain in circulation for longer and accumulate at high levels in tumors by the enhanced permeability retention (EPR) effect.

  16. Facile Synthesis, Silanization and Biodistribution of Biocompatible Quantum Dots

    PubMed Central

    Ma, Nan; Marshall, Ann F.; Gambhir, Sanjiv S.

    2016-01-01

    Here we report a facile strategy to the synthesis of silica-coated quantum dots (QDs) for in vivo imaging. All the QD synthesis and silanization steps are conducted in water and methanol under mild conditions without involving any organometallic precursors and high temperature, oxygen-free environments. The as-prepared silica-coated QDs possess high quantum yields and are extremely stable in mouse serum. In addition, the silanization method developed here produces nanoparticles (NPs) with small sizes that are difficult to achieve via conventional silanization methods. The silica coating helps to prevent the exposure of QD surface to the biological milieu and therefore increases the biocompatibility of QDs for in vivo applications. Interestingly, the silica-coated QDs exhibit a different biodistribution pattern than commercially available Invitrogen QD605 (carboxylate) with a similar size and emission wavelength. The Invitrogen QD605 exhibited predominant liver (57.2% ID g-1) and spleen (46.1% ID g-1) uptakes 30 mins after intravenous injection, whereas the silica-coated QDs exhibited much lower liver (16.2% ID g-1) and spleen (3.67% ID g-1) uptakes but higher kidney uptake (8.82% ID g-1), blood retention (15.0% ID g-1) and partial renal clearance. Overall, this straightforward synthetic strategy paves the way for routine and customized synthesis of silica-coated QDs for biological use. PMID:20564726

  17. Biodistribution of polyacrylic acid-coated iron oxide nanoparticles is associated with proinflammatory activation and liver toxicity.

    PubMed

    Couto, Diana; Freitas, Marisa; Costa, Vera Marisa; Chisté, Renan Campos; Almeida, Agostinho; Lopez-Quintela, M Arturo; Rivas, José; Freitas, Paulo; Silva, Paula; Carvalho, Félix; Fernandes, Eduarda

    2016-10-01

    Iron oxide nanoparticles (IONs) have physical and chemical properties that render them useful for several new biomedical applications. Still, so far, in vivo safety studies of IONs with coatings of biomedical interest are still scarce. The aim of this study, therefore, was to clarify the acute biological effects of polyacrylic acid (PAA)-coated IONs, by determining their biodistribution and their potential proinflammatory and toxic effects in CD-1 mice. The biodistribution of PAA-coated IONs in several organs (liver, spleen, kidneys, brain, heart, testes and lungs), the plasma cytokines, chemokine and aminotransferases levels, white blood cell count, oxidative stress parameters, adenosine triphosphate and histologic features of liver, spleen and kidneys were evaluated 24 h after a single acute (8, 20 or 50 mg kg(-1) ) intravenous administration of PAA-coated IONs in magnetite form. The obtained results showed that these IONs accumulate mainly in the liver and spleen and, to a lesser extent, in the lungs. Although our data showed that PAA-coated IONs do not cause severe organ damage, an inflammatory process was triggered in vivo, as evidenced by as evidenced by increased neutrophils and large lymphocytes in the differential blood count. Moreover, an accumulation of iron in macrophages of the liver and spleen was observed and hepatic lipid peroxidation was elicited, showing that the IONs are able to induce oxidative stress. The effects of these nanoparticles need to be further investigated regarding the mechanisms involved and the long-term consequences of intravenous administration of PAA-coated IONs. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Clinical pharmacokinetics of levetiracetam.

    PubMed

    Patsalos, Philip N

    2004-01-01

    Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 0.5-0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500-5000 mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24-48 hours. The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6-8, 6-8, 5-7 and 10-11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment. To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of

  19. New Fixed-Dose Artesunate-Mefloquine Formulation against Multidrug-Resistant Plasmodium falciparum in Adults: a Comparative Phase IIb Safety and Pharmacokinetic Study with Standard-Dose Nonfixed Artesunate plus Mefloquine▿

    PubMed Central

    Krudsood, S.; Looareesuwan, S.; Tangpukdee, N.; Wilairatana, P.; Phumratanaprapin, W.; Leowattana, W.; Chalermrut, K.; Ramanathan, S.; Navaratnam, V.; Olliaro, P.; Vaillant, M.; Kiechel, J. R.; Taylor, W. R. J.

    2010-01-01

    A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalized for 28 days with uncomplicated drug-resistant falciparum malaria. The patients (n = 25/arm) were treated with (i) two fixed-dose tablets (AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or (ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight. Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly (P ≤ 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (P ≤ 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). Fixed-nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. Fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement. PMID:20547795

  20. Biodistribution of X-ray iodinated contrast agent in nano-emulsions is controlled by the chemical nature of the oily core.

    PubMed

    Attia, Mohamed F; Anton, Nicolas; Chiper, Manuela; Akasov, Roman; Anton, Halina; Messaddeq, Nadia; Fournel, Sylvie; Klymchenko, Andrey S; Mély, Yves; Vandamme, Thierry F

    2014-10-28

    In this study, we investigated the role of the chemical nature of the oil droplet core of nano-emulsions used as contrast agents for X-ray imaging on their pharmacokinetics and biodistribution. To this end, we formulated PEGylated nano-emulsions with two iodinated oils (i.e., iodinated monoglyceride and iodinated castor oil) and compared them with another iodinated nano-emulsion based on iodinated vitamin E. By using dynamic light scattering and transmission electron microscopy, the three iodinated nano-emulsions were found to exhibit comparable morphologies, size, and surface composition. Furthermore, they were shown to be endowed with very high iodine concentration, which leads to stronger X-ray attenuation properties as compared to the commercial iodinated nano-emulsion Fenestra VC. The three nano-emulsions were i.v. administered in mice and monitored by microcomputed tomography (micro-CT). They showed high contrast enhancement in blood with similar half-life around 6 h but very different accumulation sites. While iodinated monoglycerides exhibited low accumulation in liver and spleen, high accumulation in spleen was observed for iodinated castor oil and in liver for vitamin E. These data clearly highlighted the important role of the oil composition of the nano-emulsion core to obtain strong X-ray contrast enhancement in specific targets such as liver, spleen, or only blood. These differences in biodistribution were partly attributed to differences in the uptake of the nanodroplets by the macrophages in vitro. Another key feature of these nano-emulsions is their long half-elimination time (several weeks), which offers sufficient retention for micro-CT imaging. This work paves the way for the design of nanoparticulate contrast agents for X-ray imaging of selected organs.

  1. [Pharmacokinetics of carbapenems].

    PubMed

    Suchánková, H; Rychlíčková, J; Urbánek, K

    2012-06-01

    Carbapenems, beta-lactam antibiotics, are ideal candidates for the treatment of serious nosocomial infections including sepsis for their exceptionally broad antibacterial spectrum and high efficiency. They are administered parenterally by intravenous infusion. Carbapenems penetrate well and rapidly into many different tissue compartments and the interstitial fluid. They are metabolized by renal dihydropeptidase-1. Therefore, imipenem must be co-administered with an inhibitor of dihydropeptidase-1. Other carbapenems registered in the Czech Republic (meropenem, ertapenem and doripenem) are more stable to this enzyme. Carbapenems are mainly eliminated via the kidneys and dose adjustment in patients with renal impairment is necessary. The elimination half-life of most carbapenems is around 1 hour with the exception of ertapenem, with 3.8-hour half-life, which allows its once-daily use. Carbapenems are a group of antibiotics with time-dependent effect. Their typical pharmaceutical property is a limited stability in solution after dilution. Administration in the prolonged infusion appears to be a convenient strategy to achieve higher efficiency. Pharmacokinetic parameters of carbapenems may vary individually, especially in critically ill patients and those treated by renal replacement therapy. Therefore, individualization of dosing regimens based on knowledge of pharmacokinetic parameters of individual patients may be useful.

  2. Drug metabolism: Comparison of biodistribution profile of holmium in three different compositions in healthy Wistar rats.

    PubMed

    Cerqueira-Coutinho, Cristal; Vidal, Lluis Pascual; Pinto, Suyene Rocha; Santos-Oliveira, Ralph

    2016-06-01

    Radioisotope holmium is a candidate to be used in cancer treatment and diagnosis. There are different holmium salts and they present distinct solubility and consequently different biodistribution profiles. In this work, we aimed to evaluate the biodistribution profiles of two holmium salts (chloride and sulfate) and holmium nanoparticles (oxide) through an in vivo biodistribution assay using animal model. Samples were labeled with technetium-99m and administered in Wistar rats by retro-orbital route. Holmium chloride is highly soluble in water and it was quickly filtered by the kidneys while holmium sulfate that presents lower solubility in water was mainly found in the liver and the spleen. However, both the salts showed a similar biodistribution profile. On the other hand, holmium oxide showed a very different biodistribution profile since it seemed to interact with all organs. Due to its particle size range (approximately 100nm) it was not intensively filtered by the kidneys being found in high quantities in many organs, for this reason its use as a nanoradiopharmaceutical could be promising in the oncology field.

  3. Peptide sequences mediating tropism to intact blood-brain barrier: an in vivo biodistribution study using phage display.

    PubMed

    Smith, Mathew W; Al-Jayyoussi, Ghaith; Gumbleton, Mark

    2012-11-01

    Peptide motifs that demonstrate tropism for the blood brain barrier (BBB) are of real translational value in developing innovative delivery strategies for biological brain targeted therapies. In vivo peptide-phage display affords peptide selection against the full complement of biological markers within the correct cellular macro- and micro-environments. Here a stringent in vivo biopanning protocol was employed in the rat aimed at identifying cyclic 7-mer peptide motifs that mediate tropism to brain microvasculature. Five rounds of biopanning identified 349 unique peptide motifs in the brain tissue gray matter compartment (microvasculature and parenchyma). While in general no consensus was evident linking peptide physico-chemical properties and brain tropism, peptides bearing c-SxTSSTx-c or c-xxxSSTx-c motifs were found to be present in high abundance. Based on amino acid frequency distribution of the 349 unique peptides sequences a theoretical 'idealized' peptide pattern, c-PP(S/P)SSST-c, could be derived. For the most abundant experimental peptide sequence found in brain tissue, c-SYTSSTM-c, an in vivo pharmacokinetic and whole body tissue biodistribution study was performed. Based upon tissue exposure data (i.e. tissue AUC((0-infinity))) the sequence c-SYTSSTM-c efficiently retargeted phage virions to the brain providing an approximate 5-fold greater (P<0.05) accumulation in brain over control phage; in all other organs no significant (P>0.05) difference in tissue tropism between c-SYTSSTM-c and control phages were evident. This peptide and more generally the peptide motifs, -SxTSSTx- or -xxxSSTx-, warrant further investigation as agents mediating sequence-dependent tropism to brain microvasculature potentially able to deliver biologic cargo to the CNS.

  4. Biodistribution of diphenhydramine in reproductive organs in an overdose case.

    PubMed

    Oritani, Shigeki; Michiue, Tomomi; Chen, Jian-Hua; Tani, Naoto; Ishikawa, Takaki

    2016-11-12

    Motion sickness medications such as Travelmin(®) prescribed in Japan include diphenhydramine (DPH), dyphylline, diphenidol, and/or caffeine. Herein, we report a patient who died due to rhabdomyolysis after ingesting a DPH containing motion sickness medication. A Japanese male in his 30 s reported missing after going out for a drive early in the morning was found dead in his car in the evening of the same day. An autopsy showed moderate edema, congestion, and several petechiae in both lungs. The brain was congested and edematous with no atherosclerosis of cerebral arteries. The prostate and both testes were slightly edematous. Gastric contents included approximately 15 mL of dark-brown fluid without tablets or food residue. Toxicological examination showed that blood DPH levels in all tissues were between 4.90 and 7.27 μg/mL, which represented toxic to lethal levels. DPH (μg/mL) levels were approximately 3-9 times higher in the prostate (73.42) and testes (left, 28.23; right, 30.09) than those in all regions of the brain (range 7.75-12.33). Blood dyphylline, diphenidol and caffeine levels in reproductive organs reached high, but not toxic levels. In conclusion, DPH, dyphylline, diphenidol, and caffeine levels were higher in reproductive organs such as the prostate and testes than in the central nervous system and heart. As we determined in this case, motion sickness medications might accumulate in reproductive organs. Thus, further examination of tissue biodistribution of DPH, dyphylline, diphenidol, and caffeine is necessary to assess their potential long-term effects in these sites.

  5. Principles of safety pharmacology.

    PubMed

    Pugsley, M K; Authier, S; Curtis, M J

    2008-08-01

    Safety Pharmacology is a rapidly developing discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment. The aim of Safety Pharmacology is to characterize the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects using continuously evolving methodology. Unlike toxicology, Safety Pharmacology includes within its remit a regulatory requirement to predict the risk of rare lethal events. This gives Safety Pharmacology its unique character. The key issues for Safety Pharmacology are detection of an adverse effect liability, projection of the data into safety margin calculation and finally clinical safety monitoring. This article sets out to explain the drivers for Safety Pharmacology so that the wider pharmacology community is better placed to understand the discipline. It concludes with a summary of principles that may help inform future resolution of unmet needs (especially establishing model validation for accurate risk assessment). Subsequent articles in this issue of the journal address specific aspects of Safety Pharmacology to explore the issues of model choice, the burden of proof and to highlight areas of intensive activity (such as testing for drug-induced rare event liability, and the challenge of testing the safety of so-called biologics (antibodies, gene therapy and so on.).

  6. Biodistribution of amino-functionalized diamond nanoparticles. In vivo studies based on 18F radionuclide emission.

    PubMed

    Rojas, Santiago; Gispert, Juan D; Martín, Roberto; Abad, Sergio; Menchón, Cristina; Pareto, Deborah; Víctor, Víctor M; Alvaro, Mercedes; García, Hermenegildo; Herance, J Raúl

    2011-07-26

    Nanoparticles have been proposed for several biomedical applications; however, in vivo biodistribution studies to confirm their potential are scarce. Nanodiamonds are carbon nanoparticles that have been recently proposed as a promising biomaterial. In this study, we labeled nanodiamonds with (18)F to study their in vivo biodistribution by positron emission tomography. Moreover, the impact on the biodistribution of their kinetic particle size and of the surfactant agents has been evaluated. Radiolabeled diamond nanoparticles accumulated mainly in the lung, spleen, and liver and were excreted into the urinary tract. The addition of surfactant agents did not lead to significant changes in this pattern, with the exception of a slight reduction in the urinary excretion rate. On the other hand, after filtration of the radiolabeled diamond nanoparticles to remove those with a larger kinetic size, the uptake in the lung and spleen was completely inhibited and significantly reduced in the liver.

  7. The pharmacokinetics and pharmacodynamics of iron preparations.

    PubMed

    Geisser, Peter; Burckhardt, Susanna

    2011-01-04

    Standard approaches are not appropriate when assessing pharmacokinetics of iron supplements due to the ubiquity of endogenous iron, its compartmentalized sites of action, and the complexity of the iron metabolism. The primary site of action of iron is the erythrocyte, and, in contrast to conventional drugs, no drug-receptor interaction takes place. Notably, the process of erythropoiesis, i.e., formation of new erythrocytes, takes 3-4 weeks. Accordingly, serum iron concentration and area under the curve (AUC) are clinically irrelevant for assessing iron utilization. Iron can be administered intravenously in the form of polynuclear iron(III)-hydroxide complexes with carbohydrate ligands or orally as iron(II) (ferrous) salts or iron(III) (ferric) complexes. Several approaches have been employed to study the pharmacodynamics of iron after oral administration. Quantification of iron uptake from radiolabeled preparations by the whole body or the erythrocytes is optimal, but alternatively total iron transfer can be calculated based on known elimination rates and the intrinsic reactivity of individual preparations. Degradation kinetics, and thus the safety, of parenteral iron preparations are directly related to the molecular weight and the stability of the complex. High oral iron doses or rapid release of iron from intravenous iron preparations can saturate the iron transport system, resulting in oxidative stress with adverse clinical and subclinical consequences. Appropriate pharmacokinetics and pharmacodynamics analyses will greatly assist our understanding of the likely contribution of novel preparations to the management of anemia.

  8. Pharmacokinetic study of Noni fruit extract.

    PubMed

    Issell, Brian F; Franke, Adrian; Fielding, Robert M

    2008-01-01

    Many different products containing Noni (Morinda citrifolia) fruit extracts are sold throughout the world for health restoration and maintenance. Despite a large business enterprise fueling Noni's popularity, there is a lack of standardization of products and no scientific evidence of Noni's clinical efficacy and safety. There is also no evidence to indicate an optimal therapeutic dose or dosing interval. In an initial volunteer, scopoletin was identified as a bioactive marker of Noni exposure and a candidate for product standardization and pharmacokinetic studies. Subsequently, capsules containing the whole freeze-dried fruit of Noni were orally administered to nine healthy volunteers (3 per group) at doses of 1,500 mg (3 × 500 mg), 2,000 mg (4 × 500 mg) and 2,500 mg (5 × 500 mg). Plasma and urine samples were obtained from each subject prior to dosing and at 0.5, 1, 2, 4 and 8 h after dosing. Concentrations of scopoletin were determined by HPLC with PDA (scanning at 200-700 nm) and MS detection. Scopoletin rapidly enters the plasma after Noni ingestion, maintaining levels in the range of 0.5 to 5 ng/mL for at least 8 h after dosing. Scopoletin bioavailability appears to be low, with significant intersubject variability. We conclude that scopoletin can be used as a relatively specific marker of Noni exposure in the blood and particularly in urine when its pharmacokinetics is considered appropriately.

  9. Biodistribution of a novel antiestrogen (Analog II) in the mouse and rat.

    PubMed

    Griffin, M T; Pento, J T; Magarian, R A; Mousissian, G K; Basmadjian, G P

    1990-01-01

    The biodistribution of a novel antiestrogen Analog II was determined in the mouse and rat. The tritiated product, [3H]-Analog II was prepared by New England Nuclear and was purified by preparative chromatography using silica gel and petroleum ether/methylene chloride (80:20). The fat tissue had the highest uptake due to the hydrophobic nature of Analog II. The second highest uptake was in the mouse uterine tissue which was greater than that observed in the rat. The differences in biodistribution between the mouse and rat may partially explain the differences in biological activity of Analog II previously observed in these two animal species.

  10. A fluorescent imaging method for analyzing the biodistribution of therapeutic monoclonal antibodies that can distinguish intact antibodies from their breakdown products

    PubMed Central

    Suzuki, Takuo; Miyazaki, Chihiro; Ishii-Watabe, Akiko; Tada, Minoru; Sakai-Kato, Kumiko; Kawanishi, Toru; Kawasaki, Nana

    2015-01-01

    Many monoclonal antibodies have been developed for therapy over the last 2 decades. In the development of therapeutic antibodies, the preclinical assessment of an antibody's biodistribution is important for the prediction of the antibody's efficacy and safety. For imaging analyses of such biodistributions, radioisotope (RI) labeling and fluorescence labeling methods are typically used, but the resulting data are limited because these methods cannot distinguish breakdown products from intact antibodies. To resolve this problem, we developed a novel method using fluorescent resonance energy transfer (FRET)-type labeling and a spectral unmixing tool. With FRET-type labeling (labeling with 2 species of fluorophore), different fluorescence properties of labeled intact antibodies and their breakdown products (the hydrolyzed/digested type of breakdown products) are made visible. With the spectral unmixing tool, the fluorescence of a solution containing the intact antibody and its breakdown products could be unmixed in proportion to their contents. Moreover, when labeled antibodies that targeted either human epidermal growth factor receptor-2 or epidermal growth factor receptor were injected into nude mice implanted subcutaneously with tumor cells, the accumulation of the injected labeled antibodies and their breakdown products in the tumor could be separately analyzed by both whole-mouse imaging and a tumor homogenate analysis. These results suggest that our method using FRET-type labeling and a spectral unmixing tool could be useful in distinguishing breakdown products from intact antibodies. PMID:25891896

  11. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients.

    PubMed

    Wermeling, Daniel; Drass, Michael; Ellis, David; Mayo, Martha; McGuire, Dawn; O'Connell, Damian; Hale, Victoria; Chao, Stella

    2003-06-01

    The pharmacokinetics and pharmacodynamics of ziconotide were assessed over a 48-hour period following intrathecal (i.t.) administration (1, 5, 7.5, or 10 micrograms) to 22 patients with chronic, nonmalignant pain. Plasma and cerebrospinal fluid (CSF) samples were obtained over a 24-hour period. Analgesic efficacy was monitored using Visual Analog Scale of Pain Intensity (VASPI) and Category Pain Relief Scores (CPRS) measurements. Pharmacokinetic (PK) parameters were calculated by noncompartmental methods. Plasma ziconotide data were insufficient for PK calculations. In CSF, the median half-life of ziconotide was 4.5 hours. The median CSF clearance and volume of distribution were 0.26 mL/min and 99 mL, respectively. CSF pharmacokinetics of ziconotide were linear, based on cumulative exposure and peak CSF concentrations. A dose-related analgesia was observed. Pharmacokinetic-pharmacodynamic efficacy and safety analyses showed that higher CSF ziconotide concentrations were generally associated with analgesia and increased incidence of nervous system adverse events following a 1-hour i.t. infusion.

  12. Absence of pharmacokinetic interaction between intravenous peramivir and oral oseltamivir or rimantadine in humans.

    PubMed

    Atiee, George; Lasseter, Kenneth; Baughman, Sharon; McCullough, Amy; Collis, Phil; Hollister, Alan; Hernandez, Jaime

    2012-09-01

    Peramivir, an intravenously administered neuraminidase inhibitor, may be used concomitantly with other influenza antivirals. Two studies were conducted to assess the potential for pharmacokinetic interactions of peramivir when coadministered with oseltamivir or rimantadine. Twenty-one healthy subjects were enrolled in each randomized, open-label, crossover study, and they received 1 intravenous dose of peramivir (600 mg), 1 oral dose of oseltamivir (75 mg) or rimantadine (100 mg), or a combination of peramivir with oseltamivir or rimantadine. Assessment of the 90% confidence interval for the geometric mean ratio of peramivir and oseltamivir carboxylate or rimantadine pharmacokinetic parameters showed no effect of oseltamivir or rimantadine on the pharmacokinetics of peramivir and no effect of peramivir on the pharmacokinetics of oseltamivir carboxylate or rimantadine. The drugs were well tolerated. These results suggest no reason to expect an effect of concomitant administration of oseltamivir or rimantadine on the safety profile of peramivir in patients with influenza.

  13. Pharmacokinetics and Pharmacodynamics in Space

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi; Cintron, Nitza M.

    1990-01-01

    The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic

  14. Preparation of Conjugated Linoleic Acid Microemulsions and their Biodistribution.

    PubMed

    Kishita, Kazuaki; Ibaraki, Kayo; Itakura, Shoko; Yamasaki, Yumi; Nishikata, Naoko; Yamamoto, Kenji; Shimizu, Masataka; Nishiyama, Kazuo; Yamasaki, Masao

    2016-01-01

    Conjugated linoleic acid (CLA) has several beneficial biological properties. Specifically, trans10, cis12-CLA, one of the CLA isomers, has strong physiologic activity against cancer and obesity. However, compared with cis9, trans11-CLA, a naturally occurring CLA isomer, trans10, cis12-CLA tends to be easily metabolized. Therefore, to make efficient use of its biological properties, it is necessary to overcome the rapid clearance of trans10, cis12-CLA from the blood. Here, we employed premix membrane emulsification to prepare two oil-in-water CLA microemulsions (CLA-ME), 100 nm CLA-ME and 200 nm CLA-ME, and investigated their pharmacokinetics in a mouse model. We report that 100 nm CLA-ME contributed to the concentration of blood CLA for longer than 200 nm CLA-ME, indicating that small CLA microparticles were more suitable for maintaining blood trans10, cis12-CLA levels in vivo. However, both CLA-ME could be hardly detected in blood and other tissues 24 h after administration, suggesting that additional strategies for prolonging CLA-ME half-life are required.

  15. Pharmacokinetic study of sulbactomax.

    PubMed

    Payasi, Anurag; Chaudhary, Manu; Gupta, Ankush; Dwivedi, Vivek Kumar; Bhatnagar, Anuj

    2010-08-01

    We have evaluated pharmacokinetics of a fixed dose combination (FDC) of ceftriaxone and sulbactam (2:1) or sulbactomax in eight healthy volunteers. A 1.5 g dose of sulbactomax, 1 g dose of ceftriaxone and 0.5 g sulbactam were given intravenously in a balanced two-ways cross-over study. Serially collected plasma sample was analyzed for ceftriaxone and sulbactam by high performance liquid chromatography (HPLC). The mean peaks of ceftriaxone and sulbactam concentrations in plasma were 152.06+/-6.65 microg/ml and 21.32+/-1.80 microg/ml, respectively and plasma half-lives for ceftriaxone and sulbactam were 5.2+/-0.35 hr and 0.94+/-0.038 hr, respectively. The AUC0-24 for ceftriaxone and sulbactam was 760.16+/-27.68 microg.hr/ml and 20.74+/-2.34 microg.hr/ml, respectively, with elimination rate constant of 0.133+/-0.009 hr(-1) and 0.732+/-0.029 hr(-1), respectively. The kinetics of ceftriaxone and sulbactum did not change in combination as compared to the alone treatment. Also, concentration of the ceftriaxone after 24 hr is higher than the minimum inhibitory concentration (MIC) of the most of the gram positive and gram negative bacteria indicating that one dose in a day is sufficient to treat the disease caused by these organisms.

  16. Population pharmacokinetics of daptomycin.

    PubMed

    Dvorchik, Barry; Arbeit, Robert D; Chung, Julia; Liu, Susan; Knebel, William; Kastrissios, Helen

    2004-08-01

    Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81 liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex and therefore this effect is not considered clinically meaningful. The relationship with body temperature should be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic. The volume of distribution of the peripheral compartment (V2) and intercompartmental clearance (Q) were linearly related to body weight. V2 increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V1. This analysis supports the dosing of daptomycin on a milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis.

  17. Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study

    PubMed Central

    Coriat, Romain; Faivre, Sandrine J; Mir, Olivier; Dreyer, Chantal; Ropert, Stanislas; Bouattour, Mohammed; Desjardins, Robert; Goldwasser, François; Raymond, Eric

    2016-01-01

    Background DTS-108 is a hydrosoluble prodrug, where the SN-38 moiety is covalently linked to a 20-amino acid vector peptide by a specific esterase-sensitive cross-linker, releasing 7-ethyl-10-hydroxycampthotecin (SN-38) by esterase bond cleavage. Methods The pharmacokinetics of DTS-108, adverse events graded according to NCI-CTCv3.1, dose-limiting toxicities at cycle 1, the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of intravenous DTS-108 (1–2 hours) every 2 weeks were evaluated in a first-in-human Phase I study in patients with advanced/metastatic carcinomas, according to an accelerated dose escalation design. SN-38 and SN-38 glucuronide (SN-38G) levels were evaluated with fluorescence high-performance liquid chromatography (HPLC) test, then liquid chromatography–tandem mass spectrometry (LC/MS/MS) methods. Results Forty-two patients received DTS-108 across 14 dosing cohorts (range 3–416 mg/m2). At 416 mg/m2, three out of six patients had grade 4 neutropenia thereby defining the MTD and the RP2D at 313 mg/m2. Fluorescence HPLC was inaccurate to quantify DTS-108 and its metabolites (SN-38 and SN-38G). New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At a dose of 313 mg/m2, mean DTS-108, SN-38, and SN-38G area under the plasma concentration–time curve to infinity (coefficients of variation %) were 439,293 (24%), 1,992 (34%), and 4,538 (46%) h·ng/mL. Stable disease (according to Response Evaluation Criteria in Solid Tumors) was observed in nine patients. Conclusion Assessing SN-38 concentration using fluorescence HPLC is questionable since this method failed to monitor dose escalation of DTS-108, a new topoisomerase I inhibitor, due to ex vivo degradation. LC/MS/MS methods were consistent in evaluating SN-38 exposures allowing drug monitoring. The maximum tolerated dose of DTS-108 was 416 mg/m2. The RP2D for intravenous DTS-108 was 313 mg/m2 every 2 weeks in patients with advanced/metastatic solid

  18. Biodistribution and Dosimetry of Free 211At, 125I− and 131I− in Rats

    PubMed Central

    Rudqvist, Nils; Forssell-Aronsson, Eva

    2013-01-01

    Abstract 131I is widely used for therapy in the clinic and 125I and 131I, and increasingly 211At, are often used in experimental studies. It is important to know the biodistribution and dosimetry for these radionuclides to determine potential risk organs when using radiopharmaceuticals containing these radionuclides. The purpose of this study was to investigate the biodistribution of 125I−, 131I−, and free 211At in rats and to determine absorbed doses to various organs and tissues. Male Sprague Dawley rats were injected simultaneously with 0.1–0.3 MBq 125I− and 0.1–0.3 MBq 131I−, or 0.05–0.2 MBq 211At and sacrificed 1 hour to 7 days after injection. The activities and activity concentrations in organs and tissues were determined and mean absorbed doses were calculated. The biodistribution of 125I− was similar to that of 131I− but the biodistribution of free 211At was different compared to 125I− and 131I−. The activity concentration of radioiodine was higher compared with 211At in the thyroid and lower in all extrathyroidal tissues. The mean absorbed dose per unit injected activity was highest to the thyroid. 131I gave the highest absorbed dose to the thyroid, and 211At gave the highest absorbed dose to all other tissues studied. PMID:23789969

  19. Effects of concurrent drug therapy on technetium /sup 99m/Tc gluceptate biodistribution

    SciTech Connect

    Hinkle, G.H.; Basmadjian, G.P.; Peek, C.; Barker, K.K.; Ice, R.D.

    1982-11-01

    Drug interactions with /sup 99m/Tc gluceptate resulting in altered biodistribution were studied using chart review and animal tests. Charts of nine patients who had abnormal gallbladder uptake of technetium /sup 99m/Tc gluceptate during a two-year period were reviewed to obtain data such as concurrent drug therapy, primary diagnosis, and laboratory values. Adult New Zealand white rabbits were then used for testing the biodistribution of technetium /sup 99m/Tc gluceptate when administered concurrently with possibly interacting drugs identified in the chart review--penicillamine, penicillin G potassium, penicillin V potassium, acetaminophen, and trimethoprim-sulfamethoxazole. Chart review revealed no conclusive patterns of altered biodistribution associated with other factors. The data did suggest the possibility that the five drugs listed above might cause increased hepatobiliary clearance of the radiopharmaceutical. Animal tests showed that i.v. penicillamine caused substantial distribution of radioactivity into the gallbladder and small bowel. Minimally increased gallbladder radioactivity occurred when oral acetaminophen and trimethoprim-sulfamethoxazole were administered concurrently. Oral and i.v. penicillins did not increase gallbladder activity. Penicillamine may cause substantial alteration of the biodistribution of technetium /sup 99m/Tc gluceptate.

  20. Biodistribution and dosimetry of free 211At, 125I- and 131I- in rats.

    PubMed

    Spetz, Johan; Rudqvist, Nils; Forssell-Aronsson, Eva

    2013-11-01

    131I is widely used for therapy in the clinic and 125I and 131I, and increasingly 211At, are often used in experimental studies. It is important to know the biodistribution and dosimetry for these radionuclides to determine potential risk organs when using radiopharmaceuticals containing these radionuclides. The purpose of this study was to investigate the biodistribution of 125I-, 131I-, and free 211At in rats and to determine absorbed doses to various organs and tissues. Male Sprague Dawley rats were injected simultaneously with 0.1-0.3 MBq 125I- and 0.1-0.3 MBq 131I-, or 0.05-0.2 MBq 211At and sacrificed 1 hour to 7 days after injection. The activities and activity concentrations in organs and tissues were determined and mean absorbed doses were calculated. The biodistribution of 125I- was similar to that of 131I- but the biodistribution of free 211At was different compared to 125I- and 131I-. The activity concentration of radioiodine was higher compared with 211At in the thyroid and lower in all extrathyroidal tissues. The mean absorbed dose per unit injected activity was highest to the thyroid. 131I gave the highest absorbed dose to the thyroid, and 211At gave the highest absorbed dose to all other tissues studied.

  1. Gold nanoparticle biodistribution: Cell, blood, and tissue interactions as a function of nanoparticle surface properties

    NASA Astrophysics Data System (ADS)

    Shah, Neha B.

    Intravenously injected gold nanoparticles (GNPs) hold a great promise for clinical diagnostic and therapeutic applications. A critical issue in their implementation is incomplete mechanistic understanding of their in vivo biodistribution. Two major limitations in optimizing the biodistribution of NPs are: (1) achieving the highest accumulation at the disease site, and (2) avoiding accumulation in healthy organs including liver and spleen. To overcome these limitations, the interactions of GNPs with biological system must be better understood. The research described in this dissertation sought to advance the field of GNP in vivo biodistribution by elucidating the effects of GNP surface properties such as surface charge, ligand, and polyethylene glycol (PEG) coverage. It was shown that the interactions of GNPs with cells and tissues were a function of their surface properties. A Confocal Raman Microscopy based technique was developed to study GNPs interactions with cells in vitro in fast, label-free, and non-invasive way. It was further shown that GNP surface properties strongly influence their blood circulation time in vivo. It was demonstrated that GNPs interact with circulating blood cells including platelets and monocytes, which may play a role in their clearance from blood stream. Most of the injected dose was shown to accumulate in liver and spleen; however, both organs displayed a different mechanism of uptake and distribution of GNPs. Long-term biodistribution studies further suggested that GNPs were still found in liver and spleen after 4 months, but GNPs showed clearance from liver overtime.

  2. Biodistribution of the multidentate hydroxypyridinonate ligand [(14) C]-3,4,3-LI(1,2-HOPO), a potent actinide decorporation agent.

    PubMed

    Choi, Taylor A; Endsley, Aaron N; Bunin, Deborah I; Colas, Christophe; An, Dahlia D; Morales-Rivera, Joel A; Villalobos, Jonathan A; Shinn, Walter M; Dabbs, Jack E; Chang, Polly Y; Abergel, Rebecca J

    2015-05-01

    The pharmacokinetics and biodistribution of the (14) C-labeled actinide decorporation agent 3,4,3-LI(1,2-HOPO) were investigated in young adult Swiss Webster mice and Sprague Dawley rats, after intravenous, intraperitoneal, and oral dose administration. In all routes investigated, the radiolabeled compound was rapidly distributed to various tissues and organs of the body. In mice, the 24 h fecal elimination profiles suggested that the biliary route is the predominant route of elimination. In contrast, lower fecal excretion levels were observed in rats. Tissue uptake and retention of the compound did not differ significantly between sexes although some differences were observed in the excretion patterns over time. The male mice eliminated a greater percentage of (14) C through the renal pathway than the female mice after receiving an intravenous or intraperitoneal dose, while the opposite trend was seen in rats that received an intravenous dose. Metabolite profiling performed on selected rat samples demonstrated that a putative major metabolite of [(14) C]-3,4,3-LI(1,2-HOPO) is formed, accounting for approximately 10% of an administered oral dose. Finally, to improve its oral bioavailability, 3,4,3-LI(1,2-HOPO) was coformulated with a proprietary permeability enhancer, leading to a notable increase in oral bioavailability of the compound.

  3. Radioprotective cerium oxide nanoparticles: Molecular imaging investigations of conps' pharmacokinetics, efficacy, and mechanisms of action

    NASA Astrophysics Data System (ADS)

    McDonagh, Philip Reed Wills, III

    Cerium oxide nanoparticles (CONPs) are being investigated for several anti-oxidant applications in medicine. One of their most promising applications is as a radiopr