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Sample records for drug-drug interaction study

  1. Impact of Participatory Design for Drug-Drug Interaction Alerts. A Comparison Study Between Two Interfaces.

    PubMed

    Luna, Daniel; Otero, Carlos; Risk, Marcelo; Stanziola, Enrique; González Bernaldo de Quirós, Fernán

    2016-01-01

    Decision support systems for alert drug-drug interactions have been shown as valid strategy to reduce medical error. Even so the use of these systems has not been as expected, probably due to the lack of a suitable design. This study compares two interfaces, one of them developed using participatory design techniques (based on user centered design processes). This work showed that the use of these techniques improves satisfaction, effectiveness and efficiency in an alert system for drug-drug interactions, a fact that was evident in specific situations such as the decrease of errors to meet the specified task, the time, the workload optimization and users overall satisfaction with the system.

  2. Clopidogrel-Paclitaxel Drug-Drug Interaction: A Pharmacoepidemiologic Study.

    PubMed

    Agergaard, K; Mau-Sørensen, M; Stage, T B; Jørgensen, T L; Hassel, R E; Steffensen, K D; Pedersen, J W; Milo, Mlh; Poulsen, S H; Pottegård, A; Hallas, J; Brøsen, K; Bergmann, T K

    2017-09-01

    Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl-β-D-glucuronide. To determine if this interaction has clinical relevance, we identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age- and sex-matched controls treated with paclitaxel and low-dose aspirin. By a cumulative dose of 1,500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% confidence interval, 0.9-3.0). Among those receiving a high-dose paclitaxel regimen, the hazard ratio was 2.3 (95% confidence interval, 1.1-4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high-dose paclitaxel. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  3. Using Nonexperts for Annotating Pharmacokinetic Drug-Drug Interaction Mentions in Product Labeling: A Feasibility Study

    PubMed Central

    Ning, Yifan; Hernandez, Andres; Horn, John R; Jacobson, Rebecca; Boyce, Richard D

    2016-01-01

    Background Because vital details of potential pharmacokinetic drug-drug interactions are often described in free-text structured product labels, manual curation is a necessary but expensive step in the development of electronic drug-drug interaction information resources. The use of nonexperts to annotate potential drug-drug interaction (PDDI) mentions in drug product label annotation may be a means of lessening the burden of manual curation. Objective Our goal was to explore the practicality of using nonexpert participants to annotate drug-drug interaction descriptions from structured product labels. By presenting annotation tasks to both pharmacy experts and relatively naïve participants, we hoped to demonstrate the feasibility of using nonexpert annotators for drug-drug information annotation. We were also interested in exploring whether and to what extent natural language processing (NLP) preannotation helped improve task completion time, accuracy, and subjective satisfaction. Methods Two experts and 4 nonexperts were asked to annotate 208 structured product label sections under 4 conditions completed sequentially: (1) no NLP assistance, (2) preannotation of drug mentions, (3) preannotation of drug mentions and PDDIs, and (4) a repeat of the no-annotation condition. Results were evaluated within the 2 groups and relative to an existing gold standard. Participants were asked to provide reports on the time required to complete tasks and their perceptions of task difficulty. Results One of the experts and 3 of the nonexperts completed all tasks. Annotation results from the nonexpert group were relatively strong in every scenario and better than the performance of the NLP pipeline. The expert and 2 of the nonexperts were able to complete most tasks in less than 3 hours. Usability perceptions were generally positive (3.67 for expert, mean of 3.33 for nonexperts). Conclusions The results suggest that nonexpert annotation might be a feasible option for comprehensive

  4. Comparative analysis of three drug-drug interaction screening systems against probable clinically relevant drug-drug interactions: a prospective cohort study.

    PubMed

    Muhič, Neža; Mrhar, Ales; Brvar, Miran

    2017-07-01

    Drug-drug interaction (DDI) screening systems report potential DDIs. This study aimed to find the prevalence of probable DDI-related adverse drug reactions (ADRs) and compare the clinical usefulness of different DDI screening systems to prevent or warn against these ADRs. A prospective cohort study was conducted in patients urgently admitted to medical departments. Potential DDIs were checked using Complete Drug Interaction®, Lexicomp® Online™, and Drug Interaction Checker®. The study team identified the patients with probable clinically relevant DDI-related ADRs on admission, the causality of which was assessed using the Drug Interaction Probability Scale (DIPS). Sensitivity, specificity, and positive and negative predictive values of screening systems to prevent or warn against probable DDI-related ADRs were evaluated. Overall, 50 probable clinically relevant DDI-related ADRs were found in 37 out of 795 included patients taking at least two drugs, most common of them were bleeding, hyperkalemia, digitalis toxicity, and hypotension. Complete Drug Interaction showed the best sensitivity (0.76) for actual DDI-related ADRs, followed by Lexicomp Online (0.50), and Drug Interaction Checker (0.40). Complete Drug Interaction and Drug Interaction Checker had positive predictive values of 0.07; Lexicomp Online had 0.04. We found no difference in specificity and negative predictive values among these systems. DDI screening systems differ significantly in their ability to detect probable clinically relevant DDI-related ADRs in terms of sensitivity and positive predictive value.

  5. Drug-drug interaction studies: regulatory guidance and an industry perspective.

    PubMed

    Prueksaritanont, Thomayant; Chu, Xiaoyan; Gibson, Christopher; Cui, Donghui; Yee, Ka Lai; Ballard, Jeanine; Cabalu, Tamara; Hochman, Jerome

    2013-07-01

    Recently, the US Food and Drug Administration and European Medicines Agency have issued new guidance for industry on drug interaction studies, which outline comprehensive recommendations on a broad range of in vitro and in vivo studies to evaluate drug-drug interaction (DDI) potential. This paper aims to provide an overview of these new recommendations and an in-depth scientifically based perspective on issues surrounding some of the recommended approaches in emerging areas, particularly, transporters and complex DDIs. We present a number of theoretical considerations and several case examples to demonstrate complexities in applying (1) the proposed transporter decision trees and associated criteria for studying a broad spectrum of transporters to derive actionable information and (2) the recommended model-based approaches at an early stage of drug development to prospectively predict DDIs involving time-dependent inhibition and mixed inhibition/induction of drug metabolizing enzymes. We hope to convey the need for conducting DDI studies on a case-by-case basis using a holistic scientifically based interrogative approach and to communicate the need for additional research to fill in knowledge gaps in these areas where the science is rapidly evolving to better ensure the safety and efficacy of new therapeutic agents.

  6. Mining severe drug-drug interaction adverse events using Semantic Web technologies: a case study.

    PubMed

    Jiang, Guoqian; Liu, Hongfang; Solbrig, Harold R; Chute, Christopher G

    2015-01-01

    Drug-drug interactions (DDIs) are a major contributing factor for unexpected adverse drug events (ADEs). However, few of knowledge resources cover the severity information of ADEs that is critical for prioritizing the medical need. The objective of the study is to develop and evaluate a Semantic Web-based approach for mining severe DDI-induced ADEs. We utilized a normalized FDA Adverse Event Report System (AERS) dataset and performed a case study of three frequently prescribed cardiovascular drugs: Warfarin, Clopidogrel and Simvastatin. We extracted putative DDI-ADE pairs and their associated outcome codes. We developed a pipeline to filter the associations using ADE datasets from SIDER and PharmGKB. We also performed a signal enrichment using electronic medical records (EMR) data. We leveraged the Common Terminology Criteria for Adverse Event (CTCAE) grading system and classified the DDI-induced ADEs into the CTCAE in the Web Ontology Language (OWL). We identified 601 DDI-ADE pairs for the three drugs using the filtering pipeline, of which 61 pairs are in Grade 5, 56 pairs in Grade 4 and 484 pairs in Grade 3. Among 601 pairs, the signals of 59 DDI-ADE pairs were identified from the EMR data. The approach developed could be generalized to detect the signals of putative severe ADEs induced by DDIs in other drug domains and would be useful for supporting translational and pharmacovigilance study of severe ADEs.

  7. A pilot study on the impact of known drug-drug interactions in cancer patients.

    PubMed

    Ussai, Silvia; Petelin, Riccardo; Giordano, Antonio; Malinconico, Mario; Cirillo, Donatella; Pentimalli, Francesca

    2015-08-25

    When a patient concomitantly uses two or more drugs, a drug-drug interaction (DDI) can possibly occur, potentially leading to an increased or decreased clinical effect of a given treatment. Cancer patients are at high risk of such interactions because they commonly receive multiple medications. Moreover, most cancer patients are elderly and require additional medications for comorbidities. Aim of this preliminary observational study was to evaluate the incidence of well known and established DDIs in a cohort of cancer outpatients undergoing multiple treatments. Anamnestic and clinical data were collected for 64 adult patients in the ambulatory setting with malignant solid tumors who were receiving systemic anticancer treatment. Patients also declared all drugs prescribed by other specialists or self-taken in the previous 2 weeks. DDIs were divided into two different groups: 'neoplastic DDIs' (NDDIs), involving antitumoral drugs, and 'not neoplastic DDIs' (nDDIs), involving all other classes of drugs. The severity of DDIs was classified as major, moderate and minor, according to the 'Institute for Pharmacological Research Mario Negri' definition. About 34 % of cancer outpatients within our cohort were prescribed/assumed interacting drug combinations. The most frequent major NDDIs involved the anticoagulant warfarin (33 % of total NDDIs) that, in association with tamoxifen, or capecitabine and paclitaxel, increased the risk of haemorrhage. About 60 % of nDDIs involved acetylsalicylic acid. Overall, 16 % of DDIs were related to an A-level strength of recommendation to be avoided. The lack of effective communication among specialists and patients might have a role in determining therapeutic errors. Our pilot study, although limited by a small cohort size, highlights the urgent need of implementing the clinical management of cancer outpatients with new strategies to prevent or minimize potential harmful DDIs.

  8. Potential Drug - Drug Interactions among Medications Prescribed to Hypertensive Patients

    PubMed Central

    Ganguly, Barna

    2014-01-01

    Context: Drug-drug interactions(DDIs) are significant but avoidable causes of iatrogenic morbidity and hospital admission. Aim: To detect potential drug-drug interactions among medications received by hypertensive patients. Materials and Methods: Patients of both sex and all adult age groups, who were attending medicine out -patient department (OPD) of a tertiary care teaching rural hospital since last six months and were being prescribed antihypertensive drug/s for essential hypertension, were selected for the study. Hypertensive patient with co-morbities diabetes mellitus, ischemic heart diseases, congestive heart failure, and chronic renal diseases were also included in the study. Potential drug drug interactions were checked with medscape drug interaction software. Results: With the help of medscape drug interaction software, 71.50% prescriptions were identified having atleast one drug-drug interaction. Total 918 DDIs were found in between 58 drug pairs. 55.23% DDIs were pharmacodynamic, 4.79% pharmacokinetic type of DDIs. 32.24% DDIs were found affecting serum potassium level. 95.42% DDIs were found significant type of DDIs. Drug drug interaction between atenolol & amlodipine was the most common DDI (136) followed by metoprolol and amlodine (88) in this study. Atenolol and amlodipine ( 25.92%) was the most common drugs to cause DDIs in our study. Conclusion: We detected a significant number of drug drug interaction in hypertensive patients. These interactions were between antihypertensive agents or between hypertensive and drug for co-morbid condition. PMID:25584241

  9. Text mining for drug-drug interaction.

    PubMed

    Wu, Heng-Yi; Chiang, Chien-Wei; Li, Lang

    2014-01-01

    In order to understand the mechanisms of drug-drug interaction (DDI), the study of pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenetics (PG) data are significant. In recent years, drug PK parameters, drug interaction parameters, and PG data have been unevenly collected in different databases and published extensively in literature. Also the lack of an appropriate PK ontology and a well-annotated PK corpus, which provide the background knowledge and the criteria of determining DDI, respectively, lead to the difficulty of developing DDI text mining tools for PK data collection from the literature and data integration from multiple databases.To conquer the issues, we constructed a comprehensive pharmacokinetics ontology. It includes all aspects of in vitro pharmacokinetics experiments, in vivo pharmacokinetics studies, as well as drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three-level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK corpus was demonstrated by a drug interaction extraction text mining analysis.The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions.

  10. [Drug-drug interactions: interactions between xenobiotics].

    PubMed

    Haen, E

    2014-04-01

    Drug-drug interactions (DDI) are a major topic in programs for continuous medical education (CME). Many physicians are afraid of being trapped into charges of malpractice; however, DDI cannot be avoided in many cases. They belong to routine medical practice and it is often impossible to avoid them. Moreover, they do not just occur between drugs but between any kind of foreign substance (xenobiotica), such as food (e.g. grapefruit juice, broccoli, barbecue) as well as legal (e.g. tobacco smoke, caffeine and alcohol) and illegal drugs. Therefore, the medical challenge is not just to avoid any interaction. Instead the physician faces the question of how to proceed with drug treatment in the presence of such interactions. Based on the medical education a physician has to judge first of all whether there is a risk for interactions in the prescription being planned for an individual patient. The classification of interactions proposed in this article (PD1-PD4, PK1-PK3) might help as a sort of check list. For more detailed information the physician can then consult one of the many databases available on the internet, such as PSIAConline (http://www.psiac.de) and MediQ (http://www.mediq.ch). Pharmacokinetic interactions can be easily assessed, monitored and controlled by therapeutic drug monitoring (TDM). Besides these tools it is important to keep in mind that nobody knows everything; even physicians do not know everything. So take pride in asking someone who might help and for this purpose AGATE offers a drug information service AID (http://www.amuep-agate.de). Just good for nothing, without being based on any kind of medical approach are computer programs that judge prescriptions without taking into account a patient's individual peculiarities. In case these types of programs produce red exclamation marks or traffic lights to underline their judgment, they might even work in a contrapuntal way by just eliciting insecurity and fear.

  11. Potential drug-drug interactions in hospitalized patients undergoing systemic chemotherapy: a prospective cohort study.

    PubMed

    Stoll, Paula; Kopittke, Luciane

    2015-06-01

    Adverse drug-drug interactions (DDI) are a major cause of morbidity and mortality in susceptible populations. Cancer patients are a population at high risk for DDI especially because they commonly receive several drugs concomitantly. The knowledge about the most common interactions between drugs used in oncology inpatients is essential to reduce drug-related problems and increase the safety and efficacy of the therapy. To assess the frequency of potential DDI throughout the hospital stay of cancer patients undergoing systemic chemotherapy, describe their epidemiology, and identify risk factors for major DDI. Setting An oncology-hematology inpatient unit of a public hospital in southern Brazil. Drug prescriptions were prospectively reviewed throughout the hospital stay of patients admitted for systemic chemotherapy. Descriptive statistics and Poisson regression were used for data analysis. Potential DDI and their characteristics. The cohort consisted of 113 patients, who used a mean of 8.9 ± 2.7 drugs/day. All patients had at least one potential DDI (median, 7.0/patient; 25th-75th percentile, 3.5-12.0), and 46 % of the patients had at least one DDI classified as major, i.e. that it may result in death, hospitalization, permanent injury, or therapeutic failure. Only 13.7 % of all interactions involved antineoplastic agents, identified in 62.8 % of patients. Most interactions were of moderate severity, 6.4 % were major, and 8.5 % had a recommendation for therapy modification. Multivariate analysis revealed mean number of drugs prescribed [relative risk (RR) for each additional drug: 1.12; 95 % confidence interval (CI) 1.07-1.17; P < 0.01] and age ≥60 years (RR 1.48; 95 % CI 1.03-2.14; P < 0.01) as independent risk factors for major DDI. Potential DDI were highly frequent in this cohort. Older age and number of drugs prescribed were more likely to lead to major interactions. Prospective surveillance is required to detect adverse DDI, aiming primarily at reducing the

  12. Party pills and drug-drug interactions.

    PubMed

    Murphy, Meghan; Antia, Ushtana; Chang, Hsin-Yao; Han, Jae Young; Ibrahim, Ushtana; Tingle, Malcolm; Russell, Bruce

    2009-04-24

    This study aimed to explore the potential for drug-drug interactions involving benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP). This was achieved by determining the effects of BZP and TFMPP on the metabolism of drugs commonly found in the clinical setting by using pooled human liver microsomes. Incubations consisted of a probe substrate (drug of interest), a potential inhibitor (BZP or TFMPP), a suitable enzyme co-factor (NADPH), and pooled human liver microsomes. Loss of substrate was determined by analysing pre- and post-incubation concentrations in the samples by using HPLC/UV analysis. Both TFMPP and BZP were found to inhibit the metabolism of dextromethorphan, caffeine, and ethinyloestradiol. These are reported substrates of CYP2D6, CYP1A2, and CYP3A4 respectively. Greater enzyme inhibition was observed in TFMPP microsomal assays in comparison to those using BZP. The metabolism of omeprazole was not affected, suggesting that BZP and TFMPP do not have a significant inhibitory effect on CYP2C19. The inhibitory effects of BZP and TFMPP observed in this study are of potential significance to clinical practice because CYP2D6, CYP1A2, and CYP3A4 are involved in the metabolism of many commonly used drugs. Knowledge about the observed inhibitory effects will be a useful aid in preventing toxicity when drugs metabolised by these isoenzymes are taken with party pills.

  13. Drug-Drug Interactions in Headache Medicine.

    PubMed

    Ansari, Hossein; Ziad, Sanaz

    2016-07-01

    The main treatments in a majority of headache patients are pharmacologic therapies. As a result, it is imperative to have strong background in pharmacotherapy used to treat headaches in order to provide optimal therapy and avoid drug interactions. One of the main reasons for failure of pharmacologic treatment of headaches is drug-drug interactions (DDIs). While there are many distinct pathways and mechanisms in which DDIs can occur, most occur through alterations within the cytochrome P450 pathways (CYP). Drugs that cause induction, inhibition, or are simply substrates for these pathways are responsible for many of the DDIs. We review and discuss the important and potential DDIs of commonly used headache medication often encountered in clinical practice. We divide the drugs into two classes, abortive and preventive. Within each group we select the most commonly used drugs and provide a detailed discussion of the mechanisms of interaction for each. Also included are commonly used herbal supplements, which can interact with headache medications. Drug-drug-interactions are a major concern when developing a treatment regimen for patients suffering from headaches. There is a growing need for physician attention to the pharmacokinetics of drugs to improve the quality of patient care. It is vital that prescribing physicians be aware of the DDIs associated with the commonly prescribed headache medications to optimize patient care and therapy results. © 2016 American Headache Society.

  14. Integration of heterogeneous clinical decision support systems and their knowledge sets: feasibility study with Drug-Drug Interaction alerts.

    PubMed

    Kam, Hye Jin; Kim, Jeong Ah; Cho, InSook; Kim, Yoon; Park, Rae Woong

    2011-01-01

    There exist limitations in both commercial and in-house clinical decision support systems (CDSSs) and issues related to the integration of different knowledge sources and CDSSs. We chose Standard-based Shareable Active Guideline Environment (SAGE) as a new architecture with knowledge integration and a centralized knowledge base which includes authoring/management functions and independent CDSS, and applied it to Drug-Drug Interaction (DDI) CDSS. The aim of this study was to evaluate the feasibility of the newly integrated DDI alerting CDSS into a real world hospital information system involving construction of an integrated CDSS derived from two heterogeneous systems and their knowledge sets. The proposed CDSS was successfully implemented and compensated for the weaknesses of the old CDSS from knowledge integration and management, and its applicability in actual situations was verified. Although the DDI CDSS was constructed as an example case, the new CDS architecture might prove applicable to areas of CDSSs.

  15. Detection of drug-drug interactions through data mining studies using clinical sources, scientific literature and social media.

    PubMed

    Vilar, Santiago; Friedman, Carol; Hripcsak, George

    2017-02-17

    Drug-drug interactions (DDIs) constitute an important concern in drug development and postmarketing pharmacovigilance. They are considered the cause of many adverse drug effects exposing patients to higher risks and increasing public health system costs. Methods to follow-up and discover possible DDIs causing harm to the population are a primary aim of drug safety researchers. Here, we review different methodologies and recent advances using data mining to detect DDIs with impact on patients. We focus on data mining of different pharmacovigilance sources, such as the US Food and Drug Administration Adverse Event Reporting System and electronic health records from medical institutions, as well as on the diverse data mining studies that use narrative text available in the scientific biomedical literature and social media. We pay attention to the strengths but also further explain challenges related to these methods. Data mining has important applications in the analysis of DDIs showing the impact of the interactions as a cause of adverse effects, extracting interactions to create knowledge data sets and gold standards and in the discovery of novel and dangerous DDIs.

  16. Study of Drug-Drug Interactions in Prescriptions of General Practitioners and Specialists in Iran 2007-2009

    PubMed Central

    Ahmadizar, Fariba; Soleymani, Fatemeh; Abdollahi, Mohammad

    2011-01-01

    Prescriptions written by general practitioners and medical specialists were studied and compared to determine the type, time of onset and clinical importance of drug-drug interactions (DDIs) in an attempt to reduce further complications. In 2007, 28, 956, 638 prescriptions and 15, 610, 912 prescriptions in 2008 were filled by pharmacies affiliated with medical science universities. These prescriptions, prescribed by physicians from 33 Iranian medical universities nationwide were then evaluated with a prescription processing software named Pardazesh Nosakh. After processing and analyzing the data, DDIs were discovered in 14 different medical specialists consisting of internists, cardiologists, neurologists, psychiatrists, neurosurgeons, general surgeons, infectious diseases, urologists, dermatologists, ENT, ophthalmologists, orthopedists, and pediatrician. The results were then analyzed through methods applied in the book of Drug Interaction Facts. The results revealed that in 2007-2008, 0.77% of prescriptions had DDIs out of which 0.67% were with significant clinical importance. The percentage of interactions with significant clinical importance was higher in prescriptions of medical specialists and of those, cardiologists and internists ranked top on the list, while dermatologists ranked the lowest. The most common interacting combination prescribed was digoxin and furosmide in 2007-2008, and captopril and triamteren in 2008-2009. Moreover, this study showed that polypharmacy was an important factor which led to DDIs. Drug interactions were common among outpatients prescribed multiple medications and the rate of DDIs increased with the number of drugs prescribed. It is our opinion that by being up-to-date on drug information and participating in related educational classes and workshops, physicians can increase the chances of choosing the correct drug treatment and hence significantly decrease possible DDIs side effects. PMID:24250431

  17. Best practices for the use of itraconazole as a replacement for ketoconazole in drug-drug interaction studies.

    PubMed

    Liu, Lichuan; Bello, Akintunde; Dresser, Mark J; Heald, Donald; Komjathy, Steven Ferenc; O'Mara, Edward; Rogge, Mark; Stoch, S Aubrey; Robertson, Sarah M

    2016-02-01

    Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug-drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLG's recommendations are based on careful review of available literature and internal industry experiences.

  18. Theoretical and experimental studies of the stability of drug-drug interact

    NASA Astrophysics Data System (ADS)

    Soares, Monica F. R.; Alves, Lariza D. S.; Nadvorny, Daniela; Soares-Sobrinho, José L.; Rolim-Neto, Pedro J.

    2016-11-01

    Several factors can intervene in the molecular properties and consequently in the stability of drugs. The molecular complexes formation often occur due to favor the formation of hydrogen bonds, leading the system to configuration more energy stable. This work we aim to investigate through theoretical and experimental methods the relation between stability and properties of molecular complexes the molecular complex formed between the drugs, efavirenz (EFV), lamivudine (3TC) and zidovudine (AZT). With this study was possible determining the most stable complex formed between the compounds evaluated. In addition the energy and structural properties of the complex formed in relation to its individual components allowed us to evaluate the stability of the same.

  19. Drug-drug interactions between clopidogrel and novel cardiovascular drugs.

    PubMed

    Pelliccia, Francesco; Rollini, Fabiana; Marazzi, Giuseppe; Greco, Cesare; Gaudio, Carlo; Angiolillo, Dominick J

    2015-10-15

    The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine.

  20. Participatory design for drug-drug interaction alerts.

    PubMed

    Luna, Daniel; Otero, Carlos; Almerares, Alfredo; Stanziola, Enrique; Risk, Marcelo; González Bernaldo de Quirós, Fernán

    2015-01-01

    The utilization of decision support systems, in the point of care, to alert drug-drug interactions has been shown to improve quality of care. Still, the use of these systems has not been as expected, it is believed, because of the difficulties in their knowledge databases; errors in the generation of the alerts and the lack of a suitable design. This study expands on the development of alerts using participatory design techniques based on user centered design process. This work was undertaken in three stages (inquiry, participatory design and usability testing) it showed that the use of these techniques improves satisfaction, effectiveness and efficiency in an alert system for drug-drug interactions, a fact that was evident in specific situations such as the decrease of errors to meet the specified task, the time, the workload optimization and users overall satisfaction in the system.

  1. Potential drug-drug interactions with abiraterone in metastatic castration-resistant prostate cancer patients: a prevalence study in France.

    PubMed

    Bonnet, Clément; Boudou-Rouquette, Pascaline; Azoulay-Rutman, Esther; Huillard, Olivier; Golmard, Jean-Louis; Carton, Edith; Noé, Gaëlle; Vidal, Michel; Orvoen, Galdric; Chah Wakilian, Anne; Villeminey, Clémentine; Blanchet, Benoit; Alexandre, Jérôme; Goldwasser, François; Thomas-Schoemann, Audrey

    2017-05-01

    Abiraterone acetate combined with prednisone improves survival in metastatic castration-resistant prostate cancer (mCRPC) patients. This oral anticancer agent may result in drug-drug interactions (DDI). We aimed to evaluate the prevalence of DDI with abiraterone and the possible determinants for the occurrence of these DDI. We performed a single centre retrospective review from electronic medical records of mCRPC patients treated with abiraterone from 2011 to 2015. Potential DDI with abiraterone were identified using Micromedex and were categorized by a 4-point scale severity. Seventy-two out of ninety-five mCRPC pts (median age: 77 years [68-82]) had comorbidities. The median number of drugs used per patient was 7 [5-9]. 66 potential DDI with abiraterone were detected in 49 patients (52%): 39 and 61% were classified as major and moderate DDI, respectively. In the univariate analysis, pain (p < 0.0001), hypo-albuminemia (p = 0.032), and higher ECOG performance status (PS) (p = 0.013) were significantly associated with a higher risk of DDI with abiraterone. Pain (p < 0.0001) and PS (p = 0.018) remained significant in the multivariate analysis. Polypharmacy is an issue among mCRPC patients. In our study, half of the patients have potential DDI with abiraterone. Patients with pain and poor PS are at higher risk of DDI with abiraterone. A medication review by a pharmacist is of crucial importance to prevent DDI with abiraterone.

  2. Drug-drug plasma protein binding interactions of ivacaftor.

    PubMed

    Schneider, Elena K; Huang, Johnny X; Carbone, Vincenzo; Baker, Mark; Azad, Mohammad A K; Cooper, Matthew A; Li, Jian; Velkov, Tony

    2015-06-01

    Ivacaftor is a novel cystic fibrosis (CF) transmembrane conductance regulator (CFTR) potentiator that improves the pulmonary function for patients with CF bearing a G551D CFTR-protein mutation. Because ivacaftor is highly bound (>97%) to plasma proteins, there is the strong possibility that co-administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co-administered CF drugs for human serum albumin (HSA) and α1 -acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site-selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug-drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug-drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug-drug interactions of ivacaftor with co-administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor.

  3. Potential drug-drug interactions associated with prolonged stays in the intensive care unit: a retrospective cohort study.

    PubMed

    Moura, Cristiano; Prado, Nília; Acurcio, Francisco

    2011-01-01

    Drug-drug interactions (DDIs) are one cause of adverse drug events and can cause harm to hospitalized patients. Little has been done to study the relationship between potential DDIs and an increased length of stay (LOS) in the intensive care unit (ICU). The aim of this study was to determine the frequency of potential DDIs during ICU stays and to determine whether the frequency of these adverse events was associated with ICU LOS. This retrospective cohort study was conducted from January to December 2007 in the ICU of the General Hospital of Vitória da Conquista, Brazil. The study population comprised all patients aged >18 years admitted to the hospital's ICU. Demographic and prescription data were collected from medical files. All prescriptions administered during the period were examined. Potential DDIs were identified and classified according to the book Drug Interaction Facts. The median LOS was determined by the Kaplan-Meier method and Cox proportional hazards models were fitted to analyse the relationship between potential DDIs and the LOS. The study population comprised 236 adults, 158 (67%) of them men, between the ages of 18 and 96 years, with a mean ± SD age of 50 ± 20 years. The median LOS among patients with at least one DDI was 12 days compared with 5 days among those with no DDIs (p < 0.01). Multiple Cox proportional regression analyses showed that a prolonged ICU stay was positively associated with DDIs (hazard ratio [HR] 0.54; 95% CI 0.37, 0.80; p < 0.01), where an HR <1 indicates a variable that increases the risk of prolonged stay (i.e. an adverse outcome). This association was true even after controlling for the cost of hospitalization, the number of procedures and the number of prescribed drugs. In this study, DDIs were found to be associated with a longer ICU stay. Given that LOS is an important indicator of the quality of health care delivered and that DDIs are considered avoidable, specific measures are necessary to

  4. Predicting Drug-Target Interactions Using Drug-Drug Interactions

    PubMed Central

    Kim, Shinhyuk; Jin, Daeyong; Lee, Hyunju

    2013-01-01

    Computational methods for predicting drug-target interactions have become important in drug research because they can help to reduce the time, cost, and failure rates for developing new drugs. Recently, with the accumulation of drug-related data sets related to drug side effects and pharmacological data, it has became possible to predict potential drug-target interactions. In this study, we focus on drug-drug interactions (DDI), their adverse effects () and pharmacological information (), and investigate the relationship among chemical structures, side effects, and DDIs from several data sources. In this study, data from the STITCH database, from drugs.com, and drug-target pairs from ChEMBL and SIDER were first collected. Then, by applying two machine learning approaches, a support vector machine (SVM) and a kernel-based L1-norm regularized logistic regression (KL1LR), we showed that DDI is a promising feature in predicting drug-target interactions. Next, the accuracies of predicting drug-target interactions using DDI were compared to those obtained using the chemical structure and side effects based on the SVM and KL1LR approaches, showing that DDI was the data source contributing the most for predicting drug-target interactions. PMID:24278248

  5. Irreversible enzyme inhibition kinetics and drug-drug interactions.

    PubMed

    Mohutsky, Michael; Hall, Stephen D

    2014-01-01

    This chapter describes the types of irreversible inhibition of drug-metabolizing enzymes and the methods commonly employed to quantify the irreversible inhibition and subsequently predict the extent and time course of clinically important drug-drug interactions.

  6. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned?

    PubMed

    Huang, Shiew-Mei; Lesko, Lawrence J

    2004-06-01

    Serious drug-drug interactions have contributed to recent U.S. market withdrawals and also recent nonapprovals of a few new molecular entities. Many of these interactions involved the inhibition or induction of metabolizing enzymes and efflux transporters, resulting in altered systemic exposure and adverse drug reactions or loss of efficacy. In addition to drug-drug interactions, drug-dietary supplement and drug-citrus fruit interactions, among others, could also cause adverse drug reactions or loss of efficacy and are important issues to consider in the evaluation of new drug candidates. This commentary reviews (1). the current understanding of the mechanistic basis of these interactions, (2). issues to consider in the interpretation of study results, and (3). recent labeling examples to illustrate the translation of study results to information useful for patients and health care providers.

  7. Identification of Drug-Drug Interactions In Vitro: A Case Study Evaluating the Effects of Sofosbuvir and Amiodarone on hiPSC-Derived Cardiomyocytes.

    PubMed

    Millard, Daniel C; Strock, Christopher J; Carlson, Coby B; Aoyama, Natsuyo; Juhasz, Krisztina; Goetze, Tom A; Stoelzle-Feix, Sonja; Becker, Nadine; Fertig, Niels; January, Craig T; Anson, Blake D; Ross, James D

    2016-11-01

    Drug-drug interactions pose a difficult drug safety problem, given the increasing number of individuals taking multiple medications and the relative complexity of assessing the potential for interactions. For example, sofosbuvir-based drug treatments have significantly advanced care for hepatitis C virus-infected patients, yet recent reports suggest interactions with amiodarone may cause severe symptomatic bradycardia and thus limit an otherwise extremely effective treatment. Here, we evaluated the ability of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to recapitulate the interaction between sofosbuvir and amiodarone in vitro, and more generally assessed the feasibility of hiPSC-CMs as a model system for drug-drug interactions. Sofosbuvir alone had negligible effects on cardiomyocyte electrophysiology, whereas the sofosbuvir-amiodarone combination produced dose-dependent effects beyond that of amiodarone alone. By comparison, GS-331007, the primary circulating metabolite of sofosbuvir, had no effect alone or in combination with amiodarone. Further mechanistic studies revealed that the sofosbuvir-amiodarone combination disrupted intracellular calcium (Ca(2+)) handling and cellular electrophysiology at pharmacologically relevant concentrations, and mechanical activity at supra-pharmacological (30x Cmax) concentrations. These effects were independent of the common mechanisms of direct ion channel block and P-glycoprotein activity. These results support hiPSC-CMs as a comprehensive, yet scalable model system for the identification and evaluation of cardioactive pharmacodynamic drug-drug interactions. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. [The drug-drug interactions in a psychiatric hospital].

    PubMed

    Kirilochev, O O; Umerova, A R; Dorfman, I P; Khryashchev, A V

    An analysis of 132 drugs used in a psychiatric hospital for the estimation of the possibility of drug-drug interactions has been carried out. It has been established that one in five potential combination has a drug-drug interaction with clinically significant interactions being more frequent. Psychotropic drugs occupy a leading position in the number of such interactions. This analysis is able to improve the safety of the combined pharmacotherapies by choosing an alternative drug, correction of dose or active monitoring of the clinical condition of the patient, including laboratory and instrumental data.

  9. Severe potential drug-drug interactions in older adults with dementia and associated factors

    PubMed Central

    Bogetti-Salazar, Michele; González-González, Cesar; Juárez-Cedillo, Teresa; Sánchez-García, Sergio; Rosas-Carrasco, Oscar

    2016-01-01

    OBJECTIVE: To identify the main severe potential drug-drug interactions in older adults with dementia and to examine the factors associated with these interactions. METHOD: This was a cross-sectional study. The enrolled patients were selected from six geriatrics clinics of tertiary care hospitals across Mexico City. The patients had received a clinical diagnosis of dementia based on the current standards and were further divided into the following two groups: those with severe drug-drug interactions (contraindicated/severe) (n=64) and those with non-severe drug-drug interactions (moderate/minor/absent) (n=117). Additional socio-demographic, clinical and caregiver data were included. Potential drug-drug interactions were identified using Micromedex Drug Reax 2.0® database. RESULTS: A total of 181 patients were enrolled, including 57 men (31.5%) and 124 women (68.5%) with a mean age of 80.11±8.28 years. One hundred and seven (59.1%) patients in our population had potential drug-drug interactions, of which 64 (59.81%) were severe/contraindicated. The main severe potential drug-drug interactions were caused by the combinations citalopram/anti-platelet (11.6%), clopidogrel/omeprazole (6.1%), and clopidogrel/aspirin (5.5%). Depression, the use of a higher number of medications, dementia severity and caregiver burden were the most significant factors associated with severe potential drug-drug interactions. CONCLUSIONS: Older people with dementia experience many severe potential drug-drug interactions. Anti-depressants, antiplatelets, anti-psychotics and omeprazole were the drugs most commonly involved in these interactions. Despite their frequent use, anti-dementia drugs were not involved in severe potential drug-drug interactions. The number and type of medications taken, dementia severity and depression in patients in addition to caregiver burden should be considered to avoid possible drug interactions in this population. PMID:26872079

  10. Severe potential drug-drug interactions in older adults with dementia and associated factors.

    PubMed

    Bogetti-Salazar, Michele; González-González, Cesar; Juárez-Cedillo, Teresa; Sánchez-García, Sergio; Rosas-Carrasco, Oscar

    2016-01-01

    To identify the main severe potential drug-drug interactions in older adults with dementia and to examine the factors associated with these interactions. This was a cross-sectional study. The enrolled patients were selected from six geriatrics clinics of tertiary care hospitals across Mexico City. The patients had received a clinical diagnosis of dementia based on the current standards and were further divided into the following two groups: those with severe drug-drug interactions (contraindicated/severe) (n=64) and those with non-severe drug-drug interactions (moderate/minor/absent) (n=117). Additional socio-demographic, clinical and caregiver data were included. Potential drug-drug interactions were identified using Micromedex Drug Reax 2.0® database. A total of 181 patients were enrolled, including 57 men (31.5%) and 124 women (68.5%) with a mean age of 80.11±8.28 years. One hundred and seven (59.1%) patients in our population had potential drug-drug interactions, of which 64 (59.81%) were severe/contraindicated. The main severe potential drug-drug interactions were caused by the combinations citalopram/anti-platelet (11.6%), clopidogrel/omeprazole (6.1%), and clopidogrel/aspirin (5.5%). Depression, the use of a higher number of medications, dementia severity and caregiver burden were the most significant factors associated with severe potential drug-drug interactions. Older people with dementia experience many severe potential drug-drug interactions. Anti-depressants, antiplatelets, anti-psychotics and omeprazole were the drugs most commonly involved in these interactions. Despite their frequent use, anti-dementia drugs were not involved in severe potential drug-drug interactions. The number and type of medications taken, dementia severity and depression in patients in addition to caregiver burden should be considered to avoid possible drug interactions in this population.

  11. Surveillance of Physicians Causing Potential Drug-Drug Interactions in Ambulatory Care: A Pilot Study in Switzerland

    PubMed Central

    Bucher, Heiner C.; Achermann, Rita; Stohler, Nadja; Meier, Christoph R.

    2016-01-01

    Objectives We analysed potential drug-drug interactions (DDI) in ambulatory care in Switzerland based on claims data from three large health insurers in 2010 to identify physicians with peculiar prescription behaviour differing from peers of the same specialty. Methods We analysed contraindicated or potentially contraindicated DDI from the national drug formulary and calculated for each physician the ratios of the number of patients with a potential DDI divided by the number of patients at risk and used a zero inflated binomial distribution to correct for the inflated number of observations with no DDI. We then calculated the probability that the number of caused potential DDI of physicians was unlikely (p-value < 0.05 and ≥0.01) and very unlikely (p-value <0.01) to be due to chance. Results Of 1'607'233 females and 1'525'307 males 1.3% and 1.2% were exposed to at least one potential DDI during 12 months. When analysing the 40 most common DDI, 598 and 416 of 18,297 physicians (3.3% and 2.3%) were causing potential DDI in a frequency unlikely (p<0.05 and p≥0.01) and very unlikely (p<0.01) to be explained by chance. Patients cared by general practitioners and cardiologists had the lowest probability (0.20 and 0.26) for not being exposed to DDI. Conclusions Contraindicated or potentially contraindicated DDI are frequent in ambulatory care in Switzerland, with a small proportion of physicians causing potential DDI in a frequency that is very unlikely to be explained by chance when compared to peers of the same specialty. PMID:26808430

  12. Drug-drug interaction and doping, part 1: an in vitro study on the effect of non-prohibited drugs on the phase I metabolic profile of toremifene.

    PubMed

    Mazzarino, Monica; de la Torre, Xavier; Fiacco, Ilaria; Palermo, Amelia; Botrè, Francesco

    2014-05-01

    The present study was designed to provide preliminary information on the potential impact of metabolic drug-drug interaction on the effectiveness of doping control strategies currently followed by the anti-doping laboratories to detect the intake of banned agents. In vitro assays based on the use of human liver microsomes and recombinant CYP isoforms were designed and performed to characterize the phase I metabolic profile of the prohibited agent toremifene, selected as a prototype drug of the class of selective oestrogen receptor modulators, both in the absence and in the presence of medicaments (fluconazole, ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, fluoxetine, paroxetine, nefazodone) not included in the World Anti-Doping Agency list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model developed in this study was adequate to simulate the in vivo metabolism of toremifene, confirming the results obtained in previous studies. Furthermore, our data also show that ketoconazole, itraconazole, miconazole and nefazodone cause a marked modification in the production of the metabolic products (i.e. hydroxylated and carboxylated metabolites) normally selected by the anti-doping laboratories as target analytes to detect toremifene intake; moderate variations were registered in the presence of fluconazole, paroxetine and fluoxetine; while no significant modifications were measured in the presence of ranitidine and cimetidine. This evidence imposes that the potential effect of drug-drug interactions is duly taken into account in anti-doping analysis, also for a broader significance of the analytical results.

  13. Epidemiology of Polypharmacy and Potential Drug-Drug Interactions Among Pediatric Patients in ICUs of U.S. Children's Hospitals.

    PubMed

    Dai, Dingwei; Feinstein, James A; Morrison, Wynne; Zuppa, Athena F; Feudtner, Chris

    2016-05-01

    Polypharmacy is common in hospitalized children in the United States and has been identified as a major risk factor for exposure to potential drug-drug interactions. Little is known about the characteristics and prevalence of exposure of pediatric patients to polypharmacy and potential drug-drug interactions in PICUs. Retrospective cohort study using the Pediatric Health Information System database. Forty-two freestanding children's hospitals throughout the United States. A total of 54,549 patients less than 18 years old cared for in PICUs in 2011. Patients in neonatal ICUs were not included. PICU patients were on average exposed to 10 distinct drugs each hospital day and to 20 drugs cumulatively during their hospitalization. Seventy-five percent of patients were exposed to greater than or equal to one potential drug-drug interaction regardless of severity level, 6% to greater than or equal to one contraindicated potential drug-drug interaction, 69% to greater than or equal to one major potential drug-drug interaction, 57% to greater than or equal to one moderate potential drug-drug interaction, 19% to greater than or equal to one minor potential drug-drug interaction. Potential drug-drug interaction exposures were significantly associated with specific diagnoses (p < 0.001), presence of complex chronic conditions (p < 0.001), increasing number of total distinct drugs used (p < 0.001), increasing length of stay in PICU (p < 0.001), and white race (p < 0.001). Many PICU patients are exposed to substantial polypharmacy and potential drug-drug interactions. Future research should identify the risk of adverse drug events following specific potential drug-drug interaction exposures, especially the risk of adverse drug events due to multiple potential drug-drug interaction exposures, and determine the probability and magnitude of the actual harm (if any) for each specific potential drug-drug interaction, especially for multiple potential drug-drug interaction exposures.

  14. Making Transporter Models for Drug-Drug Interaction Prediction Mobile.

    PubMed

    Ekins, Sean; Clark, Alex M; Wright, Stephen H

    2015-10-01

    The past decade has seen increased numbers of studies publishing ligand-based computational models for drug transporters. Although they generally use small experimental data sets, these models can provide insights into structure-activity relationships for the transporter. In addition, such models have helped to identify new compounds as substrates or inhibitors of transporters of interest. We recently proposed that many transporters are promiscuous and may require profiling of new chemical entities against multiple substrates for a specific transporter. Furthermore, it should be noted that virtually all of the published ligand-based transporter models are only accessible to those involved in creating them and, consequently, are rarely shared effectively. One way to surmount this is to make models shareable or more accessible. The development of mobile apps that can access such models is highlighted here. These apps can be used to predict ligand interactions with transporters using Bayesian algorithms. We used recently published transporter data sets (MATE1, MATE2K, OCT2, OCTN2, ASBT, and NTCP) to build preliminary models in a commercial tool and in open software that can deliver the model in a mobile app. In addition, several transporter data sets extracted from the ChEMBL database were used to illustrate how such public data and models can be shared. Predicting drug-drug interactions for various transporters using computational models is potentially within reach of anyone with an iPhone or iPad. Such tools could help prioritize which substrates should be used for in vivo drug-drug interaction testing and enable open sharing of models.

  15. Quantifying drug-drug interactions in pharmaco-EEG.

    PubMed

    Barbanoj, M J; Antonijoan, R M; Riba, J; Valle, M; Romero, S; Jané, F

    2006-04-01

    A drug interaction refers to an event in which the usual pharmacological effect of a drug is modified by other factors, most frequently additional drugs. When two drugs are administered simultaneously, or within a short time of each other, an interaction can occur that may increase or decrease the intended magnitude or duration of the effect of one or both drugs. Drugs may interact on a pharmaceutical, pharmacokinetic or pharmacodynamic basis. Pharmacodynamic interactions arise when the alteration of the effects occurs at the site of action. This is a wide field where not only interactions between different drugs are considered but also drug and metabolites (midazolam/alpha-hydroxy-midazolam), enantiomers (ketamine), as well as phenomena such as tolerance (nordiazepam) and sensitization (diazepam). Pharmacodynamic interactions can result in antagonism or synergism and can originate at a receptor level (antagonism, partial agonism, down-regulation, up-regulation), at an intraneuronal level (transduction, uptake), or at an interneuronal level (physiological pathways). Alternatively, psychotropic drug interactions assessed through quantitative pharmaco-EEG can be viewed according to the broad underlying objective of the study: safety-oriented (ketoprofen/theophylline, lorazepam/diphenhydramine, granisetron/haloperidol), strictly pharmacologically-oriented (benzodiazepine receptors), or broadly neuro-physiologically-oriented (diazepam/buspirone). Methodological issues are stressed, particularly drug plasma concentrations, dose-response relationships and time-course of effects (fluoxetine/buspirone), and unsolved questions are addressed (yohimbine/caffeine, hydroxizyne/alcohol).

  16. Potentially severe drug-drug interactions among older people and associations in assisted living facilities in Finland: a cross-sectional study.

    PubMed

    Teramura-Grönblad, Mariko; Raivio, Minna; Savikko, Niina; Muurinen, Seija; Soini, Helena; Suominen, Merja; Pitkälä, Kaisu

    2016-09-01

    This study aims to assess potentially severe class D drug-drug interactions (DDDIs) in residents 65 years or older in assisted living facilities with the use of a Swedish and Finnish drug-drug interaction database (SFINX). A cross-sectional study of residents in assisted living facilities in Helsinki, Finland. A total of 1327 residents were assessed in this study. Drugs were classified according to the Anatomical Therapeutic Chemical (ATC) classification system and DDDIs were coded according to the SFINX. Prevalence of DDDIs, associated factors and 3-year mortality among residents. Of the participants (mean age was 82.7 years, 78.3% were females), 5.9% (N = 78) are at risk for DDDIs, with a total of 86 interactions. Participants with DDDIs had been prescribed a higher number of drugs (10.8 (SD 3.8) vs. 7.9 (SD 3.7), p < 0.001). A larger proportion of residents with DDDIs suffered from rheumatoid arthritis or osteoarthritis than those not exposed to DDDIs (24.7% vs. 15.4%, p = 0.030). The most frequent DDDIs were related to the concomitant use of potassium with amiloride (N = 12) or spironolactone (N = 12). Carbamazepine (N = 13) and methotrexate (N = 9) treatments were also frequently linked to DDDIs. During the follow-up, no differences in mortality emerged between the participants exposed to DDDIs and the participants not exposed to DDDIs. Of the residents in assisted living, 5.9% were exposed to DDDIs associated with the use of a higher number of drugs. Physicians should be trained to find safer alternatives to drugs associated with DDDIs. KEY POINTS   Potentially severe, class D drug-drug interactions (DDDIs) have been defined in the SFINX database as clinically relevant drug interactions that should be avoided.  • Of the residents in assisted living, 5.9% were exposed to DDDIs that were associated with the use of a higher number of drugs.  • The most frequent DDDIs were related to the concomitant use of potassium

  17. Breast cancer resistance protein (ABCG2) in clinical pharmacokinetics and drug interactions: practical recommendations for clinical victim and perpetrator drug-drug interaction study design.

    PubMed

    Lee, Caroline A; O'Connor, Meeghan A; Ritchie, Tasha K; Galetin, Aleksandra; Cook, Jack A; Ragueneau-Majlessi, Isabelle; Ellens, Harma; Feng, Bo; Taub, Mitchell E; Paine, Mary F; Polli, Joseph W; Ware, Joseph A; Zamek-Gliszczynski, Maciej J

    2015-04-01

    Breast cancer resistance protein (BCRP; ABCG2) limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, immediate-release tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended. In the case of rosuvastatin, subjects with the organic anion-transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatin's cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design.

  18. In Vivo and in Vitro Study on Drug-Drug Interaction of Lovastatin and Berberine from Pharmacokinetic and HepG2 Cell Metabolism Studies.

    PubMed

    Cui, Hanming; Wang, Jialong; Zhang, Qiuyan; Dang, Mengmeng; Liu, Hui; Dong, Yu; Zhang, Lu; Yang, Fang; Wu, Jianhua; Tong, Xiaolin

    2016-04-08

    We assumed that the pharmacokinetics of lovastatin could be changed by the induction effect of berberine. An UPLC-MS/MS method was developed and validated for the pharmacokinetics tudy of lovastatin to investigate the in vivo drug-drug interactions between lovastatin and berberine. SD male rats were random divided into lovastatin group and berberine induced prior to lovastatin group for the in vivo pharmacokinetic studies. Meanwhile HepG2 cells were induced by berberine for three days to study the metabolism of lovastatin. The AUC (p < 0.01) and Cmax (p < 0.01) could be significantly decreased in the berberine-induced group in vivo, and the metabolic activity of HepG2 cell ccould be increased by berberine induction in vitro. The metabolism parameters of lovastatin such as CL, Vmax and Km were increased after the induction of berberine. From the pharmacokinetic study of lovastatin induced with berberine, we obtained pharmacokinetic parameters which are compliance with the metabolic parameters of lovastatin in HepG2 cells with berberine induction in vitro. From the in vivo pharmacokinetics study and the HepG2 cell metabolism study in vitro, berberine could be an inducer for the metabolism of lovastatin according to our previous research on berberine induction effects on HepG2 cells, which may be relevant to the fact that berberine possesses induction effects through the CYP 450 3A4 enzyme.

  19. Mechanisms and Consequences of Drug-Drug Interactions.

    PubMed

    Greenblatt, David J

    2017-03-01

    Medications used to treat human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections present a special challenge with respect to the management of potential and actual drug-drug interactions (DDIs). The HIV and HCV treatments may interact with each other, and also interact with drugs of abuse and/or with medications used to treat substance abuse. Possible mechanisms of these DDIs generally include induction or inhibition of activity/expression of human cytochromes P450, glucuronosyl transferases, or energy-dependent transport proteins. These DDIs can be complex and time-dependent in nature. Because time and resources available for new drug development are necessarily limited, not all potential DDIs can be evaluated via clinical pharmacokinetic studies in the course of development of HIV, HCV, and substance abuse treatments. Strategies are needed to refine existing in vitro models and screening techniques to allow more efficient targeting of resources to those clinical studies having the highest impact in terms of enhancing medication effectiveness and patient safety.

  20. Enterprise-wide drug-drug interaction alerting system.

    PubMed

    Greim, Julie A; Shek, Caroline; Jones, Linda; Macauley, Robert; Paterno, Marilyn; Blumenfeld, Barry H; Kuperman, Gilad

    2003-01-01

    According to the Institute of Medicine's (IOM) 1999 report To Err is Human: Building a safer Health System, "medical errors kill some 44,000-98,0001 people in U.S. hospitals each year. Partners HealthCare System (PHS) is a large integrated delivery network in Boston, MA, which has as a goal improving patient care by preventing adverse drug events (ADE) and reducing medication errors enterprise-wide. PHS has developed a drug-drug Interaction (DDI) detection feature, for the suite of clinical applications currently used by its two major teaching institutions, Brigham & Women's Hospital (BWH) and Mass General Hospital (MGH). The following clinical applications will be using this drug-drug interaction feature: NICU Order Entry (OE) at BWH, MGH OE for pediatrics and adults, the Partners outpatient medical record, The LMR, and BICS OE at BWH.

  1. Prediction of transporter-mediated drug-drug interactions using endogenous compounds.

    PubMed

    Fromm, M F

    2012-11-01

    Therapy with two or more drugs is more the rule than the exception, particularly in aging societies. Drug-drug interactions are frequently undesirable and may lead to increased toxicity and mortality. Inhibition of transporters is one major mechanism underlying drug-drug interactions. The myriad of potential drug combinations makes it very challenging to predict drug-drug interactions. This Commentary discusses potential advantages and limitations of endogenous compounds for predicting transporter-mediated drug-drug interactions.

  2. A Rapid Study of Botanical Drug-Drug Interaction with Protein by Re-ligand Fishing using Human Serum Albumin-Functionalized Magnetic Nanoparticles.

    PubMed

    Qing, Lin-Sen; Xue, Ying; Ding, Li-Sheng; Liu, Yi-Ming; Liang, Jian; Liao, Xun

    2015-12-01

    A great many active constituents of botanical drugs bind to human serum albumin (HSA) reversibly with a dynamic balance between the free- and bound-forms in blood. The curative or side effect of a drug depends on its free-form level, which is always influenced by other drugs, combined dosed or multi-constituents of botanical drugs. This paper presented a rapid and convenient methodology to investigate the drug-drug interactions with HSA. The interaction of two steroidal saponins, dioscin and pseudo-protodioscin, from a botanical drug was studied for their equilibrium time and equilibrium amount by re-ligand fishing using HSA functionalized magnetic nanoparticles. A clear competitive situation was obtained by this method. The equilibrium was reached soon about 15 s at a ratio of 0.44: 1. Furthermore, the interaction of pseudo-protodioscin to total steroidal saponins from DAXXK was also studied. The operation procedures of this method were faster and more convenient compared with other methods reported.

  3. A clinician's guide to statin drug-drug interactions.

    PubMed

    Kellick, Kenneth A; Bottorff, Michael; Toth, Peter P; The National Lipid Association's Safety Task Force

    2014-01-01

    The statins are widely used worldwide to reduce risk for cardiovascular events in both the primary and secondary prevention settings. Although generally quite safe, the statins can be associated with a variety of serious side adverse effects, including myalgia, myopathy, and changes in plasma enzymes of hepatic origin. Although rare, the most serious of these is rhabdomyolysis. Several drugs can interfere with the metabolism and disposal of the statins, thereby increasing risk for adverse events. It is important that clinicians treating patients with statins be aware of the potential for drug-drug interactions between each statin and specific other drugs and take measures to prevent them. The prediction of potential drug-drug interactions derives from basic pharmacokinetic principles. Certain drug interactions are predicted by measuring the effect of interacting drugs on blood plasma concentrations of the statin. Individual patient variations resulting in part from polymorphisms in the metabolizing enzymes confound some of these predictions. Based on these known effects, a new classification for predicting statin drug interactions is proposed. This report discusses likely prescription and nonprescription interactions as well as potential alternatives for special populations.

  4. Reaction phenotyping to assess victim drug-drug interaction risks.

    PubMed

    Di, Li

    2017-08-18

    Reaction phenotyping provides critical information regarding the fraction metabolized (fm) of drug candidates. It has become increasingly important in drug discovery and development as it can be used to assess victim drug-drug interaction potential, guide structural modification to reduce fm, inform clinical study design, predict individual variability in pharmacokinetics, and evaluate the impact of genetic polymorphisms. Areas covered: The currently available in vitro and in vivo methods for reaction phenotyping are summarized along with their advantages, limitations and timings for application during the different stages of drug discovery and development. Challenges of reaction phenotyping for low clearance compounds, non-Cytochrome P450 (CYP) enzymes, extrahepatic contribution and atypical kinetics are highlighted and various approaches are discussed. Expert opinion: Certain areas of reaction phenotyping remain challenging with the current state of the science. In order to better define fm in this challenging space, there needs to be future advances in selective inhibitors and specific substrate reactions for non-CYP enzymes, availability of high quality and low cost recombinant enzymes, tissue distribution and in vitro-in vivo correlation, scaling factors for extrahepatic enzymes and the next generation of low clearance tools.

  5. A retrospective, matched cohort study of potential drug-drug interaction prevalence and opioid utilization in a diabetic peripheral neuropathy population initiated on pregabalin or duloxetine.

    PubMed

    Ellis, Jeffrey J; Sadosky, Alesia B; Ten Eyck, Laura L; Mudumby, Pallavi; Cappelleri, Joseph C; Ndehi, Lilian; Suehs, Brandon T; Parsons, Bruce

    2015-04-15

    Anticipating and controlling drug-drug interactions (DDIs) in older patients with painful diabetic peripheral neuropaty (pDPN) presents a significant challenge to providers. The purpose of this study was to examine the impact of newly initiated pregabalin or duloxetine treatment on Medicare Advantage Prescription Drug (MAPD) plan pDPN patients' encounters with potential drug-drug interactions, the healthcare cost and utilization consequences of those interactions, and opioid utilization. Study subjects required a pregabalin or duloxetine pharmacy claim between 07/01/2008-06/30/2012 (index event), ≥1 inpatient or ≥2 outpatient medical claims with pDPN diagnosis between 01/01/2008-12/31/2012, and ≥12 months pre- and ≥6 post-index enrollment. Propensity score matching was used to balance the pregabalin and duloxetine cohorts on pre-index demographics and comorbidities. Potential DDIs were defined by Micromedex 2.0 and identified by prescription claims. Six-month post-index healthcare utilization (HCU) and costs were calculated using pharmacy and medical claims. No significant differences in pre-index demographics or comorbidities were found between pregabalin subjects (n = 446) and duloxetine subjects (n = 446). Potential DDI prevalence was significantly greater (p < 0.0001) among duoxetine subjects (56.7%) than among pregabalin subjects (2.9%). There were no significant differences in HCU or costs between pregablin subjects with and without a potential DDI. By contrast, duloxetine subjects with a potential DDI had higher mean all-cause costs ($13,908 vs. $9,830; p = 0.001), more subjects with ≥1 inpatient visits (35.6% vs 25.4%; p = 0.02), and more subjects with ≥1 emergency room visits (32.8% vs. 20.7%; p = 0.005) in comparison to duloxetine subjects without a potential DDI. There was a trend toward a difference between pregabalin and duloxetine subjects in their respective pre-versus-post differences in milligrams (mg) of

  6. Mechanism of Drug-Drug Interactions Between Warfarin and Statins.

    PubMed

    Shaik, Abdul Naveed; Bohnert, Tonika; Williams, David A; Gan, Lawrence L; LeDuc, Barbara W

    2016-06-01

    The anticoagulant drug warfarin and the lipid-lowering statin drugs are commonly co-administered to patients with cardiovascular diseases. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized through case studies for many years, but the biochemical mechanisms causing these interactions have not been explained fully. Previous theories include kinetic alterations in cytochrome P-450-mediated drug metabolism or disturbances of drug-protein binding, leading to anticoagulant activity of warfarin; however, neither the enantioselective effects on warfarin metabolism nor the potential disruption of drug transporter function have been well investigated. This study investigated the etiology of the DDIs between warfarin and statins. Liquid chromatography-mass spectrometry methods were developed and validated to quantify racemic warfarin, 6 of its hydroxylated metabolites, and pure enantiomers of warfarin; these methods were applied to study the role of different absorption, distribution, metabolism, and excretion properties, leading to DDIs. Plasma protein binding displacement of warfarin was performed in the presence of statins using equilibrium dialysis method. Substrate kinetics of warfarin and pure enantiomers were performed with human liver microsomes to determine the kinetic parameters (Km and Vmax) for the formation of all 6 hydroxywarfarin metabolites, inhibition of warfarin metabolism in the presence of statins, was determined. Uptake transport studies of warfarin were performed using overexpressing HEK cell lines and efflux transport using human adenocarcinoma colonic cell line cells. Fluvastatin significantly displaced plasma protein binding of warfarin and pure enantiomers; no other statin resulted in significant displacement of warfarin. All the statins that inhibited the formation of 10-hydroxywarfarin, atorvastatin, pitavastatin, and simvastatin were highly potent compared to other statins; in contrast, only fluvastatin

  7. Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies.

    PubMed

    Greenblatt, David J; Harmatz, Jerold S

    2015-09-01

    The regulatory prohibition of ketoconazole as a CYP3A index inhibitor in drug-drug interaction (DDI) studies has compelled consideration of alternative inhibitors. The biomedical literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either ketoconazole, itraconazole, clarithromycin, or ritonavir. The ratios (RAUC ) of total area under the curve (AUC) for MDZ with inhibitor divided by MDZ AUC in the control condition were aggregated across individual studies for each inhibitor. Mean (± SE) RAUC values were: ketoconazole (15 studies, 131 subjects), 11.5 (±1.2); itraconazole (five studies, 48 subjects), 7.3 (±1.0); clarithromycin (five studies, 73 subjects), 6.5 (±10.9); and ritonavir (13 studies, 159 subjects), 14.5 (±2.0). Differences among inhibitors were significant (F = 5.31, P < 0.005). RAUC values were not significantly related to inhibitor dosage or to duration of inhibitor pre-exposure prior to administration of MDZ. Ritonavir produces CYP3A inhibition equivalent to or greater than ketoconazole, and is the best index CYP3A inhibitor alternative to ketoconazole. Cobicistat closely resembles ritonavir in structure and function, and can also be considered. Itraconazole and clarithromycin are not suitable alternatives since they do not produce inhibition comparable with ketoconazole or ritonavir, and have other significant disadvantages as well. © 2015 The British Pharmacological Society.

  8. Clinical pharmacokinetics, metabolism, and drug-drug interaction of carfilzomib.

    PubMed

    Wang, Zhengping; Yang, Jinfu; Kirk, Christopher; Fang, Ying; Alsina, Melissa; Badros, Ashraf; Papadopoulos, Kyriakos; Wong, Alvin; Woo, Tina; Bomba, Darrin; Li, Jin; Infante, Jeffrey R

    2013-01-01

    Carfilzomib, an irreversible proteasome inhibitor, has a favorable safety profile and significant antitumor activity in patients with relapsed and refractory multiple myeloma (MM). Here we summarize the clinical pharmacokinetics (PK), metabolism, and drug-drug interaction (DDI) profile of carfilzomib. The PK of carfilzomib, infused over 2-10 minutes, was evaluated in patients with solid tumors or MM. Metabolites of carfilzomib were characterized in patient plasma and urine samples. In vitro drug metabolism and DDI studies were conducted in human liver microsomes and hepatocytes. A clinical DDI study was conducted in patients with solid tumors to evaluate the effect of carfilzomib on CYP3A activity. Plasma concentrations of carfilzomib declined rapidly and in a biphasic manner after intravenous administration. The systemic half-life was short and the systemic clearance rate was higher than hepatic blood flow. Carfilzomib was cleared largely extrahepatically via peptidase cleavage and epoxide hydrolysis. Cytochrome P450-mediated metabolism played a minor role, suggesting that coadministration of P450 inhibitors or inducers is unlikely to change its PK profile. Carfilzomib showed direct and time-dependent inhibition of CYP3A in human liver microsome preparations and exposure to carfilzomib resulted in reductions in CYP3A and 1A2 gene expression in cultured human hepatocytes. However, administration of carfilzomib did not affect the PK of midazolam in patients with solid tumors, and there were no safety signals indicative of potential drug interactions. We conclude that the rapid systemic clearance and short half-life of carfilzomib limit clinically significant DDI.

  9. DRUG-DRUG INTERACTION PROFILES OF MEDICATION REGIMENS EXTRACTED FROM A DE-IDENTIFIED ELECTRONIC MEDICAL RECORDS SYSTEM

    PubMed Central

    Butkiewicz, Mariusz; Restrepo, Nicole A.; Haines, Jonathan L.; Crawford, Dana C.

    2016-01-01

    With age, the number of prescribed medications increases and subsequently raises the risk for adverse drug-drug interactions. These adverse effects lower quality of life and increase health care costs. Quantifying the potential burden of adverse effects before prescribing medications can be a valuable contribution to health care. This study evaluated medication lists extracted from a subset of the Vanderbilt de-identified electronic medical record system. Reported drugs were cross-referenced with the Kyoto Encyclopedia of Genes and Genomes DRUG database to identify known drug-drug interactions. On average, a medication regimen contained 6.58 medications and 2.68 drug-drug interactions. Here, we quantify the burden of potential adverse events from drug-drug interactions through drug-drug interaction profiles and include a number of alternative medications as provided by the Anatomical Therapeutic Chemical Classification System. PMID:27570646

  10. Clinically relevant drug-drug interactions between antiretrovirals and antifungals

    PubMed Central

    Vadlapatla, Ramya Krishna; Patel, Mitesh; Paturi, Durga K; Pal, Dhananjay; Mitra, Ashim K

    2015-01-01

    Introduction Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide. Areas covered Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations. Expert opinion Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echino-candins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections. PMID:24521092

  11. Prevalence and Correlates of Drug-drug Interactions in the Regional Hospital of Gjilan, Kosovo.

    PubMed

    Shabani, Driton; Tahiri, Zejdush; Bara, Petrit; Hudhra, Klejda; Malaj, Ledian; Jucja, Besnik; Bozalia, Adnan; Burazeri, Genc

    2014-08-01

    Our aim was to assess the prevalence and socioeconomic and clinical correlates of drug-drug interactions among the adult population of transitional Kosovo. A cross-sectional study was conducted including a representative sample of 1921 patients aged ≥18 years (mean age: 57.8±11.2 years; 50.3% women; overall response: 96%) from the regional hospital of Gjilan, Kosovo, during 2011-2013. Potential drug-drug-interactions were assessed and clinical data as well as demographic and socioeconomic information were collected. Binary logistic regression was used to assess the correlates of drug-drug interactions. Upon multivariable adjustment for all the demographic and socioeconomic factors as well as the clinical characteristics, drug-drug interactions were positively and significantly related to older age (OR=2.1, 95%CI=1.3-2.8), a lower educational attainment (OR=1.4, 95%CI=1.1-1.9), a longer hospitalization period (OR=2.7, 95%CI=2.1-3.6), presence of three groups of diseases [infectious diseases (OR=1.7, 95%CI=1.3-2.4), cardiovascular diseases (OR=1.8, 95%CI=1.4-2.6), respiratory diseases (OR=1.6, 95%CI=1.2-2.5)], presence of comorbid conditions (OR=3.2, 95%CI=2.3-4.4) and an intake of at least four drugs (OR=5.9, 95%CI=4.6-7.1). Our study provides important evidence on the prevalence and socioeconomic and clinical correlates of drug-drug interactions among the hospitalized patients in the regional hospital of Gjilan, Kosovo. Findings from our study should raise the awareness of decision-makers and policy makers about the prevalence and determinants of drug-drug interactions in the adult population of post-war Kosovo.

  12. Prevalence and Correlates of Drug-drug Interactions in the Regional Hospital of Gjilan, Kosovo

    PubMed Central

    Shabani, Driton; Tahiri, Zejdush; Bara, Petrit; Hudhra, Klejda; Malaj, Ledian; Jucja, Besnik; Bozalia, Adnan; Burazeri, Genc

    2014-01-01

    Aim: Our aim was to assess the prevalence and socioeconomic and clinical correlates of drug-drug interactions among the adult population of transitional Kosovo. Methods: A cross-sectional study was conducted including a representative sample of 1921 patients aged ≥18 years (mean age: 57.8±11.2 years; 50.3% women; overall response: 96%) from the regional hospital of Gjilan, Kosovo, during 2011-2013. Potential drug-drug-interactions were assessed and clinical data as well as demographic and socioeconomic information were collected. Binary logistic regression was used to assess the correlates of drug-drug interactions. Results: Upon multivariable adjustment for all the demographic and socioeconomic factors as well as the clinical characteristics, drug-drug interactions were positively and significantly related to older age (OR=2.1, 95%CI=1.3-2.8), a lower educational attainment (OR=1.4, 95%CI=1.1-1.9), a longer hospitalization period (OR=2.7, 95%CI=2.1-3.6), presence of three groups of diseases [infectious diseases (OR=1.7, 95%CI=1.3-2.4), cardiovascular diseases (OR=1.8, 95%CI=1.4-2.6), respiratory diseases (OR=1.6, 95%CI=1.2-2.5)], presence of comorbid conditions (OR=3.2, 95%CI=2.3-4.4) and an intake of at least four drugs (OR=5.9, 95%CI=4.6-7.1). Conclusions: Our study provides important evidence on the prevalence and socioeconomic and clinical correlates of drug-drug interactions among the hospitalized patients in the regional hospital of Gjilan, Kosovo. Findings from our study should raise the awareness of decision-makers and policy makers about the prevalence and determinants of drug-drug interactions in the adult population of post-war Kosovo. PMID:25395892

  13. Clinical drug-drug interactions: focus on venlafaxine.

    PubMed

    Magalhães, Paulo; Alves, Gilberto; LLerena, Adrián; Falcão, Amílcar

    2015-03-01

    Venlafaxine (VEN) is an antidepressant agent widely used nowadays as an alternative to selective serotonin reuptake inhibitors (SSRIs), particularly for the treatment of SSRI-resistant depression. As the co-administration of antidepressant drugs with other medications is very common in clinical practice, the potential risk for pharmacokinetic and/or pharmacodynamic drug interactions that may be clinically meaningful increases. Bearing in mind that VEN has exhibited large variability in antidepressant response, besides the individual genetic background, several other factors may contribute to those variable clinical outcomes, such as the occurrence of significant drug-drug interactions. Indeed, the presence of drug interactions is possibly one of the major reasons for interindividual variability, and their anticipation should be considered in conjugation with other specific patients' characteristics to optimize the antidepressant therapy. Hence, a comprehensive overview of the pharmacokinetic- and pharmacodynamic-based drug interactions involving VEN is herein provided, particularly addressing their clinical relevance.

  14. Expected and actual adverse drug-drug interactions in elderly patients accessing the emergency department: data from the ANCESTRAL-ED study.

    PubMed

    Marino, A; Capogrosso-Sansone, A; Tuccori, M; Bini, G; Calsolaro, V; Mantarro, S; Convertino, I; Pasqualetti, G; Orsitto, E; Santini, M; Monzani, F; Blandizzi, C

    2016-12-01

    This study was aimed at evaluating the frequency and describing the adverse drug-drug interactions (DDIs) recorded among elderly patients accessing the emergency department (ED). Patients aged ≥65 years, accessing the ED of Pisa University Hospital (Italy) from 1 January 2015 to 31 December 2015 within the ANCESTRAL-ED program, were included in this study. 'Expected' DDIs were assessed using Thomson Micromedex®. Each ED admission (discharge diagnosis) consistent with the signs and symptoms of an expected DDI for each patient was classified as an 'actual' DDI. Throughout the study period, 3473 patients (3812 ED admissions, 58% females, mean age: 80.3) were recorded. The total number of expected DDIs was 12,578 (67 contraindicated; 3334 major; 8878 moderate; 299 minor) detected in 2147 (62%) patients. Overall 464 expected DDIs were found to be consistent with the ED admission in 194 patients (representing 9% of patients with expected DDIs). More than one half of elderly patients admitted to ED presented at least one expected DDI at the time of ED presentation. However, 9% of the expected DDIs were identified as actual DDIs, based on the consistency of the expected event with the ED discharge diagnosis.

  15. Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin

    PubMed Central

    Park, Min-Ho; Shin, Seok-Ho; Byeon, Jin-Ju; Lee, Gwan-Ho; Yu, Byung-Yong

    2017-01-01

    Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the “fit for purpose” application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in Cmax of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds. PMID:28066147

  16. 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.

  17. Lack of pharmacokinetic drug-drug interaction between ramucirumab and paclitaxel in a phase II study of patients with advanced malignant solid tumors.

    PubMed

    Chow, Laura Q M; Smith, David C; Tan, Antoinette R; Denlinger, Crystal S; Wang, Ding; Shepard, Dale R; Chaudhary, Archana; Lin, Yong; Gao, Ling

    2016-08-01

    The objective of this phase II study was to evaluate pharmacokinetic interaction potential between ramucirumab and paclitaxel in patients with advanced cancer. This study was designed to assess 2-way pharmacokinetic drug-drug interactions between ramucirumab and paclitaxel. Twenty-four patients participated in Part A, which consisted of a 2-week monotherapy period in which paclitaxel 80 mg/m(2) was administered on day 1, followed by a 4-week cycle of combination treatment with ramucirumab (8 mg/kg on days 1 and 15; paclitaxel on days 1, 8, and 15). Patients could continue to receive combination therapy with ramucirumab and paclitaxel. In 16 patients in Part B, ramucirumab monotherapy was administered on day 1 of a 3-week cycle. Patients could continue to receive ramucirumab monotherapy or combination therapy with paclitaxel. Concomitant administration of ramucirumab had no effect on pharmacokinetics of paclitaxel, with ratios of geometric least squares (LS) means (with ramucirumab vs. alone) of 1.09 (90 % confidence interval [CI] 0.93, 1.29) for AUC(0-∞) and 0.97 (90 % CI 0.83, 1.13) for C max. In addition, similar ramucirumab pharmacokinetic characteristics were observed with or without paclitaxel administration. The ratios of geometric LS means of AUC(0-∞) and C max of ramucirumab (with paclitaxel vs. alone) were 1.00 (90 % CI 0.84, 1.19) for AUC(0-∞) and 1.07 (90 % CI 0.93, 1.24) for C max, respectively. Concomitant paclitaxel administration is unlikely to affect the pharmacokinetics of ramucirumab, and vice versa. The incidence and severity of adverse events were consistent with the known safety profiles of paclitaxel and ramucirumab.

  18. Prolonged Drug-Drug Interaction between Terbinafine and Perphenazine.

    PubMed

    Park, Young-Min

    2012-12-01

    I report here an elderly woman receiving perphenazine together with terbinafine. After 1 week of terbinafine treatment she experienced extrapyramidal symptoms and, in particular, akathisia. Her symptoms did not disappear for 6 weeks, and so at 2 weeks prior to this most recent admission she had stopped taking terbinafine. However, these symptoms persisted for 3 weeks after discontinuing terbinafine. It is well known that terbinafine inhibits CYP2D6 and that perphenazine is metabolized mainly by CYP2D6. Thus, when terbinafine and perphenazine are coadministrated, the subsequent increase in the concentration of perphenazine may induce extrapyramidal symptoms. Thus, terbinafine therapy may be associated with the induction and persistence of extrapyramidal symptoms, including akathisia. This case report emphasizes the importance of monitoring drug-drug interactions in patients undergoing terbinafine and perphenazine therapy.

  19. Drug-Drug Interaction Extraction via Convolutional Neural Networks.

    PubMed

    Liu, Shengyu; Tang, Buzhou; Chen, Qingcai; Wang, Xiaolong

    2016-01-01

    Drug-drug interaction (DDI) extraction as a typical relation extraction task in natural language processing (NLP) has always attracted great attention. Most state-of-the-art DDI extraction systems are based on support vector machines (SVM) with a large number of manually defined features. Recently, convolutional neural networks (CNN), a robust machine learning method which almost does not need manually defined features, has exhibited great potential for many NLP tasks. It is worth employing CNN for DDI extraction, which has never been investigated. We proposed a CNN-based method for DDI extraction. Experiments conducted on the 2013 DDIExtraction challenge corpus demonstrate that CNN is a good choice for DDI extraction. The CNN-based DDI extraction method achieves an F-score of 69.75%, which outperforms the existing best performing method by 2.75%.

  20. Drug-Drug Interaction Extraction via Convolutional Neural Networks

    PubMed Central

    Liu, Shengyu; Tang, Buzhou; Chen, Qingcai; Wang, Xiaolong

    2016-01-01

    Drug-drug interaction (DDI) extraction as a typical relation extraction task in natural language processing (NLP) has always attracted great attention. Most state-of-the-art DDI extraction systems are based on support vector machines (SVM) with a large number of manually defined features. Recently, convolutional neural networks (CNN), a robust machine learning method which almost does not need manually defined features, has exhibited great potential for many NLP tasks. It is worth employing CNN for DDI extraction, which has never been investigated. We proposed a CNN-based method for DDI extraction. Experiments conducted on the 2013 DDIExtraction challenge corpus demonstrate that CNN is a good choice for DDI extraction. The CNN-based DDI extraction method achieves an F-score of 69.75%, which outperforms the existing best performing method by 2.75%. PMID:26941831

  1. Evaluation of drug-drug interaction screening software combined with pharmacist intervention.

    PubMed

    Moura, Cristiano S; Prado, Nília M; Belo, Najara O; Acurcio, Francisco A

    2012-08-01

    Drug-drug interactions (DDI) in hospitalized patients are highly prevalent and an important source of adverse drug reactions. DI computerized screening system can prevent the occurrence of some of these events. To evaluate the impact of drug-drug interaction (DDI) screening software combined with active intervention in preventing drug interactions. The study was conducted at General Hospital of Vitória da Conquista (HGVC), Brazil. A quasi-experimental study was used to evaluate the impact of IM-Pharma, a locally developed drug-drug interaction screening system, coupled with pharmacist intervention on adverse drug events in the hospital setting. The proportion of patients co-prescribed two interacting drugs were measured in two phases, prior the implementation of IM-Pharma and during the intervention period. DDI rates per 100 patient days were calculated before and after implementation. Risk ratios were estimated by Poisson regression models. A total of 6,834 instances of drug-drug interactions were identified; there was an average of 3.3 DDIs per patient in phase one and 2.5 in phase two, a reduction of 24 % (P = 0.03). There was a 71 % reduction in high-severity drug-drug interaction (P < 0.01). The risk for all DDIs decreased 50 % after the implementation of IM-Pharma (P < 0.01), and for those with high-severity, the reduction was 81 % (P < 0.01). The performance of IM-Pharma combined with pharmacist intervention was positive with an expressive reduction in the risk of DDIs.

  2. USING SEMANTIC PREDICATIONS TO UNCOVER DRUG-DRUG INTERACTIONS IN CLINICAL DATA

    PubMed Central

    Zhang, Rui; Cairelli, Michael J.; Fiszman, Marcelo; Rosemblat, Graciela; Kilicoglu, Halil; Rindflesch, Thomas C.; Pakhomov, Serguei V.; Melton, Genevieve B.

    2014-01-01

    In this study we report on potential drug-drug interactions between drugs occurring in patient clinical data. Results are based on relationships in SemMedDB, a database of structured knowledge extracted from all MEDLINE citations (titles and abstracts) using SemRep. The core of our methodology is to construct two potential drug-drug interaction schemas, based on relationships extracted from SemMedDB. In the first schema, Drug1 and Drug2 interact through Drug1’s effect on some gene, which in turn affects Drug2. In the second, Drug1 affects Gene1, while Drug2 affects Gene2. Gene1 and Gene2, together, then have an effect on some biological function. After checking each drug pair from the medication lists of each of 22 patients, we found 19 known and 62 unknown drug-drug interactions using both schemas. For example, our results suggest that the interaction of Lisinopril, an ACE inhibitor commonly prescribed for hypertension, and the antidepressant sertraline can potentially increase the likelihood and possibly the severity of psoriasis. We also assessed the relationships extracted by SemRep from a linguistic perspective and found that the precision of SemRep was 0.58 for 300 randomly selected sentences from MEDLINE. Our study demonstrates that the use of structured knowledge in the form of relationships from the biomedical literature can support the discovery of potential drug-drug interactions occurring in patient clinical data. Moreover, SemMedDB provides a good knowledge resource for expanding the range of drugs, genes, and biological functions considered as elements in various drug-drug interaction pathways. PMID:24448204

  3. Using a Simulated Infobutton Linked to an Evidence-Based Resource to Research Drug-Drug Interactions: A Pilot Study with Third-Year Dental Students.

    PubMed

    Dragan, Irina F; Newman, Michael; Stark, Paul; Steffensen, Bjorn; Karimbux, Nadeem

    2015-11-01

    Many health professions students and clinicians are using evidence-based databases that allow for quicker and more accurate clinical decisions. The aims of this pilot study were to compare third-year dental students' speed and accuracy in researching questions about drug-drug interactions (DDI) when using two different methods: a simulated infobutton linked to the evidence-based clinical decision support resource UpToDate versus traditional Internet resources accessed through a computer or smart device. Students researched two simulated cases during two sessions. In the first session, half the students used the infobutton, while the other half used traditional electronic tools only. In the second session, ten days later, a cross-over took place. The sessions were timed, and after researching the case, students answered three questions on the use of antibiotics, analgesics, and local anesthetics. Of the 50 students who volunteered for the study, two were excluded, and 44 participated in both sessions and the exam. The results showed that the students took a similar amount of time to identify DDI whether they used the infobutton (mean=286.5 seconds) or traditional tools (265.2 seconds); the difference was not statistically significant (p=0.429). Their scores using the two research methods were similar in all three content areas: antibiotics (p=0.797), analgesics (p=0.850), and local anesthetics (p=0.850). In a post-intervention survey, students were generally favorable about infobutton and UpToDate, reporting the tool was easy to use (62.5%), provided the answer they were looking for (53.1%), was fast (50%), and they would use it again (68.8%). This pilot study found that the time and accuracy of these students conducting DDI research with the infobutton and UpToDate were about the same as using traditional Internet resources.

  4. Drug-drug interactions that interfere with statin metabolism.

    PubMed

    Hirota, Takeshi; Ieiri, Ichiro

    2015-01-01

    Lipid-lowering drugs, especially hydroxymethylglutaryl-CoA reductase inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic diseases. The benefits of statins are well documented. However, myotoxic side effects, which can sometimes be severe, including myopathy or rhabdomyolysis, have been associated with the use of statins. In some cases, this toxicity is associated with pharmacokinetic alterations. Potent inhibitors of CYP 3A4 significantly increase plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin. Fluvastatin is metabolized by CYP2C9, while pravastatin, rosuvastatin and pitavastatin are not susceptible to inhibition by any CYP. This review discusses the pharmacokinetic aspects of the drug-drug interaction with statins and genetic polymorphisms in CYPs, which are involved in the metabolism of statins, and highlights the importance of establishing a system utilizing electronic medical information practically to avoid adverse drug reactions. An understanding of the mechanisms underlying statin interactions will help to minimize drug interactions and develop statins that are less prone to adverse interactions. Quantitatively analyzed information for the low-density lipoprotein cholesterol lowering effects of statin based on electronic medical records may be useful for avoiding the adverse effect of statins.

  5. Importance of cytochrome P450 (CYP450) in adverse drug reactions due to drug-drug interactions: a PharmacoVigilance study in France.

    PubMed

    Danton, Anne Charlotte; Montastruc, François; Sommet, Agnès; Durrieu, Geneviève; Bagheri, Haleh; Bondon-Guitton, Emmanuelle; Lapeyre-Mestre, Maryse; Montastruc, Jean-Louis

    2013-04-01

    Our aim was to characterize Adverse Drug Reactions (ADRs) related to drug-drug interactions (DDIs) related to involvement of cytochrome P450 (CYP450) isoenzymes in a pharmacovigilance database. ADRs recorded by Midi-Pyrénées PharmacoVigilance center (France) between 1 January and 31 August 2008 were extracted from the French PharmacoVigilance Database (FPVD). Among the 1,205 reported ADRs, 16 (1.3 %), can be explained by involvement of CYP450 isoenzymes (including 4 "serious"). All interactions involved CYP inhibitors, mainly for CYP3A4/5. The percentage of ADRs reported in the pharmacovigilance database and related to CYP450-induced DDIs appears to be relatively low (~ 1-2 %).

  6. The prevalence and preventability of potentially relevant drug-drug interactions in patients admitted for cardiovascular diseases: A cross-sectional study.

    PubMed

    Kovačević, Milena; Vezmar Kovačević, Sandra; Miljković, Branislava; Radovanović, Slavica; Stevanović, Predrag

    2017-10-01

    The aim was to describe the type and prevalence of potentially relevant drug-drug interactions (pDDIs) in a population of patients admitted for cardiovascular diseases (CVD), and management strategies for reducing the occurrence of pDDIs. A retrospective cross-sectional study was performed on Cardiology ward of University Clinical Hospital Center in Belgrade, Serbia. A total of 527 patients, with more than one prescription during hospital stay, were enrolled in this study. Data were obtained from medical records. LexiInteract was used as the screening tool. At least one potentially relevant pDDI was identified in 83.9% of patients. Occurrence was significantly more prevalent in patients with higher number of drugs, multimorbidity, longer length of stay, arrhythmia, heart failure, infectious and respiratory disease. About 13% of pDDIs exposures were accompanied with concurrent renal or liver disease, as an additional risk for DDI manifestation. Among CVD, patients with a history of myocardial infarction possessed the highest additional risk. The most common potential clinical outcome was the effect on cardiovascular system 48.5%, renal function and/or potassium 22.3%, bleeding 9.5%, impaired glucose control 6.8% and digoxin toxicity 4.6%. Main management strategies to avoid X or D class included using paracetamol instead of NSAID or alternative NSAID (38%), alternative antibiotic or antifungal (20.4%), H2 receptor antagonist instead of PPI (8.3%), avoiding therapeutic duplication (7.3%), and alternative HMG-CoA reductase inhibitor (7%). Heart rate, blood pressure, electrolytes/potassium and blood glucose could have been employed in monitoring for potential consequence of 72.2% C class pDDIs. Use of drug interaction screening tools can be beneficial risk mitigation strategy for potentially relevant pDDIs in CVD patients. DDI screening software could be linked to the patient's laboratory results or clinical data regarding renal or liver function, as an approach to

  7. Data mining for potential adverse drug-drug interactions.

    PubMed

    Hammann, Felix; Drewe, Juergen

    2014-05-01

    Patients, in particular elderly ones, frequently receive more than one drug at a time. With each drug added to a regime, the number of potential drug-drug interactions (DDIs) increases by a power law. Early prediction of relevant interactions by computerized tools greatly aids clinicians and can guide their prescribing choices. In this article, we discuss different types of DDIs, on which levels they can arise and what efforts have been made in the past to detect and predict them. The emphasis is on data mining technology and network analysis, but overlaps with traditional pharmacovigilance are also discussed. Finally, we discuss strategies to focus and simplify mining efforts to get meaningful results with less effort. The necessary technology for detecting adverse DDIs exists and is quite refined, although it is more often implied in lower risk scenarios (such as syntactic analysis in web searches and online libraries). Data mining for DDIs, on the other hand, still requires a great deal of human intervention, not only to validate the results but also, more importantly, to separate the relevant from the spurious. The fields of network analysis and graph theory show great promise but have not yet shown much beyond descriptive analyses.

  8. Assessment tool for pharmacy drug-drug interaction software.

    PubMed

    Warholak, Terri L; Hines, Lisa E; Saverno, Kim R; Grizzle, Amy J; Malone, Daniel C

    2011-01-01

    To assess the performance of pharmacy clinical decision support (CDS) systems for drug-drug interaction (DDI) detection and to identify approaches for improving the ability to recognize important DDIs. Pharmacists rely on CDS systems to assist in the identification of DDIs, and research suggests that these systems perform suboptimally. The software evaluation tool described here may be used in all pharmacy settings that use electronic decision support to detect potential DDIs, including large and small community chain pharmacies, community independent pharmacies, hospital pharmacies, and governmental facility pharmacies. A tool is provided to determine the ability of pharmacy CDS systems to identify established DDIs. It can be adapted to evaluate potential DDIs that reflect local practice patterns and patient safety priorities. Beyond assessing software performance, going through the evaluation processes creates the opportunity to evaluate inadequacies in policies, procedures, workflow, and training of all pharmacy staff relating to pharmacy information systems and DDIs. The DDI evaluation tool can be used to assess pharmacy information systems' ability to recognize relevant DDIs. Suggestions for improvement include determining whether the software allows for customization, creating standard policies for handling specific interactions, and ensuring that drug knowledge database updates occur frequently.

  9. Drug-drug interactions: antiretroviral drugs and recreational drugs.

    PubMed

    Staltari, Orietta; Leporini, Christian; Caroleo, Benedetto; Russo, Emilio; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2014-01-01

    With the advances in antiretroviral (ARV) therapy, patients with Human Immunodeficiency Virus (HIV) infection are living longer, however, some patients encounter co- morbidities which sometimes require treatment. Therefore, during the treatment with ARV drugs these patients could take several recreational drugs (e.g. amphetamines, hallucinogenes, opiates, or alcohol) with a possible development of drug-drug interactions (DDIs). In particular, Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) are mainly excreted through the kidney and are not substrates of the cytochrome P450 or P-glycoprotein, therefore the DDIs during this treatment are minimal. In contrast, the other ARV drugs (i.e. non-nucleoside reversetranscriptase inhibitors, Protease inhibitors, Integrase inhibitors, chemokine receptor 5 antagonists and HIV-fusion inhibitors) are an important class of antiretroviral medications that are frequent components of HAART regimens but show several DDIs related to interaction with the cytochrome P450 or P-glycoprotein. In this paper we will review data concerning the possibility of DDI in HIV patients treated with ARV and taking recreational drugs.

  10. Prevalence of QT interval prolonging drug-drug interactions (QT-DDIs) in psychiatry wards of tertiary care hospitals in Pakistan: a multicenter cross-sectional study.

    PubMed

    Khan, Qasim; Ismail, Mohammad; Haider, Iqbal; Khan, Fahadullah

    2017-09-12

    Background QT prolongation and associated arrhythmias, torsades de pointes (TdP), are considerable negative outcomes of many antipsychotic and antidepressant agents frequently used by psychiatric patients. Objective To identify the prevalence, levels, and predictors of QT prolonging drug-drug interactions (QT-DDIs), and AZCERT (Arizona Center for Education and Research on Therapeutics) classification of drugs involved in QT-DDIs. Setting Psychiatry wards of three major tertiary care hospitals of Khyber-Pakhtunkhwa, Pakistan. Method This was a multicenter cross-sectional study. Micromedex DrugReax was used for identification of QT-DDIs. TdP risks were identified by the AZCERT classification. Multivariate logistic regression analysis was performed to identify predictors of QT-DDIs. Main outcome measure Prevalence of QT-DDIs (overall, age-wise and gender-wise) and their levels of severity and documentation; AZCERT classes of drugs involved in QT-DDIs; and odds ratios for predictors of QT-DDIs. Results Of 600 patients, 58.5% were female. Median age was 25 years (IQR = 20-35). Overall 51.7% patients had QT-DDIs. Of total 698 identified QT-DDIs, most were of major-severity (98.4%) and fair-documentation (93.7%). According to the AZCERT classification, 36.4% of the interacting drugs were included in list-1 (known risk of TdP), 26.9% in list-2 (possible risk of TdP) and 27.5% in list-3 (conditional risk of TdP). Drugs commonly involved in QT-DDI were olanzapine (n = 146), haloperidol (138), escitalopram (122), risperidone (91), zuclopenthixol (87), quetiapine (n80) and fluoxetine (74). In multivariate logistic regression analysis, QT-DDIs were significantly associated with 6-7 prescribed medications (p = 0.04) and >7 medications (p = 0.03). Similarly, there was significant association of occurrence of QT-DDIs with 2-3 QT drugs (p < 0.001) and >3 QT drugs (p < 0.001). Conclusion A considerable number of patients are exposed to QT-DDIs in psychiatry. There is a

  11. Application of Mice Humanized for CYP2D6 to the Study of Tamoxifen Metabolism and Drug-Drug Interaction with Antidepressants.

    PubMed

    MacLeod, A Kenneth; McLaughlin, Lesley A; Henderson, Colin J; Wolf, C Roland

    2017-01-01

    Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. It is a prodrug that is converted by several cytochrome P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Antidepressants (ADs), which are often coprescribed to patients receiving tamoxifen, are also metabolized by CYP2D6 and evidence suggests that a drug-drug interaction between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. We evaluated this potentially important drug-drug interaction in vivo in mice humanized for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLMs) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes. Coincubation with quinidine, a CYP2D6 inhibitor, ablated endoxifen generation by hCYP2D6 MLMs. The NDT-hydroxylation activity of wild-type MLMs was 7.4 times higher than that of hCYP2D6, whereas MLMs from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the human liver microsome panel. In vitro, ADs of the selective serotonin reuptake inhibitor class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLMs than were compounds of the tricyclic class. At a clinically relevant dose, paroxetine pretreatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy. Copyright © 2016 The Author(s).

  12. Using Linked Data for Mining Drug-Drug Interactions in Electronic Health Records

    PubMed Central

    Pathak, Jyotishman; Kiefer, Richard C.; Chute, Christopher G.

    2014-01-01

    By nature, healthcare data is highly complex and voluminous. While on one hand, it provides unprecedented opportunities to identify hidden and unknown relationships between patients and treatment outcomes, or drugs and allergic reactions for given individuals, representing and querying large network datasets poses significant technical challenges. In this research, we study the use of Semantic Web and Linked Data technologies for identifying drug-drug interaction (DDI) information from publicly available resources, and determining if such interactions were observed using real patient data. Specifically, we apply Linked Data principles and technologies for representing patient data from electronic health records (EHRs) at Mayo Clinic as Resource Description Framework (RDF), and identify potential drug-drug interactions (PDDIs) for widely prescribed cardiovascular and gastroenterology drugs. Our results from the proof-of-concept study demonstrate the potential of applying such a methodology to study patient health outcomes as well as enabling genome-guided drug therapies and treatment interventions. PMID:23920643

  13. Using linked data for mining drug-drug interactions in electronic health records.

    PubMed

    Pathak, Jyotishman; Kiefer, Richard C; Chute, Christopher G

    2013-01-01

    By nature, healthcare data is highly complex and voluminous. While on one hand, it provides unprecedented opportunities to identify hidden and unknown relationships between patients and treatment outcomes, or drugs and allergic reactions for given individuals, representing and querying large network datasets poses significant technical challenges. In this research, we study the use of Semantic Web and Linked Data technologies for identifying drug-drug interaction (DDI) information from publicly available resources, and determining if such interactions were observed using real patient data. Specifically, we apply Linked Data principles and technologies for representing patient data from electronic health records (EHRs) at Mayo Clinic as Resource Description Framework (RDF), and identify potential drug-drug interactions (PDDIs) for widely prescribed cardiovascular and gastroenterology drugs. Our results from the proof-of-concept study demonstrate the potential of applying such a methodology to study patient health outcomes as well as enabling genome-guided drug therapies and treatment interventions.

  14. Bedaquiline: a review of human pharmacokinetics and drug-drug interactions.

    PubMed

    van Heeswijk, R P G; Dannemann, B; Hoetelmans, R M W

    2014-09-01

    Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies.

  15. QSAR Modeling and Prediction of Drug-Drug Interactions.

    PubMed

    Zakharov, Alexey V; Varlamova, Ekaterina V; Lagunin, Alexey A; Dmitriev, Alexander V; Muratov, Eugene N; Fourches, Denis; Kuz'min, Victor E; Poroikov, Vladimir V; Tropsha, Alexander; Nicklaus, Marc C

    2016-02-01

    Severe adverse drug reactions (ADRs) are the fourth leading cause of fatality in the U.S. with more than 100,000 deaths per year. As up to 30% of all ADRs are believed to be caused by drug-drug interactions (DDIs), typically mediated by cytochrome P450s, possibilities to predict DDIs from existing knowledge are important. We collected data from public sources on 1485, 2628, 4371, and 27,966 possible DDIs mediated by four cytochrome P450 isoforms 1A2, 2C9, 2D6, and 3A4 for 55, 73, 94, and 237 drugs, respectively. For each of these data sets, we developed and validated QSAR models for the prediction of DDIs. As a unique feature of our approach, the interacting drug pairs were represented as binary chemical mixtures in a 1:1 ratio. We used two types of chemical descriptors: quantitative neighborhoods of atoms (QNA) and simplex descriptors. Radial basis functions with self-consistent regression (RBF-SCR) and random forest (RF) were utilized to build QSAR models predicting the likelihood of DDIs for any pair of drug molecules. Our models showed balanced accuracy of 72-79% for the external test sets with a coverage of 81.36-100% when a conservative threshold for the model's applicability domain was applied. We generated virtually all possible binary combinations of marketed drugs and employed our models to identify drug pairs predicted to be instances of DDI. More than 4500 of these predicted DDIs that were not found in our training sets were confirmed by data from the DrugBank database.

  16. The importance of drug-drug interactions as a cause of adverse drug reactions: a pharmacovigilance study of serotoninergic reuptake inhibitors in France.

    PubMed

    Montastruc, Francois; Sommet, Agnès; Bondon-Guitton, Emmanuelle; Durrieu, Geneviève; Bui, Eric; Bagheri, Haleh; Lapeyre-Mestre, Maryse; Schmitt, Laurent; Montastruc, Jean-Louis

    2012-05-01

    To quantify the importance of drug-drug interactions (DDIs) in the occurrence of adverse drug reactions (ADRs) reported with serotoninergic reuptake inhibitors in a pharmacovigilance database. All spontaneous reports of ADRs registered in 2008 by the Midi-Pyrénées PharmacoVigilance Centre that contained mention of one of the serotoninergic reuptake inhibitor (SRI) antidepressants marketed in France were reviewed. DDIs were identified according to the French National Drug Formulary (Vidal) and the interaction supplement of the French independent drug bulletin La Revue Prescrire. ADRs explained by DDIs were characterised. Among the 2,101 spontaneous reports recorded, 177 involved at least one SRI antidepressant. Among the 156 ADRs with at least one theoretical DDI, 41% (95% confidence interval 34-49%) could be explained by a DDI. The most frequent antidepressant involved in DDIs was escitalopram, followed by fluoxetine and citalopram. Among the 65 ADRs related to DDIs, 37 (52.9%) were "serious", mainly bleedings, confusion and falls, hyponatremia and serotoninergic syndromes. The most frequent drug interactions occurred with psychotropics (antipsychotics, benzodiazepines, among others), followed by antithrombotic agents (antagonists of vitamin K, antiplatelets), diuretics and angiotensin II antagonists. The group with ADRs related to DDIs was older than the group with ADRs not related to DDIs. ADRs were threefold more "serious" in the case of DDIs. Around 40% of ADRs reported with SRIs were related to DDIs. Most of these occurred after association with psychotropics, antithrombotics, or diuretics, especially in the elderly.

  17. Clinically important drug-drug interactions in primary care.

    PubMed

    Dhabali, A A H; Awang, R; Zyoud, S H

    2012-08-01

    Drug-drug interactions (DDIs) cause considerable morbidity and mortality worldwide and may lead to hospital admission. Sophisticated computerized drug information and monitoring systems, more recently established in many of the emerging economies, including Malaysia, are capturing useful information on prescribing. Our aim is to report on an investigation of potentially serious DDIs, using a university primary care-based system capturing prescription records from its primary care services. We retrospectively collected data from two academic years over 20 months from computerized databases at the Universiti Sains Malaysia (USM) from users of the USM primary care services. Three hundred and eighty-six DDI events were observed in a cohort of 208 exposed patients from a total of 23,733 patients, representing a 2-year period prevalence of 876·4 per 100,000 patients. Of the 208 exposed patients, 138 (66·3%) were exposed to one DDI event, 29 (13·9%) to two DDI events, 15 (7·2%) to three DDI events, 6 (2·9%) to four DDI events and 20 (9·6%) to more than five DDI events. Overall, an increasing mean number of episodes of DDIs was noted among exposed patients within the age category ≥70 years (P=0·01), an increasing trend in the number of medications prescribed (P<0·001) and an increasing trend in the number of long-term therapeutic groups (P<0·001). We describe the prevalence of clinically important DDIs in an emerging economy setting and identify the more common potentially serious DDIs. In line with the observations in developed economies, a higher number of episodes of DDIs were seen in patients aged ≥70 years and with more medications prescribed. The easiest method to reduce the frequency of DDIs is to reduce the number of medications prescribed. Therapeutic alternatives should be selected cautiously. © 2011 Blackwell Publishing Ltd.

  18. Laboratory tests in the clinical risk management of potential drug-drug interactions: a cross-sectional study using drug-dispensing data from 100 Dutch community pharmacies.

    PubMed

    Geerts, Arjen F J; De Koning, Fred H P; De Smet, Peter A G M; Van Solinge, Wouter W; Egberts, Toine C G

    2009-01-01

    Patient safety and the life cycle of a drug are negatively influenced by the still increasing occurrence of potential drug-drug interactions (DDIs). Clinical risk management of potential DDIs is required in patients using drugs to influence the benefit-risk profile positively. Information about laboratory test results, in particular, may be useful in the assessment of potential DDIs for the individual patient. The objective of this study was to examine the frequency and nature of laboratory tests required for the assessment of the clinical relevance of potential DDIs in Dutch community pharmacies. In addition, the nature and clinical relevance of these potential DDIs is analysed. All patients from 100 Dutch community pharmacies using, according to dispensing information, two or more drugs concomitantly on a specified date (Wednesday, 4 April 2007), were included (n = 223,019). The anonymous dispensing data of the included patients were analysed against a list of DDIs requiring laboratory tests for the assessment of their clinical relevance. The number of patients at risk for these potential DDIs with severe adverse reactions was calculated. The frequency of potential DDIs requiring laboratory tests were stratified by age, sex and degree of polypharmacy. Of the included patients, 24.4% had one or more potential DDIs (n = 54,427). In 9.0% of the included patients, one or more laboratory tests for the assessment of clinical relevance of the potential DDI were required (n = 19,968). The frequency of DDIs requiring laboratory tests increased with increasing age and number of drugs, but was not related to sex. The most commonly required laboratory tests were for renal function (42.2%), electrolytes (20.1%) and coagulation (13.1%). The percentage of patients at risk for potential DDIs requiring laboratory tests with adverse reaction category F (serious, irrecoverable disablement or death) was 2.5%; category E (increased risk of failure of life-saving therapy) was 0

  19. Evaluation of drug-drug interactions with fesoterodine.

    PubMed

    Malhotra, Bimal; Sachse, Richard; Wood, Nolan

    2009-06-01

    To assess drug-drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C(max); from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C(max) (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives.

  20. Assessment of potential drug-drug interactions and its associated factors in the hospitalized cardiac patients.

    PubMed

    Murtaza, Ghulam; Khan, Muhammad Yasir Ghani; Azhar, Saira; Khan, Shujaat Ali; Khan, Tahir M

    2016-03-01

    Drug-drug interactions (DDIs) may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug-drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug-drug interactions (pDDIs) in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug-drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55%) or major severity (45%); established (24.2%), theoretical (18.8%) or probable (57%) type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p < 0.001), hospital stay of 7 days or longer (p < 0.001) and taking 7 or more drugs (p < 0.001). We found a high prevalence for pDDIs in the Department of Cardiology, most of which were of moderate severity. Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs.

  1. Clinically significant drug-drug interactions involving opioid analgesics used for pain treatment in patients with cancer: a systematic review.

    PubMed

    Kotlinska-Lemieszek, Aleksandra; Klepstad, Pål; Haugen, Dagny Faksvåg

    2015-01-01

    Opioids are the most frequently used drugs to treat pain in cancer patients. In some patients, however, opioids can cause adverse effects and drug-drug interactions. No advice concerning the combination of opioids and other drugs is given in the current European guidelines. To identify studies that report clinically significant drug-drug interactions involving opioids used for pain treatment in adult cancer patients. Systematic review with searches in Embase, MEDLINE, and Cochrane Central Register of Controlled Trials from the start of the databases (Embase from 1980) through January 2014. In addition, reference lists of relevant full-text papers were hand-searched. Of 901 retrieved papers, 112 were considered as potentially eligible. After full-text reading, 17 were included in the final analysis, together with 15 papers identified through hand-searching of reference lists. All of the 32 included publications were case reports or case series. Clinical manifestations of drug-drug interactions involving opioids were grouped as follows: 1) sedation and respiratory depression, 2) other central nervous system symptoms, 3) impairment of pain control and/or opioid withdrawal, and 4) other symptoms. The most common mechanisms eliciting drug-drug interactions were alteration of opioid metabolism by inhibiting the activity of cytochrome P450 3A4 and pharmacodynamic interactions due to the combined effect on opioid, dopaminergic, cholinergic, and serotonergic activity in the central nervous system. Evidence for drug-drug interactions associated with opioids used for pain treatment in cancer patients is very limited. Still, the cases identified in this systematic review give some important suggestions for clinical practice. Physicians prescribing opioids should recognize the risk of drug-drug interactions and if possible avoid polypharmacy.

  2. Pharmacokinetic and pharmacodynamic drug-drug interaction assessment between pradigastat and digoxin or warfarin.

    PubMed

    Yan, Jing-He; Meyers, Dan; Lee, Zachary; Danis, Kate; Neelakantham, Srikanth; Majumdar, Tapan; Rebello, Sam; Sunkara, Gangadhar; Chen, Jin

    2014-07-01

    Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions when co-administered with digoxin or warfarin in healthy subjects. This open-label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R-warfarin, and S-warfarin PK parameters (AUC and Cmax) were all within 0.80-1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax) were within 0.80-1.25 interval when co-administered with warfarin; while co-administration with digoxin slightly reduced pradigastat exposure (∼15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUC(PT), PTmax, AUC(INR), and INRmax) were within 0.80-1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug-drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated.

  3. Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions

    PubMed Central

    Schmidt, Linnéa; Kling, Teresia; Monsefi, Naser; Olsson, Maja; Hansson, Caroline; Baskaran, Sathishkumar; Lundgren, Bo; Martens, Ulf; Häggblad, Maria; Westermark, Bengt; Forsberg Nilsson, Karin; Uhrbom, Lene; Karlsson-Lindahl, Linda; Gerlee, Philip; Nelander, Sven

    2013-01-01

    Background Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, and despite state-of-the-art treatment, survival remains poor and novel therapeutics are sorely needed. The aim of the present study was to identify new synergistic drug pairs for GBM. In addition, we aimed to explore differences in drug-drug interactions across multiple GBM-derived cell cultures and predict such differences by use of transcriptional biomarkers. Methods We performed a screen in which we quantified drug-drug interactions for 465 drug pairs in each of the 5 GBM cell lines U87MG, U343MG, U373MG, A172, and T98G. Selected interactions were further tested using isobole-based analysis and validated in 5 glioma-initiating cell cultures. Furthermore, drug interactions were predicted using microarray-based transcriptional profiling in combination with statistical modeling. Results Of the 5 × 465 drug pairs, we could define a subset of drug pairs with strong interaction in both standard cell lines and glioma-initiating cell cultures. In particular, a subset of pairs involving the pharmaceutical compounds rimcazole, sertraline, pterostilbene, and gefitinib showed a strong interaction in a majority of the cell cultures tested. Statistical modeling of microarray and interaction data using sparse canonical correlation analysis revealed several predictive biomarkers, which we propose could be of importance in regulating drug pair responses. Conclusion We identify novel candidate drug pairs for GBM and suggest possibilities to prospectively use transcriptional biomarkers to predict drug interactions in individual cases. PMID:24101737

  4. Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data.

    PubMed

    Benet, L Z; Cummins, C L; Wu, C Y

    2003-10-01

    As discussed in earlier articles, predictions of in vivo drug-drug interactions from in vitro studies is a subject of high interest with obvious therapeutic as well as economic benefits. Up until now little attention has been given to the potential interplay between metabolic enzymes and transporters that could confound the in vivo-in vitro relationships. Drug efflux by intestinal P-glycoprotein (P-gp) is known to decrease the bioavailability of many CYP3A4 substrates. We have demonstrated that the interplay between P-gp and CYP3A4 at the apical intestinal membrane can increase the opportunity for drug metabolism by determining bidirectional extraction ratios across CYP3A4 transfected Caco-2 cells for two dual P-gp/CYP3A4 substrates, K77 (an experimental cysteine protease inhibitor) and sirolimus, as well as two negative control, CYP3A4 only substrates, midazolam and felodipine. Studies were carried out under control conditions, with a P-gp inhibitor (GG918) and with a dual inhibitor (cyclosporine). Measurement of intracellular concentration changes is an important component in calculating the extraction ratios. We hypothesize that the inverse orientation of P-gp and CYP3A4 in the liver will result in an opposite interactive effect in that organ. In vivo rat intestinal perfusion studies with K77 and rat liver perfusion studies with tacrolimus under control conditions and with inhibitors of CYP3A4 (troleandomycin), P-gp (GG918) and both CYP3A4/P-gp (cyclosporine) lend support to our hypotheses. These results serve as a template for predicting enzyme- transporter (both absorptive and efflux) interactions in the intestine and the liver.

  5. Frovatriptan: a review of drug-drug interactions.

    PubMed

    Buchan, P; Wade, A; Ward, C; Oliver, S D; Stewart, A J; Freestone, S

    2002-04-01

    To investigate the potential for interactions involving drugs likely to be coadministered with frovatriptan. Frovatriptan is a new 5-hydroxytryptamine (5-HT)(1B/1D) agonist. Preclinical data suggest that the pharmacokinetic and pharmacological profile of frovatriptan may differ from that of the currently available triptans. The potential for interactions between frovatriptan and other drugs was investigated using in vitro methods, studies in healthy volunteers, and retrospective analysis of data from phase I trials. In vitro, frovatriptan was principally metabolized by cytochrome P-450 (CYP) 1A2 but was found not to be an inhibitor or inducer of this or other CYP isoenzymes. Frovatriptan was only a weak inhibitor of monoamine oxidase at very high concentrations in vitro and was not a substrate for this enzyme (unlike some other triptans). Coadministration with moclobemide, at doses known to inhibit monoamine oxidase-A, did not affect the pharmacokinetics of frovatriptan. Binding to plasma proteins was low (15%), and binding to erythrocytes was moderate (60%) and unlikely to be a source of interaction with other drugs. The pharmacokinetics of frovatriptan were not affected by moderate alcohol intake. There were slight increases in area under the curve and maximum concentration on concomitant administration with the combined oral contraceptives, propranolol, and fluvoxamine; and slight decreases in these parameters on concomitant administration with ergotamine and in tobacco smokers; these findings were considered to have no clinical significance in view of frovatriptan's large therapeutic index (well tolerated at doses ranging from 2.5 to 40 mg). These effects can be attributed primarily to modification of CYP1A2 activity but their impact is limited, probably due to frovatriptan also undergoing renal clearance and the likely role of blood cell binding in controlling the amount of unbound drug available for elimination. Because it has no inhibitory or inducing effect

  6. Systematic Prediction of Pharmacodynamic Drug-Drug Interactions through Protein-Protein-Interaction Network

    PubMed Central

    Huang, Jialiang; Niu, Chaoqun; Green, Christopher D.; Yang, Lun; Mei, Hongkang; Han, Jing-Dong J.

    2013-01-01

    Identifying drug-drug interactions (DDIs) is a major challenge in drug development. Previous attempts have established formal approaches for pharmacokinetic (PK) DDIs, but there is not a feasible solution for pharmacodynamic (PD) DDIs because the endpoint is often a serious adverse event rather than a measurable change in drug concentration. Here, we developed a metric “S-score” that measures the strength of network connection between drug targets to predict PD DDIs. Utilizing known PD DDIs as golden standard positives (GSPs), we observed a significant correlation between S-score and the likelihood a PD DDI occurs. Our prediction was robust and surpassed existing methods as validated by two independent GSPs. Analysis of clinical side effect data suggested that the drugs having predicted DDIs have similar side effects. We further incorporated this clinical side effects evidence with S-score to increase the prediction specificity and sensitivity through a Bayesian probabilistic model. We have predicted 9,626 potential PD DDIs at the accuracy of 82% and the recall of 62%. Importantly, our algorithm provided opportunities for better understanding the potential molecular mechanisms or physiological effects underlying DDIs, as illustrated by the case studies. PMID:23555229

  7. Concomitant therapy in people with epilepsy: potential drug-drug interactions and patient awareness.

    PubMed

    Eyal, Sara; Rasaby, Sivan; Ekstein, Dana

    2014-02-01

    People with epilepsy (PWE) may use prescription and over-the-counter (OTC) drugs for the treatment of concomitant diseases. Combinations of these drugs, as well as dietary supplements, with antiepileptic drugs (AEDs) may lead to reduced control of seizures and of coexisting medical conditions and increased risk of adverse drug reactions (ADRs). The aims of this study were to obtain comprehensive lists of medications, dietary supplements, botanicals, and specific food components used by adult PWE and to evaluate the potential for interactions involving AEDs and patients' awareness of such potential interactions. We conducted a prospective, questionnaire-based study of PWE attending the Hadassah-Hebrew University Epilepsy Clinic over a period of 7months. The questionnaire interview included the listing of medications, medicinal herbs, dietary supplements, and specific food components consumed and the knowledge of potential drug-drug interactions (DDIs), and it was conducted by a pharmacist. Drug-drug interactions were analyzed via the Micromedex online database. Out of 179 patients who attended the clinic over the study period, we interviewed 73 PWE, of which 71 were included in our final analysis. The mean number of AEDs consumed per subject was 1.7 (SD: 0.8, range: 1-4). Forty (56%) subjects were also treated with other prescription and/or OTC medications, and thirty-four (48%) took dietary supplements. Drug families most prone to DDIs involving AEDs included antipsychotic agents, selective serotonin reuptake inhibitors, and statins. Two-thirds of study participants (67%) knew that DDIs may lead to ADRs, but only half (56%) were aware of the potential for reduced seizure control. Only 44% always reported treatment with AEDs to medical professionals. This study provides for the first time a comprehensive picture of prescription and OTC drugs and food supplements used by PWE. Despite a considerable potential for DDIs involving AEDs, patient awareness is limited

  8. Evaluation of linear classifiers on articles containing pharmacokinetic evidence of drug-drug interactions.

    PubMed

    Kolchinsky, A; Lourenço, A; Li, L; Rocha, L M

    2013-01-01

    Drug-drug interaction (DDI) is a major cause of morbidity and mortality. DDI research includes the study of different aspects of drug interactions, from in vitro pharmacology, which deals with drug interaction mechanisms, to pharmaco-epidemiology, which investigates the effects of DDI on drug efficacy and adverse drug reactions. Biomedical literature mining can aid both kinds of approaches by extracting relevant DDI signals from either the published literature or large clinical databases. However, though drug interaction is an ideal area for translational research, the inclusion of literature mining methodologies in DDI workflows is still very preliminary. One area that can benefit from literature mining is the automatic identification of a large number of potential DDIs, whose pharmacological mechanisms and clinical significance can then be studied via in vitro pharmacology and in populo pharmaco-epidemiology. We implemented a set of classifiers for identifying published articles relevant to experimental pharmacokinetic DDI evidence. These documents are important for identifying causal mechanisms behind putative drug-drug interactions, an important step in the extraction of large numbers of potential DDIs. We evaluate performance of several linear classifiers on PubMed abstracts, under different feature transformation and dimensionality reduction methods. In addition, we investigate the performance benefits of including various publicly-available named entity recognition features, as well as a set of internally-developed pharmacokinetic dictionaries. We found that several classifiers performed well in distinguishing relevant and irrelevant abstracts. We found that the combination of unigram and bigram textual features gave better performance than unigram features alone, and also that normalization transforms that adjusted for feature frequency and document length improved classification. For some classifiers, such as linear discriminant analysis (LDA), proper

  9. A Model for Predicting the Interindividual Variability of Drug-Drug Interactions.

    PubMed

    Tod, M; Bourguignon, L; Bleyzac, N; Goutelle, S

    2017-03-01

    Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc. First, a model was derived to link sd(Ln Rauc) with the substrate fraction metabolized by each cytochrome and the potency of the interactors, in case of induction or inhibition. Second, the parameters involved in these equations were estimated by a Bayesian hierarchical model, using the data from 56 interaction studies retrieved from the literature. Third, the model was evaluated by several metrics based on the fold prediction error (PE) of sd(Ln Rauc). The median PE was 0.998 (the ideal value is 1) and the interquartile range was 0.96-1.03. The PE was in the acceptable interval (0.5 to 2) in 52 cases out of 56. Fourth, a surface plot of sd(Ln Rauc) as a function of the characteristics of the substrate and the interactor has been built. The minimal value of sd(Ln Rauc) was about 0.08 (obtained for Rauc = 1) while the maximal value, 0.7, was obtained for interactions involving highly metabolized substrates with strong interactors.

  10. Resolving anaphoras for the extraction of drug-drug interactions in pharmacological documents

    PubMed Central

    2010-01-01

    Background Drug-drug interactions are frequently reported in the increasing amount of biomedical literature. Information Extraction (IE) techniques have been devised as a useful instrument to manage this knowledge. Nevertheless, IE at the sentence level has a limited effect because of the frequent references to previous entities in the discourse, a phenomenon known as 'anaphora'. DrugNerAR, a drug anaphora resolution system is presented to address the problem of co-referring expressions in pharmacological literature. This development is part of a larger and innovative study about automatic drug-drug interaction extraction. Methods The system uses a set of linguistic rules drawn by Centering Theory over the analysis provided by a biomedical syntactic parser. Semantic information provided by the Unified Medical Language System (UMLS) is also integrated in order to improve the recognition and the resolution of nominal drug anaphors. Besides, a corpus has been developed in order to analyze the phenomena and evaluate the current approach. Each possible case of anaphoric expression was looked into to determine the most effective way of resolution. Results An F-score of 0.76 in anaphora resolution was achieved, outperforming significantly the baseline by almost 73%. This ad-hoc reference line was developed to check the results as there is no previous work on anaphora resolution in pharmalogical documents. The obtained results resemble those found in related-semantic domains. Conclusions The present approach shows very promising results in the challenge of accounting for anaphoric expressions in pharmacological texts. DrugNerAr obtains similar results to other approaches dealing with anaphora resolution in the biomedical domain, but, unlike these approaches, it focuses on documents reflecting drug interactions. The Centering Theory has proved being effective at the selection of antecedents in anaphora resolution. A key component in the success of this framework is the

  11. The rising tide of polypharmacy and drug-drug interactions: population database analysis 1995-2010.

    PubMed

    Guthrie, Bruce; Makubate, Boikanyo; Hernandez-Santiago, Virginia; Dreischulte, Tobias

    2015-04-07

    The escalating use of prescribed drugs has increasingly raised concerns about polypharmacy. This study aims to examine changes in rates of polypharmacy and potentially serious drug-drug interactions in a stable geographical population between 1995 and 2010. This is a repeated cross-sectional analysis of community-dispensed prescribing data for all 310,000 adults resident in the Tayside region of Scotland in 1995 and 2010. The number of drug classes dispensed and the number of potentially serious drug-drug interactions (DDIs) in the previous 84 days were calculated, and age-sex standardised rates in 1995 and 2010 compared. Patient characteristics associated with receipt of ≥ 10 drugs and with the presence of one or more DDIs were examined using multilevel logistic regression to account for clustering of patients within primary care practices. Between 1995 and 2010, the proportion of adults dispensed ≥ 5 drugs doubled to 20.8%, and the proportion dispensed ≥ 10 tripled to 5.8%. Receipt of ≥ 10 drugs was strongly associated with increasing age (20-29 years, 0.3%; ≥ 80 years, 24.0%; adjusted OR, 118.3; 95% CI, 99.5-140.7) but was also independently more common in people living in more deprived areas (adjusted OR most vs. least deprived quintile, 2.36; 95% CI, 2.22-2.51), and in people resident in a care home (adjusted OR, 2.88; 95% CI, 2.65-3.13). The proportion with potentially serious drug-drug interactions more than doubled to 13% of adults in 2010, and the number of drugs dispensed was the characteristic most strongly associated with this (10.9% if dispensed 2-4 drugs vs. 80.8% if dispensed ≥ 15 drugs; adjusted OR, 26.8; 95% CI 24.5-29.3). Drug regimens are increasingly complex and potentially harmful, and people with polypharmacy need regular review and prescribing optimisation. Research is needed to better understand the impact of multiple interacting drugs as used in real-world practice and to evaluate the effect of medicine optimisation

  12. A novel approach to the prediction of drug-drug interactions in humans based on the serum incubation method.

    PubMed

    Shibata, Yoshihiro; Takahashi, Hiroyuki; Chiba, Masato; Ishii, Yasuyuki

    2008-01-01

    A novel method for the prediction of drug-drug interaction has been established based on the in vitro metabolic stability in the "serum incubation method" using cryopreserved human hepatocytes suspended in 100% human serum. As a novel approach, the inhibitory effect of inhibitors on the metabolism of substrates during the first-pass elimination process in the liver (hepatic availability) and in the elimination process from the systemic circulation (hepatic clearance) were separately predicted with the anticipated inhibitor/substrate concentrations during absorption and in the systemic circulation, respectively. Ketoconazole strongly inhibited CYP3A4-mediated terfenadine metabolism in vitro, and the method predicted 6- to 37-fold increase of terfenadine AUC by the concomitant dosing of ketoconazole, which reasonably well agreed with the observed 13- to 59-fold increase of AUC in clinical studies. The CYP3A4-mediated metabolism of indinavir was also subject to the inhibition by ketoconazole in vitro at the lower indinavir concentration (2 microM), whereas no substantial inhibition was observed at 12 microM due to the saturation of indinavir metabolism. Predicted no interaction between ketoconazole and indinavir was consistent with the minimal increase (1.3-fold increase) of indinavir AUC by ketoconazole observed in clinical study. In addition, the method was applied to the CYP2D6-mediated desipramine-quinidine interaction: the predicted 6.4-fold increase of desipramine AUC by quinidine was consistent with the observed 6.7-fold increase of AUC in the clinical drug-drug interaction study. On the other hand, desipramine metabolism was little affected by ketoconazole in vitro, and consequently, it predicted no drug-drug interaction between desipramine and ketoconazole in humans, which agreed with the negligible interaction observed in clinical study. The accuracy of predictions for drug-drug interaction by the serum incubation method was evaluated by comparing the

  13. Predicting potential drug-drug interactions by integrating chemical, biological, phenotypic and network data.

    PubMed

    Zhang, Wen; Chen, Yanlin; Liu, Feng; Luo, Fei; Tian, Gang; Li, Xiaohong

    2017-01-05

    Drug-drug interactions (DDIs) are one of the major concerns in drug discovery. Accurate prediction of potential DDIs can help to reduce unexpected interactions in the entire lifecycle of drugs, and are important for the drug safety surveillance. Since many DDIs are not detected or observed in clinical trials, this work is aimed to predict unobserved or undetected DDIs. In this paper, we collect a variety of drug data that may influence drug-drug interactions, i.e., drug substructure data, drug target data, drug enzyme data, drug transporter data, drug pathway data, drug indication data, drug side effect data, drug off side effect data and known drug-drug interactions. We adopt three representative methods: the neighbor recommender method, the random walk method and the matrix perturbation method to build prediction models based on different data. Thus, we evaluate the usefulness of different information sources for the DDI prediction. Further, we present flexible frames of integrating different models with suitable ensemble rules, including weighted average ensemble rule and classifier ensemble rule, and develop ensemble models to achieve better performances. The experiments demonstrate that different data sources provide diverse information, and the DDI network based on known DDIs is one of most important information for DDI prediction. The ensemble methods can produce better performances than individual methods, and outperform existing state-of-the-art methods. The datasets and source codes are available at https://github.com/zw9977129/drug-drug-interaction/ .

  14. [Clinically significant drug-drug interactions between analgesics and psychotopics].

    PubMed

    Strobach, Dorothea

    2012-07-01

    Combining analgesic and psychotropic drugs can lead to pharmacodynamic and pharmacokinetic drug interactions. Under treatment with several serotonergic substances serotonin syndrome can occur, e.g., with certain opioids and antidepressant drugs. Serotonin reuptake inhibitors also affect the serotonin level in platelets, this can raise the risk for gastrointestinal bleeding especially in combination with non-steroidal antirheumatic drugs. Anticholinergic effects and sedation are common side effects of psychotropic but also analgesic drugs with possible additive results. A wide range of interactions between analgesics and psychotropics can occure during metabolism, especially via the cytochrome-P-system. The clinical relevance of warnings on drug interactions from data banks has always to be judged for the individual patient.

  15. Endogenous Biomarkers to Assess Drug-Drug Interactions by Drug Transporters and Enzymes.

    PubMed

    Mariappan, T Thanga; Shen, Hong; Marathe, Punit

    2017-07-24

    Drug-drug interactions (DDI) by modulation of drug transporters or drug metabolizing enzymes are common in multi-drug therapy. DDI potential of any new drugs are assessed by conducting separate clinical studies using relevant probe substrates, which involves additional resource and cost. Recently, several endogenous compounds were evaluated as substrates of transporters and enzymes that could be assessed as part of early clinical trials along with the assessment of drug pharmacokinetics, pharmacodynamics and safety studies. This enables an early readout on potential DDIs avoiding or minimally delaying the conduct of definitive DDI studies until later in clinical development. This review describes various endogenous biomarkers reported for drug transporters and metabolizing enzymes with their advantages and limitations. Further the authors describe strategies to adopt while exploring a new endogenous biomarker, factors to be considered in selection of biomarkers with the current challenges and opportunities. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Determinants of potential drug-drug interaction associated dispensing in community pharmacies in the Netherlands.

    PubMed

    Becker, Matthijs L; Caspers, Peter W J; Kallewaard, Marjon; Bruinink, Riekert J; Kylstra, Nico B; Heisterkamp, Siem; de Valk, Vincent; van der Veen, André A; Stricker, Bruno H Ch

    2007-04-01

    There are many drug-drug interactions (D-DI) of which some may cause severe adverse patient outcomes. Dispensing interacting drug combinations should be avoided when the risks are higher than the benefits. The objective of this study was to identify determinants of dispensing undesirable interacting drug combinations by community pharmacies in the Netherlands. A total of 256 Dutch community pharmacies were selected, based on the dispensing of 11 undesirable interacting drug combinations between January 1st, 2001 and October 31st, 2002. These pharmacies were sent a questionnaire by the Inspectorate for Health Care (IHC) concerning their process and structure characteristics. The number of times the 11 undesirable interacting drug combinations were dispensed. Two hundred and forty-six questionnaires (response rate 96.1%) were completed. Dispensing determinants were only found for the D-DI between macrolide antibiotics and digoxin but not for the other 10 D-DIs. Pharmacies using different medication surveillance systems differed in the dispensing of this interacting drug combination, and pharmacies, which were part of a health care centre dispensed this interacting drug combination more often. Medication surveillance in Dutch community pharmacies seems to be effective. Although for most D-DIs no determinants were found, process and structure characteristics may have consequences for the dispensing of undesirable interacting drug combinations.

  17. Enhancing Extraction of Drug-Drug Interaction from Literature Using Neutral Candidates, Negation, and Clause Dependency

    PubMed Central

    Bokharaeian, Behrouz; Diaz, Alberto; Chitsaz, Hamidreza

    2016-01-01

    Motivation Supervised biomedical relation extraction plays an important role in biomedical natural language processing, endeavoring to obtain the relations between biomedical entities. Drug-drug interactions, which are investigated in the present paper, are notably among the critical biomedical relations. Thus far many methods have been developed with the aim of extracting DDI relations. However, unfortunately there has been a scarcity of comprehensive studies on the effects of negation, complex sentences, clause dependency, and neutral candidates in the course of DDI extraction from biomedical articles. Results Our study proposes clause dependency features and a number of features for identifying neutral candidates as well as negation cues and scopes. Furthermore, our experiments indicate that the proposed features significantly improve the performance of the relation extraction task combined with other kernel methods. We characterize the contribution of each category of features and finally conclude that neutral candidate features have the most prominent role among all of the three categories. PMID:27695078

  18. A Successful Model and Visual Design for Creating Context-Aware Drug-Drug Interaction Alerts

    PubMed Central

    Duke, Jon D.; Bolchini, Davide

    2011-01-01

    Evaluating the potential harm of a drug-drug interaction (DDI) requires knowledge of a patient’s relevant co-morbidities and risk factors. Current DDI alerts lack such patient-specific contextual data. In this paper, we present an efficient model for integrating pertinent patient data into DDI alerts. This framework is designed to be interoperable across multiple drug knowledge bases and clinical information systems. To evaluate the model, we generated a set of contextual DDI data using our local drug knowledge base then conducted an evaluation study of a prototype contextual alert design. The alert received favorable ratings from study subjects, who agreed it was an improvement over traditional alerts and was likely to support clinical management and save physician time. This framework may ultimately help reduce alert fatigue through the dynamic display of DDI alerts based on patient risk. PMID:22195086

  19. Adverse events caused by potential drug-drug interactions in an intensive care unit of a teaching hospital

    PubMed Central

    Alvim, Mariana Macedo; da Silva, Lidiane Ayres; Leite, Isabel Cristina Gonçalves; Silvério, Marcelo Silva

    2015-01-01

    Objective To evaluate the incidence of potential drug-drug interactions in an intensive care unit of a hospital, focusing on antimicrobial drugs. Methods This cross-sectional study analyzed electronic prescriptions of patients admitted to the intensive care unit of a teaching hospital between January 1 and March 31, 2014 and assessed potential drug-drug interactions associated with antimicrobial drugs. Antimicrobial drug consumption levels were expressed in daily doses per 100 patient-days. The search and classification of the interactions were based on the Micromedex® system. Results The daily prescriptions of 82 patients were analyzed, totaling 656 prescriptions. Antimicrobial drugs represented 25% of all prescription drugs, with meropenem, vancomycin and ceftriaxone being the most prescribed medications. According to the approach of daily dose per 100 patient-days, the most commonly used antimicrobial drugs were cefepime, meropenem, sulfamethoxazole + trimethoprim and ciprofloxacin. The mean number of interactions per patient was 2.6. Among the interactions, 51% were classified as contraindicated or significantly severe. Highly significant interactions (clinical value 1 and 2) were observed with a prevalence of 98%. Conclusion The current study demonstrated that antimicrobial drugs are frequently prescribed in intensive care units and present a very high number of potential drug-drug interactions, with most of them being considered highly significant. PMID:26761473

  20. Evaluation of the performance of drug-drug interaction screening software in community and hospital pharmacies.

    PubMed

    Abarca, Jacob; Colon, Lisa R; Wang, Victoria S; Malone, Daniel C; Murphy, John E; Armstrong, Edward P

    2006-06-01

    Computerized drug-drug interaction (DDI) screening is widely used to identify potentially harmful drug combinations in the inpatient and outpatient setting. To evaluate the performance of drug-drug interaction (DDI) screening software in identifying select clinically significant DDIs in pharmacy computer systems in community and hospital pharmacies. Ten community pharmacies and 10 hospital pharmacies in the Tucson metropolitan area were invited to participate in the study in 2004. To test the performance of each of the systems used by the pharmacies, 25 medications were used to create 6 mock patient profiles containing 37 drug-drug pairs, 16 of which are clinically meaningful DDIs that pose a potential risk to patient safety. Each profile was entered into the computer pharmacy system, and the system response in terms of the presence or absence of a DDI alert was recorded for each drug pair. The percentage of correct responses and the sensitivity, specificity, positive predictive value, and negative predictive value of each system to correctly classify each drug pair as a DDI or not was calculated. Summary statistics of these measures were calculated separately for community and hospital pharmacies. Eight community pharmacies and 5 hospital pharmacies in the Tucson metropolitan area agreed to participate in the study. The median sensitivity and median specificity for community pharmacies was 0.88 (range, 0.81-0.94) and 0.91 (range, 0.67-1.00), respectively. For hospital pharmacies, the median sensitivity and median specificity was 0.38 (range, 0.15-0.94) and 0.95 (range, 0.81-0.95), respectively. Based on this convenience sample of 8 community pharmacies and 5 hospital pharmacies in 1 metropolitan area, the performance of community pharmacy computer systems in screening DDIs appears to have improved over the last several years compared with research published previously in 2001. However, significant variation remains in the performance of hospital pharmacy computer

  1. Drug-drug Interaction Discovery Using Abstraction Networks for "National Drug File - Reference Terminology" Chemical Ingredients.

    PubMed

    Ochs, Christopher; Zheng, Ling; Gu, Huanying; Perl, Yehoshua; Geller, James; Kapusnik-Uner, Joan; Zakharchenko, Aleksandr

    2015-01-01

    The National Drug File - Reference Terminology (NDF-RT) is a large and complex drug terminology. NDF-RT provides important information about clinical drugs, e.g., their chemical ingredients, mechanisms of action, dosage form and physiological effects. Within NDF-RT such information is represented using tens of thousands of roles. It is difficult to comprehend large, complex terminologies like NDF-RT. In previous studies, we introduced abstraction networks to summarize the content and structure of terminologies. In this paper, we introduce the Ingredient Abstraction Network to summarize NDF-RT's Chemical Ingredients and their associated drugs. Additionally, we introduce the Aggregate Ingredient Abstraction Network, for controlling the granularity of summarization provided by the Ingredient Abstraction Network. The Ingredient Abstraction Network is used to support the discovery of new candidate drug-drug interactions (DDIs) not appearing in First Databank, Inc.'s DDI knowledgebase.

  2. Transwell-grown HepG2 cell monolayers as in vitro permeability model to study drug-drug or drug-food interactions.

    PubMed

    Berginc, Katja; Kristl, Albin

    2011-01-01

    HepG2 cell monolayers, formed during cell growth on collagen-coated Transwell® (Corning® Inc., Corning, NY, USA) inserts, can be used for the evaluation of interactions between food supplements and drugs that are substrates for P-glycoprotein (Pgp) and/or multidrug resistance-associated protein 2 (MRP-2). Samples obtained during such permeability studies were relatively free of intracellular proteins or cell debris compared to usually performed uptake experiments with HepG2 cells; therefore no special preparation protocol prior to the analysis was needed. In the presence of aged garlic extract the activities of hepatic efflux transporters (Pgp, MRP-2) changed, which was observed as significant permeability changes of tested human immunodeficiency virus (HIV) protease inhibitors. Darunavir efflux significantly increased, whereas that of saquinavir significantly decreased. Because of the observed in vitro interactions between aged garlic extract and HIV protease inhibitors (darunavir, saquinavir), any alterations of in vivo liver transport in the presence of garlic phytochemicals could also significantly influence darunavir/saquinavir hepatocyte intracellular concentrations and hence their bioavailabilities. Therefore this aspect needs further in vivo animal evaluation.

  3. Pharmacokinetics and pharmacodynamics of propofol and fentanyl in patients undergoing abdominal aortic surgery - a study of pharmacodynamic drug-drug interactions.

    PubMed

    Wiczling, Paweł; Bieda, Krzysztof; Przybyłowski, Krzysztof; Hartmann-Sobczyńska, Roma; Borsuk, Agnieszka; Matysiak, Jan; Kokot, Zenon J; Sobczyński, Paweł; Grześkowiak, Edmund; Bienert, Agnieszka

    2016-07-01

    Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target-controlled infusion system. Fentanyl 2-3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non-linear mixed-effect model (NONMEM 7.2 software) was conducted. Two-compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect-site concentrations through an additive Emax model. Context-sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol-fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two-fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  4. Core drug-drug interaction alerts for inclusion in pediatric electronic health records with computerized prescriber order entry.

    PubMed

    Harper, Marvin B; Longhurst, Christopher A; McGuire, Troy L; Tarrago, Rod; Desai, Bimal R; Patterson, Al

    2014-03-01

    The study aims to develop a core set of pediatric drug-drug interaction (DDI) pairs for which electronic alerts should be presented to prescribers during the ordering process. A clinical decision support working group composed of Children's Hospital Association (CHA) members was developed. CHA Pharmacists and Chief Medical Information Officers participated. Consensus was reached on a core set of 19 DDI pairs that should be presented to pediatric prescribers during the order process. We have provided a core list of 19 high value drug pairs for electronic drug-drug interaction alerts to be recommended for inclusion as high value alerts in prescriber order entry software used with a pediatric patient population. We believe this list represents the most important pediatric drug interactions for practical implementation within computerized prescriber order entry systems.

  5. Drug-drug interactions among elderly patients hospitalized for drug toxicity.

    PubMed

    Juurlink, David N; Mamdani, Muhammad; Kopp, Alexander; Laupacis, Andreas; Redelmeier, Donald A

    2003-04-02

    Drug-drug interactions are a preventable cause of morbidity and mortality, yet their consequences in the community are not well characterized. To determine whether elderly patients admitted to hospital with specific drug toxicities were likely to have been prescribed an interacting drug in the week prior to admission. Three population-based, nested case-control studies. Ontario, Canada, from January 1, 1994, to December 31, 2000. All Ontario residents aged 66 years or older treated with glyburide, digoxin, or an angiotensin-converting enzyme (ACE) inhibitor. Case patients were those admitted to hospital for drug-related toxicity. Prescription records of cases were compared with those of controls (matched on age, sex, use of the same medication, and presence or absence of renal disease) for receipt of interacting medications (co-trimoxazole with glyburide, clarithromycin with digoxin, and potassium-sparing diuretics with ACE inhibitors). Odds ratio for association between hospital admission for drug toxicity (hypoglycemia, digoxin toxicity, or hyperkalemia, respectively) and use of an interacting medication in the preceding week, adjusted for diagnoses, receipt of other medications, the number of prescription drugs, and the number of hospital admissions in the year preceding the index date. During the 7-year study period, 909 elderly patients receiving glyburide were admitted with a diagnosis of hypoglycemia. In the primary analysis, those patients admitted for hypoglycemia were more than 6 times as likely to have been treated with co-trimoxazole in the previous week (adjusted odds ratio, 6.6; 95% confidence interval, 4.5-9.7). Patients admitted with digoxin toxicity (n = 1051) were about 12 times more likely to have been treated with clarithromycin (adjusted odds ratio, 11.7; 95% confidence interval, 7.5-18.2) in the previous week, and patients treated with ACE inhibitors admitted with a diagnosis of hyperkalemia (n = 523) were about 20 times more likely to have

  6. Optimization of drug-drug interaction study design: comparison of minimal physiologically based pharmacokinetic models on prediction of CYP3A inhibition by ketoconazole.

    PubMed

    Han, Bing; Mao, Jialin; Chien, Jenny Y; Hall, Stephen D

    2013-07-01

    Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f(m)) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.

  7. In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity.

    PubMed

    Monbaliu, Johan; Gonzalez, Martha; Bernard, Apexa; Jiao, James; Sensenhauser, Carlo; Snoeys, Jan; Stieltjes, Hans; Wynant, Inneke; Smit, Johan W; Chien, Caly

    2016-10-01

    Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 µM, 1.6-2.9 µM, 0.044-0.15 µM, and 5.4-5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.

  8. Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide.

    PubMed

    Scheen, André J

    2007-01-01

    This review describes the current knowledge on drug-drug and food-drug interactions with repaglinide and nateglinide. These two meglitinide derivatives, commonly called glinides, have been developed for improving insulin secretion of patients with type 2 diabetes mellitus. They are increasingly used either in monotherapy or in combination with other oral antihyperglycaemic agents for the treatment of type 2 diabetes. Compared with sulfonylureas, glinides have been shown to (i) provide a better control of postprandial hyperglycaemia, (ii) overcome some adverse effects, such as hypoglycaemia, and (iii) have a more favourable safety profile, especially in patients with renal failure. The meal-related timing of administration of glinides and the potential influence of food and meal composition on their bioavailability may be important. In addition, some food components (e.g. grapefruit juice) may cause pharmacokinetic interactions. Because glinides are metabolised via cytochrome P450 (CYP) 3A4 isoenzyme, they are indeed exposed to pharmacokinetic interactions. In addition to CYP3A4, repaglinide is metabolised via CYP2C8, while nateglinide metabolism also involves CYP2C9. Furthermore, both compounds and their metabolites may undergo specialised transport/uptake in the intestine, another source of pharmacokinetic interactions. Clinically relevant drug-drug interactions are those that occur when glinides are administered together with other glucose-lowering agents or compounds widely coadministered to diabetic patients (e.g. lipid-lowering agents), with drugs that are known to induce (risk of lower glinide plasma levels and thus of deterioration of glucose control) or inhibit (risk of higher glinide plasma levels leading to hypoglycaemia) CYP isoenzymes concerned in their metabolism, or with drugs that have a narrow efficacy : toxicity ratio. Pharmacokinetic interactions reported in the literature appear to be more frequent and more important with repaglinide than with

  9. Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors.

    PubMed

    Chauvin, Benoit; Drouot, Sylvain; Barrail-Tran, Aurélie; Taburet, Anne-Marie

    2013-10-01

    The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent CYP3A inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through CYP3A have the highest potency for drug-drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the

  10. Phase 1 and Pharmacokinetic Drug-Drug Interaction Study of Metformin, Losartan, and Linagliptin Coadministered With DW1029M in Healthy Volunteers.

    PubMed

    Moon, Seol Ju; Kim, Sun-Young; Lim, Cheol-Hee; Jang, Hwan Bong; Kim, Min-Gul; Jeon, Ji-Young

    2016-10-14

    We investigated botanical drug-pharmaceutical drug interactions between DW1029M (a botanical extract of Morus alba linne root bark and Puerariae radix) and metformin, losartan, and linagliptin in the steady state. Three studies were conducted as randomized, open-label, 2-period, 2-treatment, multiple-dose, 2-way crossover designs. Eligible subjects received metformin (500 mg twice daily), losartan (50 mg once daily), or linagliptin (5 mg once daily) with DW1029M (300 mg × 2T twice daily) every 12 hours on days 1 through 6 and a single dose on the morning of day 7. Coadministration of DW1029M with metformin, losartan, or linagliptin had no clinically relevant effects based on the area under the plasma concentration-time curve (AUCτ ) geometric least-squares mean ratio (GMR) - AUCτ GMR, 89.7; 90% confidence interval (CI), 81.0-99.4 for metformin; AUCτ GMR, 96.2; 90%CI, 86.3-107.1 for losartan; and AUCτ GMR, 89.7; 90%CI, 83.2-96.6 for linagliptin. In addition, coadministration of DW1029M did not have any clinically meaningful effect on the maximum plasma concentration (Cmax,ss ) - Cmax,ss GMR, 87.3; 90%CI, 76.2-100.0 for metformin; Cmax,ss GMR, 90.5; 90%CI, 78.3-104.6 for losartan; and Cmax,ss GMR, 81.4; 90%CI, 69.5-95.3 for linagliptin. Coadministration of DW1029M with metformin, losartan, or linagliptin was well tolerated.

  11. Herb-drug, food-drug, nutrient-drug, and drug-drug interactions: mechanisms involved and their medical implications.

    PubMed

    Sørensen, Janina Maria

    2002-06-01

    Adverse drug reactions (ADRs) and iatrogenic diseases have been identified as significant factors responsible for patient morbidity and mortality. Significant studies on drug metabolism in humans have been published during the last few years, offering a deeper comprehension of the mechanisms underlying adverse drug reactions and interactions. More understanding of these mechanisms, and of recent advances in laboratory technology, can help to evaluate potential drug interactions when drugs are prescribed concurrently. Increasing knowledge of interindividual variation in drug breakdown capacity and recent findings concerning the influence of environment, diet, nutrients, and herbal products can be used to reduce ADRs and iatrogenic diseases. Reviewed data suggest that drug treatment should be increasingly custom tailored to suit the individual patient and that appropriately co-prescribed diet and herbal remedies, could increase drug efficacy and lessen drug toxicity. This review focuses mainly on recently published research material. The cytochrome p450 enzymes, their role in metabolism, and their mechanisms of action are reviewed, and their role in drug-drug interactions are discussed. Drug-food and drug-herb interactions have garnered attention. Interdisciplinary communication among medical herbalists, medical doctors, and dietetic experts needs to be improved and encouraged. Internet resources for obtaining current information regarding drug-drug, drug-herb, and drug-nutrient interactions are provided.

  12. A Randomized Study Evaluating Oral Fusidic Acid (CEM-102) in Combination With Oral Rifampin Compared With Standard-of-Care Antibiotics for Treatment of Prosthetic Joint Infections: A Newly Identified Drug-Drug Interaction.

    PubMed

    Pushkin, Richard; Iglesias-Ussel, Maria D; Keedy, Kara; MacLauchlin, Chris; Mould, Diane R; Berkowitz, Richard; Kreuzer, Stephan; Darouiche, Rabih; Oldach, David; Fernandes, Prabha

    2016-12-15

     Fusidic acid (FA) has been used for decades for bone infection, including prosthetic joint infection (PJI), often in combination with rifampin (RIF). An FA/RIF pharmacokinetic interaction has not previously been described.  In a phase 2 open-label randomized study, we evaluated oral FA/RIF vs standard-of-care (SOC) intravenous antibiotics for treatment of hip or knee PJI. Outcome assessment occurred at reimplantation (week 12) for subjects with 2-stage exchange, and after 3 or 6 months of treatment for subjects with hip or knee debride and retain strategies, respectively.  Fourteen subjects were randomized 1:1 to FA/RIF or SOC. Pharmacokinetic profiles were obtained for 6 subjects randomized to FA/RIF. FA concentrations were lower than anticipated in all subjects during the first week of therapy, and at weeks 4 and 6, blood levels continued to decline. By week 6, FA exposures were 40%-45% lower than expected.  The sponsor elected to terminate this study due to a clearly illustrated drug-drug interaction between FA and RIF, which lowered FA levels to a degree that could influence subject outcomes. Optimization of FA exposure if used in combination with RIF should be a topic of future research.  NCT01756924. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  13. The Hypoxia-inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat (FG-4592) and Warfarin in Healthy Volunteers: A Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction Study.

    PubMed

    Groenendaal-van de Meent, Dorien; den Adel, Martin; Rijnders, Sanne; Krebs-Brown, Axel; Kerbusch, Virginie; Golor, Georg; Schaddelee, Marloes

    2016-04-01

    Roxadustat is a small-molecule hypoxia-inducible factor prolyl-hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in patients with chronic kidney disease (CKD). Warfarin is an oral anticoagulant with a narrow therapeutic window that is often prescribed to treat coexisting cardiovascular diseases in patients with CKD. This clinical trial was designed to evaluate the effect of roxadustat on warfarin pharmacokinetic and pharmacodynamic parameters. This open-label, single-sequence crossover study was conducted in healthy volunteers (male or female) aged 18 to 55 years with a body mass index of 18.5 to 30.0 kg/m(2). The study consisted of 2 periods separated by a minimum washout period of 14 days. After an overnight fast, volunteers received a single oral dose of 25 mg (5 × 5 mg tablets) warfarin on Day 1 of Period 1 and Day 7 of Period 2. Volunteers received oral doses of 200 mg (2 × 100 mg tablets) roxadustat on Days 1, 3, 5, 7 (concomitant with warfarin), 9, 11, 13, and 15 of Period 2. Plasma S- and R-warfarin (unbound and total concentrations) and prothrombin time were determined at multiple time points up to 216 hours postdose. Pharmacokinetic and pharmacodynamic parameters were estimated via noncompartmental methods. Tolerability was evaluated by monitoring adverse events, laboratory assays, vital signs, and 12-lead ECGs. The geometric mean ratios and 90% CIs for Cmax and AUC∞ of total and unbound S- and R-warfarin (with and without roxadustat) were within the standard bioequivalence interval of 80.00% to 125.00%. Roxadustat increased the geometric mean (GM) prothrombin (PT) and international normalized ratio (INR) AUC from time zero to last measurable sample (AUCPT,last and AUCINR,last) by 24.4%. Coadministration of roxadustat and warfarin in healthy volunteers was associated with a favorable tolerability profile, with most treatment-associated adverse events mild in severity. Based on the lack of clinically significant

  14. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective.

    PubMed

    van Leeuwen, Roelof W F; van Gelder, Teun; Mathijssen, Ron H J; Jansman, Frank G A

    2014-07-01

    In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug-drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug-drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug-drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice.

  15. Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized Patients

    PubMed Central

    Azie, Nkechi; Yang, Hongbo; Harrington, Rachel; Kelley, Caroline; Tan, Ruo-Ding; Wu, Eric Q.; Franks, Billy; Kristy, Rita; Lee, Edward; Khandelwal, Nikhil; Spalding, James

    2016-01-01

    The majority of hospitalized patients receiving mold-active triazoles are at risk of drug-drug interactions (DDIs). Efforts are needed to increase awareness of DDIs that pose a serious risk of adverse events. Triazoles remain the most commonly utilized antifungals. Recent developments have included the mold-active triazoles (MATs) itraconazole, voriconazole, and posaconazole, which are first-line agents for the treatment of filamentous fungal infections but have the potential for DDIs. This objective of this study was to evaluate the prevalence of triazole DDIs. Hospitalized U.S. adults with MAT use were identified in the Cerner HealthFacts database, which contained data from over 150 hospitals (2005 to 2013). The severities of DDIs with MATs were categorized, using drug labels and the drug information from the Drugdex system (Thompson Micromedex), into four groups (contraindicated, major, moderate, and minor severity). DDIs of minor severity were not counted. A DDI event was considered to have occurred if the following two conditions were met: (i) the patient used at least one drug with a classification of at least a moderate interaction with the MAT during the hospitalization and (ii) there was a period of overlap between the administration of the MAT and that of the interacting drug of at least 1 day. A total of 6,962 hospitalizations with MAT use were identified. Among them, 88% of hospitalizations with voriconazole use, 86% of hospitalizations with itraconazole use, and 93% of hospitalizations with posaconazole use included the use of a concomitant interacting drug. A total of 68% of hospitalizations with posaconazole use, 34% of hospitalizations with itraconazole use, and 20% of hospitalizations with voriconazole use included the use of at least one drug with a DDI of contraindicated severity. A total of 83% of hospitalizations with posaconazole use, 61% of hospitalizations with itraconazole use, and 82% of hospitalizations with voriconazole use included the

  16. Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized Patients.

    PubMed

    Andes, David; Azie, Nkechi; Yang, Hongbo; Harrington, Rachel; Kelley, Caroline; Tan, Ruo-Ding; Wu, Eric Q; Franks, Billy; Kristy, Rita; Lee, Edward; Khandelwal, Nikhil; Spalding, James

    2016-06-01

    The majority of hospitalized patients receiving mold-active triazoles are at risk of drug-drug interactions (DDIs). Efforts are needed to increase awareness of DDIs that pose a serious risk of adverse events. Triazoles remain the most commonly utilized antifungals. Recent developments have included the mold-active triazoles (MATs) itraconazole, voriconazole, and posaconazole, which are first-line agents for the treatment of filamentous fungal infections but have the potential for DDIs. This objective of this study was to evaluate the prevalence of triazole DDIs. Hospitalized U.S. adults with MAT use were identified in the Cerner HealthFacts database, which contained data from over 150 hospitals (2005 to 2013). The severities of DDIs with MATs were categorized, using drug labels and the drug information from the Drugdex system (Thompson Micromedex), into four groups (contraindicated, major, moderate, and minor severity). DDIs of minor severity were not counted. A DDI event was considered to have occurred if the following two conditions were met: (i) the patient used at least one drug with a classification of at least a moderate interaction with the MAT during the hospitalization and (ii) there was a period of overlap between the administration of the MAT and that of the interacting drug of at least 1 day. A total of 6,962 hospitalizations with MAT use were identified. Among them, 88% of hospitalizations with voriconazole use, 86% of hospitalizations with itraconazole use, and 93% of hospitalizations with posaconazole use included the use of a concomitant interacting drug. A total of 68% of hospitalizations with posaconazole use, 34% of hospitalizations with itraconazole use, and 20% of hospitalizations with voriconazole use included the use of at least one drug with a DDI of contraindicated severity. A total of 83% of hospitalizations with posaconazole use, 61% of hospitalizations with itraconazole use, and 82% of hospitalizations with voriconazole use included the

  17. MDR- and CYP3A4-mediated drug-drug interactions.

    PubMed

    Pal, Dhananjay; Mitra, Ashim K

    2006-09-01

    P-glycoprotein (P-gp), multiple drug resistance associated proteins (MRPs), and cytochrome P450 3A4 together constitute a highly efficient barrier for many orally absorbed drugs. Multidrug regimens and corresponding drug-drug interactions are known to cause many adverse drug reactions and treatment failures. Available literature, clinical reports, and in vitro studies from our laboratory indicate that many drugs are substrates for both P-gp and CYP3A4. Our primary hypothesis is that transport and metabolism of protease inhibitors (PIs) and NNRTIs will be altered when administered in combination with azole antifungals, macrolide, fluroquinolone antibiotics, statins, cardiovascular agents, immune modulators, and recreational drugs [benzodiazepines, cocaine, lysergic acid dithylamide (LSD), marijuana, amphetamine (Meth), 3,4-methylenedioxymethamphetamine (MDMA), and opiates] due to efflux, and/or metabolism at cellular targets. Therefore, such drug combinations could be a reason for the unexpected and unexplainable therapeutic outcomes. A number of clinical reports on drug interaction between PIs and other classes (macrolide antibiotics, azole antifungals, cholesterol lowering statins, cardiovascular medicines, and immunomodulators) are discussed in this article. MDCKII-MDR1 was employed as an in vitro model to evaluate the effects of antiretrovirals, azole antifungals, macrolide, and fluroquinolone antibiotics on efflux transporters. Ketoconazole (50 muM) enhanced the intracellular concentration of (3)H ritonavir. The inhibitory effects of ketoconazole and MK 571 on the efflux of (3)H ritonavir were comparable. An additive effect was observed with simultaneous incorporation of ketoconazole and MK 571. Results of (3)H ritonavir uptake studies were confirmed with transcellular transport studies. Several fluroquinolones were also evaluated on P-gp-mediated efflux of (3)H cyclosporin and 14C erythromycin. These in vitro studies indicate that grepafloxacin, levofloxacin

  18. User-centered design improves the usability of drug-drug interaction alerts: Experimental comparison of interfaces.

    PubMed

    Luna, Daniel R; Rizzato Lede, Daniel A; Otero, Carlos M; Risk, Marcelo R; González Bernaldo de Quirós, Fernán

    2017-02-01

    Clinical Decision Support Systems can alert health professionals about drug interactions when they prescribe medications. The Hospital Italiano de Buenos Aires in Argentina developed an electronic health record with drug-drug interaction alerts, using traditional software engineering techniques and requirements. Despite enhancing the drug-drug interaction knowledge database, the alert override rate of this system was very high. We redesigned the alert system using user-centered design (UCD) and participatory design techniques to enhance the drug-drug interaction alert interface. This paper describes the methodology of our UCD. We used crossover method with realistic, clinical vignettes to compare usability of the standard and new software versions in terms of efficiency, effectiveness, and user satisfaction. Our study showed that, compared to the traditional alert system, the UCD alert system was more efficient (alerts faster resolution), more effective (tasks completed with fewer errors), and more satisfying. These results indicate that UCD techniques that follow ISO 9241-210 can generate more usable alerts than traditional design. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug-Drug Interactions.

    PubMed

    de Kanter, Ruben; Sidharta, Patricia N; Delahaye, Stéphane; Gnerre, Carmela; Segrestaa, Jerome; Buchmann, Stephan; Kohl, Christopher; Treiber, Alexander

    2016-03-01

    Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577. A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro. The model predicted the observed pharmacokinetics of macitentan and its active metabolite ACT-132577 after single and multiple dosing. It performed well in recovering the observed effect of the CYP3A4 inhibitors ketoconazole and cyclosporine, and the CYP3A4 inducer rifampicin, as well as in predicting interactions with S-warfarin and sildenafil. The model was robust enough to allow prospective predictions of macitentan-drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs. Among these were the HIV drugs ritonavir and saquinavir, which were included because HIV infection is a known risk factor for the development of PAH. This example of the application of PBPK modeling to predict drug-drug interactions was used to support the labeling of macitentan (Opsumit).

  20. The Effect of CYP2D6 Drug-Drug Interactions on Hydrocodone Effectiveness

    PubMed Central

    Monte, Andrew A.; Heard, Kennon J.; Campbell, Jenny; Hamamura, D.; Weinshilboum, Richard M.; Vasiliou, Vasilis

    2014-01-01

    Objectives The hepatic cytochrome 2D6 (CYP2D6) is a saturable enzyme responsible for metabolism of approximately 25% of known pharmaceuticals. CYP interactions can alter the efficacy of prescribed medications. Hydrocodone is largely dependent on CYP2D6 metabolism for analgesia, ondansetron is inactivated by CYP2D6, and oxycodone analgesia is largely independent of CYP2D6. The objective was to determine if CYP2D6 medication co-ingestion decreases the effectiveness of hydrocodone. Methods This was a prospective observational study conducted in an academic U.S. emergency department (ED). Subjects were included if they had self-reported pain or nausea; and were excluded if they were unable to speak English, were less than 18 years of age, had liver or renal failure, or carried diagnoses of chronic pain or cyclic vomiting. Detailed drug ingestion histories for the preceding 48 hours prior to the ED visit were obtained. The patient's pain and nausea were quantified using a 100-millimeter visual analogue scale (VAS) at baseline prior to drug administration and following doses of hydrocodone, oxycodone, or ondansetron. We used a mixed model with random subject effect to determine the interaction between CYP2D6 drug ingestion and study drug effectiveness. Odds ratios (OR) were calculated to compare clinically significant VAS changes between CYP2D6 users and non-users. Results Two hundred fifty (49.8%) of the 502 subjects enrolled had taken at least one CYP2D6 substrate, inhibitor, or inducing pharmaceutical, supplement, or illicit drug in the 48 hours prior to ED presentation. CYP2D6-drug users were one third as likely to respond to hydrocodone (OR 0.33, 95% CI = 0.1 to 0.8), and more than three times as likely as non-users to respond to ondansetron (OR 3.4, 95% CI = 1.3 to 9.1). There was no significant difference in oxycodone effectiveness between CYP2D6 users and non-users (OR 0.53, 95% CI = 0.3 to 1.1). Conclusions CYP2D6 drug-drug interactions appear to change

  1. Usability of mobile technology to screen for drug-drug interactions in kidney transplant patients.

    PubMed

    De Silva, Lalitha; Diamantidis, Clarissa J; Prakash, Divya; Zuckerman, Marni; Weir, Matthew R

    2014-01-01

    Kidney transplant recipients are at increased risk for adverse safety events related to reduced renal function and polypharmacy. Health information technology tools have a precautionary role in improving safety in patients with kidney transplants who are at risk of drug-drug interactions. Usability testing of a drug-drug interaction inquiry system on a convenience sample of kidney transplant patients and their family members was conducted between January and April 2013 by a single interviewer. Each participant was provided with 35 tasks to complete on a cell phone with a manual keypad. The tasks were classified according to how it was completed: easily completed, noncritical error, or critical error (where a participant was unable to complete the given task without intervention by the interviewer). The final task was timed using a stop watch. Out of a total of 16 volunteers, 15 completed the testing. The median time to complete the final task was 4 min (range: 2-9). In a cumulative total of 525 tasks, 33 critical errors were noted. Twelve participants had one or more critical errors. The most frequent critical errors were related to typing and spelling mistakes. Twelve out 15 participants were able to complete the final task without any critical errors. Understanding transplant patients' preference in technology use and adapting applications to a variety of technological portals will ensure the most effective use of targeted interventions in patient safety, particularly when applied to preventing drug-drug interactions. © 2014 S. Karger AG, Basel

  2. Validated UPLC-MS/MS method for simultaneous determination of simvastatin, simvastatin hydroxy acid and berberine in rat plasma: Application to the drug-drug pharmacokinetic interaction study of simvastatin combined with berberine after oral administration in rats.

    PubMed

    Liu, Mei; Su, Xianying; Li, Guofei; Zhao, Guilian; Zhao, Limei

    2015-12-01

    A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method was developed and validated for simultaneous quantification of simvastatin (SV), its metabolite simvastatin hydroxy acid (SVA) and berberine (BBR) in rat plasma. Separation was performed on Poroshell 120 EC-C18 column (4.6×50mm, 2.7μm) using gradient elution by mobile phase containing acetonitrile and 10mM ammonium acetate (pH 4.5). Polarity switch (positive-negative-positive ionization mode) was performed in a total run time of 4.0min. The lower limits of quantification (LLOQ) for SV, SVA and BBR were 0.10, 0.20 and 0.10ng/mL, respectively. The response function was established for concentration range of 0.10-100ng/mL for SV and BBR and 0.20-3000ng/mL for SVA, with a coefficient of correlation of >0.99 for all the compounds. The proposed method was applied to the drug-drug pharmacokinetic interaction study of SV combined with BBR after oral administration in rats.

  3. Quantitative Prediction of CYP3A4 Induction: Impact of Measured, Free and Intracellular Perpetrator Concentrations from Human Hepatocyte Induction Studies on Drug-Drug Interaction Predictions.

    PubMed

    Sun, Yongkai; Chothe, Paresh P; Sager, Jennifer; Tsao, Hong; Moore, Amanda; Laitinen, Leena; Hariparsad, Niresh

    2017-03-23

    Typically, concentration-response curves are generated based upon nominal new chemical entity (NCE) concentrations for in-vitro-to-in-vivo extrapolation of CYP3A4 induction. These data are then used to determine the induction risk of an NCE employing various modeling approaches. The limitation to this practice is that it assumes the hepatocyte culture model to be a static system. In the current study, we assessed whether correcting for; 1) changes in perpetrator concentration in the induction medium during the assay incubation period, 2) perpetrator binding to proteins in the induction medium and 3) non-specific binding of perpetrator can improve the accuracy of CYP3A4 induction predictions. Of the seven validation compounds used in our studies, we noted significant parent loss and a high degree of medium protein binding with pioglitazone and rosiglitazone while pleconaril had very high non-specific binding. Predictions of clinical induction were determined using the relative induction score, basic-static, and mechanistic static models. In general, we observed that the precision and accuracy of our predictions improved when corrections were made for measured medium concentrations, medium protein binding, and non-specific binding of the perpetrator. As a follow-up, we noted that for substrates of uptake transporters, the use of free intracellular concentrations could result in improved predictions of CYP3A4 induction. In conclusion, our data indicates that quantifying perpetrator levels in induction medium can improve the accuracy and precision of CYP3A4 induction predictions. Continued efforts are necessary to improve our understanding of the impact of free intracellular concentrations on induction predictions.

  4. Evaluation of Potential Drug-Drug Interactions with Antidepressants in Two Tertiary Care Hospitals

    PubMed Central

    Rafi, Muhammad Salman; Naqvi, Syed Baqir Shyum; Khan, Muhammad Umair; Fayyaz, Muhammad; Ashraf, Nida; Khan, Maqsood Ahmed; Ahmad, Akram

    2015-01-01

    Background Limited resources of healthcare system and high use of antidepressants have raised some serious concerns regarding proper surveillance system of prescribed medicines. Not much literature is available from Pakistan regarding the potential drug-drug interactions (pDDIs) associated with antidepressants. Objective The objective of this study was to assess the frequency of pDDIs associated with antidepressants, their severity, significance and their association with patient characteristics. Materials and Methods A prospective, observational study was conducted in two major hospitals of Karachi for the period of three months. Patient profiles, medication charts, and physician notes were thoroughly reviewed to gather all the relevant information. Inclusion and exclusion criteria were set prior to data collection. The collected data was then analysed using Micromedex Drug-REAX System. Descriptive and binomial logistic regression analysis was used to express results. Results Of 245 prescriptions reviewed, 141 prescriptions had at least one pDDI (57.5%). A total of 181 pDDIs were identified in prescription containing antidepressant. The ratio of pDDI per prescriptions was 0.78. 42.5% interactions were moderate in severity, 30% of interactions were rapid in onset, and 43% were considered as significant interactions. Polypharmacy (OR=3.41, p< 0.001) and presence of chronic problems (OR=2.14, p=0.002) were significantly associated with the occurrence of pDDIs. Citalopram and diclofenac (11.6%) was commonly prescribed interacting pair in this study. Conclusion The findings of this study recorded high frequency of antidepressants associated pDDIs. Our results confirm the significant association of polypharmacy with the occurrence of pDDIs with antidepressants. Future studies are warranted to establish these results by including hospitals in different parts of the country. PMID:26393139

  5. A novel algorithm for analyzing drug-drug interactions from MEDLINE literature.

    PubMed

    Lu, Yin; Shen, Dan; Pietsch, Maxwell; Nagar, Chetan; Fadli, Zayd; Huang, Hong; Tu, Yi-Cheng; Cheng, Feng

    2015-11-27

    Drug-drug interaction (DDI) is becoming a serious clinical safety issue as the use of multiple medications becomes more common. Searching the MEDLINE database for journal articles related to DDI produces over 330,000 results. It is impossible to read and summarize these references manually. As the volume of biomedical reference in the MEDLINE database continues to expand at a rapid pace, automatic identification of DDIs from literature is becoming increasingly important. In this article, we present a random-sampling-based statistical algorithm to identify possible DDIs and the underlying mechanism from the substances field of MEDLINE records. The substances terms are essentially carriers of compound (including protein) information in a MEDLINE record. Four case studies on warfarin, ibuprofen, furosemide and sertraline implied that our method was able to rank possible DDIs with high accuracy (90.0% for warfarin, 83.3% for ibuprofen, 70.0% for furosemide and 100% for sertraline in the top 10% of a list of compounds ranked by p-value). A social network analysis of substance terms was also performed to construct networks between proteins and drug pairs to elucidate how the two drugs could interact.

  6. Predicting Pharmacodynamic Drug-Drug Interactions through Signaling Propagation Interference on Protein-Protein Interaction Networks

    PubMed Central

    Park, Kyunghyun; Kim, Docyong; Ha, Suhyun; Lee, Doheon

    2015-01-01

    As pharmacodynamic drug-drug interactions (PD DDIs) could lead to severe adverse effects in patients, it is important to identify potential PD DDIs in drug development. The signaling starting from drug targets is propagated through protein-protein interaction (PPI) networks. PD DDIs could occur by close interference on the same targets or within the same pathways as well as distant interference through cross-talking pathways. However, most of the previous approaches have considered only close interference by measuring distances between drug targets or comparing target neighbors. We have applied a random walk with restart algorithm to simulate signaling propagation from drug targets in order to capture the possibility of their distant interference. Cross validation with DrugBank and Kyoto Encyclopedia of Genes and Genomes DRUG shows that the proposed method outperforms the previous methods significantly. We also provide a web service with which PD DDIs for drug pairs can be analyzed at http://biosoft.kaist.ac.kr/targetrw. PMID:26469276

  7. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor.

    PubMed

    Chen, Jiezhong; Raymond, Kenneth

    2006-02-15

    Rifampicin, an important drug in the treatment of tuberculosis, is used extensively despite its broad effects on drug-drug interactions, creating serious problems. The clinical importance of such interactions includes autoinduction leading to suboptimal or failed treatment. The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver. This review paper summarises recent findings with emphases on the molecular mechanisms used to explain these broad drug-drug interactions. In general, rifampicin can act on a pattern: rifampicin activates the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This pattern of action may explain many of the rifampicin inducing drug-drug interactions. However, effects through other mechanisms have also been reported and these make any explanation of such drug-drug interactions more complex.

  8. [Prevalence of potential drug-drug interactions involving antiretroviral drugs in Buenos Aires, Argentina].

    PubMed

    Córdova, Ezequiel; Porteiro, Norma; Loiza, Eliana; Mingrone, Horacio

    2016-10-01

    Antiretroviral agents (ARVs) have a high potential for drug interactions. However, the prevalence and risk factors for clinically significant drug-drug interactions (CSDDIs) with ARVs from Latin American countries is unknown. To evaluate the prevalence and risk factors for CSDDIs in HIV outpatients attending at two centers in Buenos Aires, Argentina. Descriptive cross-sectional study (september to november 2012). HIV-1 infected patients under ARV treatment at the time of the study were randomly assessed for concomitant medication. CSDDIs were screened using the University of Liverpool Drug Interactions Program (www.hiv-druginteractions.org). A total of 217 patients were included. Male sex: 64% (CI 95: 57-70). Median age (IQR): 41 (36-48). Presence of comorbidities: 19%. ARV regimen: NNRTI-based: 48%, PI-based: 50% and NNRTI plus PI: 2%. Median of CD4 T-cell count (IQR): 402 cells/mL (235-588). Viral load < 50 copies/mL: 78%. Overall, 64% (CI 95: 57-70) of patients had > 1 co-medication of whom a 49% had at least one CSDDI. Two patients had a CSDDI between ARVs. The most frequent co-medications observed were antimicrobial (40%), cardiovascular (25%) and gastrointestinal agents (22%). In the multivariate analysis the number of co-medications and use of CNS agents were associated with the presence of CSDDIs. Co-medications and CSDDIs were common in our setting. In this context, training of HIV physicians in drug interactions is of major importance for adequate management of these patients.

  9. Computerized techniques pave the way for drug-drug interaction prediction and interpretation

    PubMed Central

    Safdari, Reza; Ferdousi, Reza; Aziziheris, Kamal; Niakan-Kalhori, Sharareh R.; Omidi, Yadollah

    2016-01-01

    Introduction: Health care industry also patients penalized by medical errors that are inevitable but highly preventable. Vast majority of medical errors are related to adverse drug reactions, while drug-drug interactions (DDIs) are the main cause of adverse drug reactions (ADRs). DDIs and ADRs have mainly been reported by haphazard case studies. Experimental in vivo and in vitro researches also reveals DDI pairs. Laboratory and experimental researches are valuable but also expensive and in some cases researchers may suffer from limitations. Methods: In the current investigation, the latest published works were studied to analyze the trend and pattern of the DDI modelling and the impacts of machine learning methods. Applications of computerized techniques were also investigated for the prediction and interpretation of DDIs. Results: Computerized data-mining in pharmaceutical sciences and related databases provide new key transformative paradigms that can revolutionize the treatment of diseases and hence medical care. Given that various aspects of drug discovery and pharmacotherapy are closely related to the clinical and molecular/biological information, the scientifically sound databases (e.g., DDIs, ADRs) can be of importance for the success of pharmacotherapy modalities. Conclusion: A better understanding of DDIs not only provides a robust means for designing more effective medicines but also grantees patient safety. PMID:27525223

  10. mTOR inhibitors in pancreas transplant: adverse effects and drug-drug interactions.

    PubMed

    Fernandes-Silva, Gabriel; Ivani de Paula, Mayara; Rangel, Érika B

    2017-04-01

    Patient and pancreas allograft survival improved following reductions in surgical complications, tighter donor selection and optimization in immunosuppressive protocols. However, long-term survival of pancreas allografts is adversely affected by rejection and immunosuppressive regimen toxicity. Areas covered: This article reviews the existing literature and knowledge of mammalian target of rapamycin inhibitors (mTORi). Some clinically relevant drug-drug interactions are highlighted. We summarize the nephrotoxic and diabetogenic mechanisms of mTORi after pancreas transplant, the alternatives to minimize these effects, and report on other adverse events. Expert opinion: Calcineurin inhibitor (CNI)-based regimens remain the mainstay treatment after pancreas-kidney transplant. However, long-term use of CNIs may be associated with nephrotoxicity. Switching from CNIs to mTORi (sirolimus/SRL and everolimus/EVR) may preserve kidney function, mainly EVR conversion. However, mTORi promote an imbalance of mTOR signaling during long-term follow-up and may ultimately contribute to proteinuria and hyperglycemia. These drugs disrupt autophagy, inhibit cell proliferation, and downregulate VEGF. Therefore, it is important to comprehend and interpret the experimental data. It is equally important to critically analyze clinical studies. Of importance, minimization of side effects, based on safe approaches, can prolong kidney allograft survival. Additional randomized-controlled studies are required to assess the impact of mTORi on pancreas allograft survival.

  11. Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for atorvastatin and its metabolites.

    PubMed

    Zhang, Tao

    2015-09-18

    Atorvastatin is the most commonly used of all statins to lower cholesterol. Atorvastatin is extensively metabolized in both gut and liver to produce several active metabolites. The purpose of the present study is to develop a physiologically based pharmacokinetic (PBPK) model for atorvastatin and its two primary metabolites, 2-hydroxy-atorvastatin acid and atorvastatin lactone, using in vitro and in vivo data. The model was used to predict the pharmacokinetic profiles and drug-drug interaction (DDI) effect for atorvastatin and its metabolites in different DDI scenarios. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministration of atorvastatin with different medications such as itraconazole, clarithromycin, cimetidine, rifampin and phenytoin. This population based PBPK model was able to describe the concentration-time profiles of atorvastatin and its two metabolites reasonably well in the absence or presence of those drugs at different dose regimens. The predicted maximum concentration (Cmax), area under the concentration-time curve (AUC) values and between-phase ratios were in good agreement with clinically observed data. The model has also revealed the importance of different metabolic pathways on the disposition of atorvastatin metabolites. This PBPK model can be utilized to assess the safety and efficacy of atorvastatin in the clinic. This study demonstrated the feasibility of applying PBPK approach to predict the DDI potential of drugs undergoing complex metabolism.

  12. Optimizing hepatitis C virus treatment through pharmacist interventions: Identification and management of drug-drug interactions

    PubMed Central

    Langness, Jacob A; Nguyen, Matthew; Wieland, Amanda; Everson, Gregory T; Kiser, Jennifer J

    2017-01-01

    AIM To quantify drug-drug-interactions (DDIs) encountered in patients prescribed hepatitis C virus (HCV) treatment, the interventions made, and the time spent in this process. METHODS As standard of care, a clinical pharmacist screened for DDIs in patients prescribed direct acting antiviral (DAA) HCV treatment between November 2013 and July 2015 at the University of Colorado Hepatology Clinic. HCV regimens prescribed included ledipasvir/sofosbuvir (LDV/SOF), paritaprevir/ritonavir/ombitasvir/dasabuvir (OBV/PTV/r + DSV), simeprevir/sofosbuvir (SIM/SOF), and sofosbuvir/ribavirin (SOF/RBV). This retrospective analysis reviewed the work completed by the clinical pharmacist in order to measure the aims identified for the study. The number and type of DDIs identified were summarized with descriptive statistics. RESULTS Six hundred and sixty four patients (83.4% Caucasian, 57% male, average 56.7 years old) were identified; 369 for LDV/SOF, 48 for OBV/PTV/r + DSV, 114 for SIM/SOF, and 133 for SOF/RBV. Fifty-one point five per cent of patients were cirrhotic. Overall, 5217 medications were reviewed (7.86 medications per patient) and 781 interactions identified (1.18 interactions per patient). The number of interactions were fewest for SOF/RBV (0.17 interactions per patient) and highest for OBV/PTV/r + DSV (2.48 interactions per patient). LDV/SOF and SIM/SOF had similar number of interactions (1.28 and 1.48 interactions per patient, respectively). Gastric acid modifiers and vitamin/herbal supplements commonly caused interactions with LDV/SOF. Hypertensive agents, analgesics, and psychiatric medications frequently caused interactions with OBV/PTV/r + DSV and SIM/SOF. To manage these interactions, the pharmacists most often recommended discontinuing the medication (28.9%), increasing monitoring for toxicities (24.1%), or separating administration times (18.2%). The pharmacist chart review for each patient usually took approximately 30 min, with additional time for more complex

  13. Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support.

    PubMed

    Scheife, Richard T; Hines, Lisa E; Boyce, Richard D; Chung, Sophie P; Momper, Jeremiah D; Sommer, Christine D; Abernethy, Darrell R; Horn, John R; Sklar, Stephen J; Wong, Samantha K; Jones, Gretchen; Brown, Mary L; Grizzle, Amy J; Comes, Susan; Wilkins, Tricia Lee; Borst, Clarissa; Wittie, Michael A; Malone, Daniel C

    2015-02-01

    Healthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug-drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations. The aim of this study was to provide recommendations for systematic evaluation of evidence for DDIs from the scientific literature, drug product labeling, and regulatory documents. A conference series was conducted to develop a structured process to improve the quality of DDI alerting systems. Three expert workgroups were assembled to address the goals of the conference. The Evidence Workgroup consisted of 18 individuals with expertise in pharmacology, drug information, biomedical informatics, and clinical decision support. Workgroup members met via webinar 12 times from January 2013 to February 2014. Two in-person meetings were conducted in May and September 2013 to reach consensus on recommendations. We developed expert consensus answers to the following three key questions. (i) What is the best approach to evaluate DDI evidence? (ii) What evidence is required for a DDI to be applicable to an entire class of drugs? (iii) How should a structured evaluation process be vetted and validated? Evidence-based decision support for DDIs requires consistent application of transparent and systematic methods to evaluate the evidence. Drug compendia and clinical decision support systems in which these recommendations are implemented should be able to provide higher-quality information about DDIs.

  14. Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

    PubMed

    Ogilvie, Brian W; Torres, Rosarelis; Dressman, Marlene A; Kramer, William G; Baroldi, Paolo

    2015-09-01

    Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%. © 2015 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

  15. Tacrolimus in pancreas transplant: a focus on toxicity, diabetogenic effect and drug-drug interactions.

    PubMed

    Rangel, Erika B

    2014-11-01

    With further reduction in surgical complications and improvement in immunosuppressive protocols, pancreas transplant offers excellent outcomes for patients with diabetes. However, long-term survival of pancreas allograft is affected not only by rejection but also by immunosuppressive regimen toxicity. This article reviews the existing literature and knowledge of tacrolimus toxicity and focuses on its diabetogenic effect after pancreas transplant. Some clinically relevant drug-drug interactions with glucocorticoids and sirolimus are also highlighted. This review also summarizes the diabetogenic mechanisms of tacrolimus, the alternatives to minimize these effects, and the main differential diagnosis of hyperglycemia after pancreas transplant. Tacrolimus is a potent calcineurin inhibitor, an important pathway that regulates pancreatic development. Tacrolimus can induce β-cell apoptosis, decrease insulin exocytosis and reduce insulin gene transcription, which ultimately lead to impaired functional β-cell mass after pancreas transplant. Furthermore, insulin resistance can exacerbate the diabetogenic effect of tacrolimus due to inhibition of insulin gene transcription and β-cell proliferation. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

  16. Knowledge Integration and Use-Case Analysis for a Customized Drug-Drug Interaction CDS Service

    NASA Astrophysics Data System (ADS)

    Kam, Hye Jin; Park, Man Young; Kim, Woojae; Yoon, Duk Yong; Ahn, Eun Kyoung; Park, Rae Woong

    Clinical decision support systems (CDSSs) are thought to reduce adverse drug events (ADEs) by monitoring drug-drug interactions(DDIs). However, clinically improper or excessive alerts can result in high alert overrides. A tailored CDS service, which is appropriate for clinicians and their ordering situations, is required to increase alert acceptance. In this study, we conducted a 12-week pilot project adopting a tailed CDSS at an emergency department. The new CDSS was conducted via a stepwise integration of additional new rules. The alert status with changes in acceptance rate was analyzed. The most frequent DDI alerts were related to prescriptions of anti-inflammatory drugs. The percentages of alert overrides for each stage were 98.0%, 96.0%, 96.9%, and 98.1%, respectively. 91.5% of overridden alerts were related to discharge medications. To reduce the potential hazards of ADEs, the development of an effective customized DDI CDSS is required, via in-depth analysis on alert patterns and overridden reasons.

  17. ITC commentary on the prediction of digoxin clinical drug-drug interactions from in vitro transporter assays.

    PubMed

    Lee, C A; Kalvass, J C; Galetin, A; Zamek-Gliszczynski, M J

    2014-09-01

    The "P-glycoprotein" IC50 working group reported an 18- to 796-fold interlaboratory range in digoxin transport IC50 (inhibitor concentration achieving 50% of maximal inhibition), raising concerns about the predictability of clinical transporter-based drug-drug interactions (DDIs) from in vitro data. This Commentary describes complexities of digoxin transport, which involve both uptake and efflux processes. We caution against attributing digoxin transport IC50 specifically to P-glycoprotein (P-gp) or extending this composite uptake/efflux IC50 variability to individual transporters. Clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not P-gp DDIs.

  18. Sorivudine and 5-fluorouracil; a clinically significant drug-drug interaction due to inhibition of dihydropyrimidine dehydrogenase

    PubMed Central

    Diasio, Robert B

    1998-01-01

    Sorivudine (1-β-d-arabinofuranosyl-E-5-[2-bromovinyl] uracil; BV-araU; SQ32,756) is an antimetabolite which is a synthetic analogue of thymidine. This drug has demonstrated antiviral activity against varicella zoster virus, herpes simplex type 1 virus, and Epstein-Barr virus. Clinical studies in Japan and subsequently worldwide showed this drug to be a potent agent for treating varicella zoster infections. Although in general well tolerated, a fatal drug interaction with fluoropyrimidine drugs was subsequently observed. While three deaths resulting from this interaction were recognized to have occurred during the initial clinical evaluation in Japan, the full impact of the interaction was not recognized in Japan until post-marketing when an additional 23 cases of severe toxicity were reported including 16 patients who subsequently died from fluoro-pyrimidine toxicity. Worldwide recognition of this potentially fatal drug-drug interaction led to subsequent disapproval in the US and elsewhere. The interaction has been shown to be due to suppression of 5-fluorouracil (5-FU) catabolism, resulting in higher levels of 5-FU than would normally be observed. The mechanism of this interaction is mediated through inhibition of the 5-FU rate-limiting catabolizing enzyme dihydropyrimidine dehydrogenase (DPD) by the BV-araU metabolite BVU. This drug-drug interaction of sorivudine and 5-FU further emphasizes the critical importance of DPD on the clinical pharmacology of 5-FU. PMID:9690942

  19. A review of drug-drug interactions in older HIV-infected patients.

    PubMed

    Chary, Aarthi; Nguyen, Nancy N; Maiton, Kimberly; Holodniy, Mark

    2017-09-19

    The number of older HIV-infected people is growing due to increasing life expectancies resulting from the use of antiretroviral therapy (ART). Both HIV and aging increase the risk of other comorbidities, such as cardiovascular disease, osteoporosis, and some malignancies, leading to greater challenges in managing HIV with other conditions. This results in complex medication regimens with the potential for significant drug-drug interactions and increased morbidity and mortality. Area covered: We review the metabolic pathways of ART and other medications used to treat medical co-morbidities, highlight potential areas of concern for drug-drug interactions, and where feasible, suggest alternative approaches for treating these conditions as suggested from national guidelines or articles published in the English language. Expert commentary: There is limited evidence-based data on ART drug interactions, pharmacokinetics and pharmacodynamics in the older HIV-infected population. Choosing and maintaining effective ART regimens for older adults requires consideration of side effect profile, individual comorbidities, interactions with concurrent prescriptions and non-prescription medications and supplements, dietary patterns with respect to dosing, pill burden and ease of dosing, cost and affordability, patient preferences, social situation, and ART resistance history. Practitioners must remain vigilant for potential drug interactions and intervene when there is a potential for harm.

  20. Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing

    PubMed Central

    Udrescu, Lucreţia; Sbârcea, Laura; Topîrceanu, Alexandru; Iovanovici, Alexandru; Kurunczi, Ludovic; Bogdan, Paul; Udrescu, Mihai

    2016-01-01

    Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection algorithms, we link the network clusters to 9 relevant pharmacological properties. Out of the 1141 drugs from the DrugBank 4.1 database, our extensive literature survey and cross-checking with other databases such as Drugs.com, RxList, and DrugBank 4.3 confirm the predicted properties for 85% of the drugs. As such, we argue that network analysis offers a high-level grasp on a wide area of pharmacological aspects, indicating possible unaccounted interactions and missing pharmacological properties that can lead to drug repositioning for the 15% drugs which seem to be inconsistent with the predicted property. Also, by using network centralities, we can rank drugs according to their interaction potential for both simple and complex multi-pathology therapies. Moreover, our clustering approach can be extended for applications such as analyzing drug-target interactions or phenotyping patients in personalized medicine applications. PMID:27599720

  1. The Utility of a Population Approach in Drug-Drug Interaction Assessments: A Simulation Evaluation.

    PubMed

    Wang, Diane D; Yu, Yanke; Kassir, Nastya; Zhu, Min; Hanley, William D; Earp, Justin C; Chow, Andrew T; Gupta, Manish; Hu, Chuanpu

    2017-10-01

    This study aims at evaluating the utility of the population pharmacokinetics approach in therapeutic protein drug-drug-interaction (DDI) assessment. Simulations were conducted for 2 representative victim drugs, methotrexate and trastuzumab, using a parallel-group design with and without the interaction drug. The effect of a perpetrator on the exposure of the victim drug is described as the ratio of clearance/apparent clearance of the victim drug given with or without the perpetrator. The power of DDI assessment was calculated as the percentage of runs with 90% confidence interval of the estimated DDI effect within 80% to 125% for the scenarios of no DDI, benchmarked with the noncompartmental approach with intensive sampling. The impact of the number of subjects, the number of sampling points per subject, sampling time error, and model misspecification on the power of DDI determination were evaluated. Results showed that with equal numbers of subjects in each arm, the population pharmacokinetics approach with sparse sampling may need about the same or a higher number of subjects compared to a noncompartmental approach in order to achieve similar power. Increasing the number of subjects, even if only in the study drug alone arm, can increase the power. Sampling or dosing time error had notable impacts on the power for methotrexate but not for trastuzumab. Model misspecification had no notable impacts on the power for trastuzumab. Overall, the population pharmacokinetics approach with sparse sampling built in phase 2/3 studies allows appropriate DDI assessment with adequate study design and analysis and can be considered as an alternative to dedicated DDI studies. © 2017, The American College of Clinical Pharmacology.

  2. Drug-drug Interaction between Pravastatin and Gemfibrozil (Antihyperlipidemic) with Gliclazide (Antidiabetic) in Rats.

    PubMed

    Sultanpur, Cm; Satyanarayana, S; Reddy, Ns; Kumar, Ke; Kumar, S

    2010-04-01

    Diabetes mellitus is a condition of increased blood glucose level in the body. Antihyperlipidemic drugs like statins and fibrates are widely used for prophylactic treatment in dyslipideamia and atherosclerosis. Diabetic dislipidemia exists with increased triglycerides, low HDL and high LDL levels. Hence, with oral hypoglycemic drugs, the addition of a lipid-lowering drug is necessary for controlling dislipidemia. In such a situation, there may be chances of drug-drug interactions between antidiabetic and antihyperlipidemic drugs. The present study is planned to evaluate the safety of gliclazide (antidiabetic) in the presence of pravastatin and gemfibrozil (antihyperlpidemic) in rats. Studies in normal and alloxan-induced diabetic rats were conducted with oral doses of gliclazide and their combination with pravastatin and gemfibrozil, with an adequate washout period in between the treatments. Blood samples were collected in rats by retroorbital puncture at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h. All the blood samples were analyzed for glucose by GOD -POD. Gliclazide (½ TD) produced hypoglycemic activity in normal and diabetic rats, with peak activity at 2 and 8 h. Pravastatin (TD) + gemfibrozil (TD) combination treatment increased the hypoglycemic effect of gliclazide in normal rats or diabetic rats when administered together. The interaction observed due to inhibition of both the enzymes (CYP 450 2C9 and CYP 450 3A4) responsible for the metabolism of gliclazide showed increased half-life, which was seen in the present study. Because concomitant administration of gliclazide with provastatin and gemfibrozil in diabetes is associated with atherosclerosis, it should be contraindicated or used with caution.

  3. Clinical Drug-Drug Pharmacokinetic Interaction Potential of Sucralfate with Other Drugs: Review and Perspectives.

    PubMed

    Sulochana, Suresh P; Syed, Muzeeb; Chandrasekar, Devaraj V; Mullangi, Ramesh; Srinivas, Nuggehally R

    2016-10-01

    Sucralfate, a complex of aluminium hydroxide with sulfated sucrose, forms a strong gastrointestinal tract (GIT) mucosal barrier with excellent anti-ulcer property. Because sucralfate does not undergo any significant oral absorption, sucralfate resides in the GIT for a considerable length of time. The unabsorbed sucralfate may alter the pharmacokinetics of the oral drugs by impeding its absorption and reducing the oral bioavailability. Because of the increased use of sucralfate, it was important to provide a reappraisal of the published clinical drug-drug interaction studies of sucralfate with scores of drugs. This review covers several category of drugs such as non-steroidal anti-inflammatory drugs, fluoroquinolones, histamine H2-receptor blockers, macrolides, anti-fungals, anti-diabetics, salicylic acid derivatives, steroidal anti-inflammatory drugs and provides pharmacokinetic data summary along with study design, objectives and key remarks. While the loss of oral bioavailability was significant for the fluoroquinolone class, it generally varied for other classes of drugs, suggesting that impact of the co-administration of sucralfate is manageable in clinical situations. Given the technology advancement in formulation development, it may be in order feasible to develop appropriate formulation strategies to either avoid or minimize the absorption-related issues when co-administered with sucralfate. It is recommended that consideration of both in vitro and preclinical studies may be in order to gauge the level of interaction of a drug with sucralfate. Such data may aid in the development of appropriate strategies to navigate the co-administration of sucralfate with other drugs in this age of polypharmacy.

  4. Effect of an educational outreach program on prescribing potential drug-drug interactions.

    PubMed

    Malone, Daniel C; Liberman, Joshua N; Sun, Diana

    2013-09-01

    The topic of improving prescribing practices is a major focus of many national initiatives, not only to enhance the quality of health care but also to reduce medical care costs. Educational outreach (also known as academic detailing) is a type of postgraduate education where trained clinical consultants meet face-to-face with prescribers to provide one-on-one information. Ideally, such visits promote evidence-based knowledge, create trusting relationships, and induce practice change, particularly with regard to prescribing potentially interacting medications. To evaluate the effect of an educational outreach program delivered by clinical pharmacists on reducing the rate of prescribing potential drug-drug interactions (DDIs). The intervention was a prescriber-directed educational outreach program focused on 25 clinically important DDIs. The effect of the educational outreach was evaluated using a retrospective pre-post study design with a control group was conducted. A total of 19,606 prescribers were educated on the DDIs of interest. A control group of 19,606 prescribers, matched on prescribing volume and who did not receive the educational session were selected. Multivariate regression models were used to assess the impact of the educational program on the rate of prescribing potential DDIs. The 2 groups were significantly different with respect to age, profession, specialty, and geographic region. At baseline, mean DDI rates per 100 drug prescriptions were 0.8 and 0.7 for prescribers who received the educational session and those who did not, respectively. Following delivery of the educational outreach program, mean potential DDI rates increased to 1.46 and 1.53 per 100 precipitant drug prescriptions, an increase of 13.9% and 9.15% for the intervention and control groups, respectively. The current study was not able to demonstrate a significant beneficial effect of the educational outreach program on reducing the rate of prescribing potential DDIs.

  5. Addressing drug-drug and drug-food interactions through personalized empowerment services for healthcare.

    PubMed

    Spanakis, Marios; Spanakis, Emmanouil G; Kondylakis, Haridimos; Sfakianakis, Stelios; Genitsaridi, Irini; Sakkalis, Vangelis; Tsiknakis, Manolis; Marias, Kostas

    2016-08-01

    Personalized healthcare systems support the provision of timely and appropriate information regarding healthcare options and treatment alternatives. Especially for patients that receive multi-drug treatments a key issue is the minimization of the risk of adverse effects due to drug-drug interactions (DDIs). DDIs may be the result of doctor prescribed drugs but also due to self-medication of conventional drugs, alternative medicines, food habits, alcohol or smoking. It is therefore crucial for personalized health systems, apart from assisting physicians for optimal prescription practices, to also provide appropriate information for individual users for drug-drug interactions or similar information regarding risks for modulation of the ensuing treatment. In this manuscript we describe a DDI service including drug-food, drug-herb and other lifestyle-related factors, developed in the context of a personalized patient empowerment platform. The solution enables guidance to patients for their medication on how to reduce the risk of unwanted drug interactions and side effects in a seamless and transparent way. We present and analyze the implemented services and provide examples on using an alerting service to identify potential DDIs in two different chronic diseases, congestive heart failure and osteoarthritis.

  6. Drug-drug interaction between voriconazole and oral hypoglycemic agents in diabetic rats

    PubMed Central

    Kumar, Boyina Hemanth; Joshi, Bheemachari; Singh, Jayasingh Chellammal Hanish; Diwan, Prakash V.

    2013-01-01

    Objective: The objective was to study the of drug-drug interaction between voriconazole and oral hypoglycemic agents in normal and alloxan induced diabetic rats. Materials and Methods: The study was designed in two phases. In the first phase, influence of glibenclamide (0.45 mg/kg, p.o.) and pioglitazone (2.7 mg/kg, p.o. once daily) on blood glucose levels in normoglycemic rats was studied and then influence of voriconazole (18 mg/kg, p.o. twice daily.) pre-treatment on the hypoglycemic activity studied. Simultaneously the influence of voriconazole treatment for seven consecutive days (per se effect) on blood glucose levels was also studied in normoglycemic rats. In the second phase of the study alloxan-induced diabetic rats were used to find out the influence of voriconazole pre-treatment on glibenclamide and pioglitazone induced hypoglycemic effect in pathophysiological condition. Blood samples were collected from retro orbital plexus at regular intervals of 0.0, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 18.0 and 24.0 h after drug treatment. All the blood samples were analyzed for plasma glucose by glucose oxidase peroxidase method (GOD/POD). Results: The therapeutic dose of voriconazole potentiates the hypoglycemic activity of glibenclamide and pioglitazone both in normoglycemic and diabetic rats respectively. Conclusion: The results indicate that the dose of oral hypoglycemic agents needs to be adjusted if co-administered with voriconazole. PMID:23716892

  7. Potential drug-drug interactions in infant, child, and adolescent patients in children's hospitals.

    PubMed

    Feinstein, James; Dai, Dingwei; Zhong, Wenjun; Freedman, Jason; Feudtner, Chris

    2015-01-01

    Hospitalized infants, children, and adolescents are typically exposed to numerous distinct medications during inpatient admissions, increasing their risk of potential drug-drug interactions (PDDIs). We assessed the prevalence and characteristics of PDDI exposure of pediatric patients treated in children's hospitals. This retrospective cohort study included patients <21 years old hospitalized in children's hospitals throughout the United States. PDDIs were identified by using the MicroMedex DRUG-REAX system. We calculated the patients exposed to PDDIs, stratified according to the seriousness of the interaction; daily and cumulative counts of PDDI exposures; and characterization of the cited potential adverse effects. Of 498 956 hospitalizations in 2011, 49% were associated with ≥1 PDDI, with a "contraindicated" PDDI occurring in 5% of all hospitalizations, a "major" PDDI present in 41%, a "moderate" PDDI in 28%, and a "minor" PDDI in 11%. Opioids were involved in 25% of all PDDIs, followed by antiinfective agents (17%), neurologic agents (15%), gastrointestinal agents (13%), and cardiovascular agents (13%). One-half of all PDDI exposures were due to specific drug pairs occurring in ≤3% of patients per hospital day. The most common potential adverse drug events included additive respiratory depression (in 21% of PDDIs), bleeding risk (5%), QT interval prolongation (4%), reduced iron absorption/availability (4%), central nervous system depression (4%), hyperkalemia (3%), and altered diuretic effectiveness (3%). Exposure to PDDIs is common among hospitalized children. Empirical data are needed to determine the probability and magnitude of the actual harm for each specific PDDI, particularly for less common drug pairs. Copyright © 2015 by the American Academy of Pediatrics.

  8. Estimation of Severe Drug-Drug Interaction Warnings by Medical Specialist Groups for Austrian Nationwide eMedication

    PubMed Central

    Sauter, S. K.; Neuhofer, L. M.; Edlinger, D.; Grossmann, W.; Wolzt, M.; Endel, G.; Gall, W.

    2014-01-01

    Summary Objective The objective of this study is to estimate the amount of severe drug-drug interaction warnings per medical specialist group triggered by prescribed drugs of a patient before and after the introduction of a nationwide eMedication system in Austria planned for 2015. Methods The estimations of interaction warnings are based on patients’ prescriptions of a single health care professional per patient, as well as all patients’ prescriptions from all visited health care professionals. We used a research database of the Main Association of Austrian Social Security Organizations that contains health claims data of the years 2006 and 2007. Results The study cohort consists of about 1 million patients, with 26.4 million prescribed drugs from about 3,400 different health care professionals. The estimation of interaction warnings show a heterogeneous pattern of severe drug-drug-interaction warnings across medical specialist groups. Conclusion During an eMedication implementation it must be taken into consideration that different medical specialist groups require customized support. PMID:25298801

  9. Estimation of severe drug-drug interaction warnings by medical specialist groups for Austrian nationwide eMedication.

    PubMed

    Rinner, C; Sauter, S K; Neuhofer, L M; Edlinger, D; Grossmann, W; Wolzt, M; Endel, G; Gall, W

    2014-01-01

    The objective of this study is to estimate the amount of severe drug-drug interaction warnings per medical specialist group triggered by prescribed drugs of a patient before and after the introduction of a nationwide eMedication system in Austria planned for 2015. The estimations of interaction warnings are based on patients' prescriptions of a single health care professional per patient, as well as all patients' prescriptions from all visited health care professionals. We used a research database of the Main Association of Austrian Social Security Organizations that contains health claims data of the years 2006 and 2007. The study cohort consists of about 1 million patients, with 26.4 million prescribed drugs from about 3,400 different health care professionals. The estimation of interaction warnings show a heterogeneous pattern of severe drug-drug-interaction warnings across medical specialist groups. During an eMedication implementation it must be taken into consideration that different medical specialist groups require customized support.

  10. Pattern of potential drug-drug interactions in diabetic out-patients in a tertiary care teaching hospital in Nepal.

    PubMed

    Dinesh, K U; Subish, P; Pranaya, M; Shankar, P Ravi; Anil, S K; Durga, B

    2007-10-01

    A prospective study was conducted at Manipal Teaching Hospital, Pokhara, Nepal to identify and analyze the pattern of the potential DDIs (drug-drug interaction) in diabetes patients. A total of 182 patients who were prescribed 685 drugs (average, 3.76 drugs per prescription) were enrolled. Patients 51 to 60 years of age had a higher risk [43 patients, or (23.6%)] of developing DDIs. It was found that 174 (92.1%) of the potential DDIs were of "moderate" severity. Cardiovascular drugs carried a risk of DDIs (187 drugs, or 49.5%). The most common potential DDI observed was between metformin and enalapril (n = 64).

  11. Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin.

    PubMed

    Kwon, Mihwa; Choi, Young A; Choi, Min-Koo; Song, Im-Sook

    2015-01-01

    Berberine, the main active component of the herbal medicine Rhizoma Coptidis, has been reported to have hypoglycemic and insulin-sensitizing effects and, therefore, could be combined with metformin therapy. Thus, we assessed the potential drug-drug interactions between berberine and metformin. We investigated the in vitro inhibitory potency of berberine on metformin uptake in HEK293 cells overexpressing organic cation transporter (OCT) 1 and 2. To investigate whether this inhibitory effect of berberine on OCT1 and OCT2 could change the pharmacokinetics of metformin in vivo, we measured the effect of berberine co-administration on the pharmacokinetics of metformin at a single intravenous dose of 2 mg/kg metformin and 10 mg/kg berberine. In HEK293 cells, berberine inhibited OCT1- and OCT2-mediated metformin uptake in a concentration dependent manner and IC50 values for OCT1 and OCT2 were 7.28 and 11.3 μM, respectively. Co-administration of berberine increased the initial plasma concentration and AUC of metformin and decreased systemic clearance and volume of distribution of metformin in rats, suggesting that berberine inhibited disposition of metformin, which is governed by OCT1 and OCT2. Berberine inhibited the transport activity of OCT1 and OCT2 and showed significant potential drug-drug interactions with metformin in in vivo rats.

  12. Inhibition of human liver aldehyde oxidase: implications for potential drug-drug interactions.

    PubMed

    Barr, John T; Jones, Jeffrey P

    2011-12-01

    During the course of our research efforts to understand the kinetics of human aldehyde oxidase as a xenobiotic-clearing enzyme, we investigated the effect of eight different inhibitors on the oxidation of the probe substrate phthalazine. Saturation kinetic parameters for phthalazine oxidation in human liver cytosol were found to be the following: K(m) = 8.0 ± 0.4 μM and V(max) = 4.3 ± 0.1 nmol · min(-1) · mg protein(-1). Inhibitory potency of the inhibitors tested ranged from 0.1 to 5 μM. Of the eight different inhibitor compounds tested, seven were observed to inhibit through a mixed mode and one through a strictly competitive mode. A ratio of the K(ii) and K(is) values was used to assess the relative competitiveness of each inhibitor. For the mixed inhibitors, the mode of inhibition varied from mostly uncompetitive to predominantly competitive (K(ii)/K(is) values ranging from 0.1 to 15). The implications for potential drug-drug interactions and inhibition mechanism are discussed. We found two inhibitors, clozapine and chlorpromazine, that have a moderate predicted risk of drug-drug interactions based on the K(i) value relative to the inhibitor concentration in human plasma, having a calculated [I]/K(i) value of 0.4 and 0.8, respectively.

  13. Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study

    PubMed Central

    Kondili, Loreta A.; Gaeta, Giovanni Battista; Ieluzzi, Donatella; Zignego, Anna Linda; Monti, Monica; Gori, Andrea; Soria, Alessandro; Raimondo, Giovanni; Filomia, Roberto; Di Leo, Alfredo; Iannone, Andrea; Massari, Marco; Corsini, Romina; Gulminetti, Roberto; Gatti Comini, Alberto; Toniutto, Pierluigi; Dissegna, Denis; Russo, Francesco Paolo; Zanetto, Alberto; Rumi, Maria Grazia; Brancaccio, Giuseppina; Danieli, Elena; Brunetto, Maurizia Rossana; Weimer, Liliana Elena; Quaranta, Maria Giovanna; Vella, Stefano; Puoti, Massimo

    2017-01-01

    Background There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used. Aim To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study. Methods Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org). Results Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI. Conclusions Based on these results, we can estimate that 30–44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from “dose adjustment/closer monitoring”, in mild to moderate liver disease, to

  14. The metabolism and drug-drug interaction potential of the selective prostacyclin receptor agonist selexipag.

    PubMed

    Gnerre, Carmela; Segrestaa, Jérôme; Seeland, Swen; Äänismaa, Päivi; Pfeifer, Thomas; Delahaye, Stephane; de Kanter, Ruben; Ichikawa, Tomohiko; Yamada, Tetsuhiro; Treiber, Alexander

    2017-08-30

    1. The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified. 2. The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces. 3. The formation of the active metabolite ACT-333679 is catalysed by carboxylesterases, while the oxidation and dealkylation reactions are metabolized by CYP2C8 and CYP3A4. CYP2C8 is the only P450 isoform catalysing the aromatic hydroxylation to P10. CYP2C8 together with CYP3A4 are also involved in the formation of several minor ACT-333679 metabolites. UGT1A3 and UGT2B7 catalyse the glucuronidation of ACT-333679. 4. The potential of selexipag to inhibit or induce cytochrome P450 enzymes or drug transport proteins was studied in vitro. Selexipag is an inhibitor of CYP2C8 and CYP2C9 and induces CYP3A4 and CYP2C9 in vitro. Also, selexipag inhibits the transporters OATP1B1, OATP1B3, OAT1, OAT3, and BCRP. However, due to its low dose and relatively low unbound exposure, selexipag has a low potential for causing drug-drug interactions.

  15. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.

    PubMed

    Geffrey, Alexandra L; Pollack, Sarah F; Bruno, Patricia L; Thiele, Elizabeth A

    2015-08-01

    Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article. Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction. Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

  16. Drug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir.

    PubMed

    Ouwerkerk-Mahadevan, Sivi; Snoeys, Jan; Peeters, Monika; Beumont-Mauviel, Maria; Simion, Alexandru

    2016-02-01

    Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug-drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.

  17. A Single Kernel-Based Approach to Extract Drug-Drug Interactions from Biomedical Literature

    PubMed Central

    Zhang, Yijia; Lin, Hongfei; Yang, Zhihao; Wang, Jian; Li, Yanpeng

    2012-01-01

    When one drug influences the level or activity of another drug this is known as a drug-drug interaction (DDI). Knowledge of such interactions is crucial for patient safety. However, the volume and content of published biomedical literature on drug interactions is expanding rapidly, making it increasingly difficult for DDIs database curators to detect and collate DDIs information manually. In this paper, we propose a single kernel-based approach to extract DDIs from biomedical literature. This novel kernel-based approach can effectively make full use of syntactic structural information of the dependency graph. In particular, our approach can efficiently represent both single subgraph topological information and the relation of two subgraphs in the dependency graph. Experimental evaluations showed that our single kernel-based approach can achieve state-of-the-art performance on the publicly available DDI corpus without exploiting multiple kernels or additional domain resources. PMID:23133662

  18. A linguistic rule-based approach to extract drug-drug interactions from pharmacological documents

    PubMed Central

    2011-01-01

    Background A drug-drug interaction (DDI) occurs when one drug influences the level or activity of another drug. The increasing volume of the scientific literature overwhelms health care professionals trying to be kept up-to-date with all published studies on DDI. Methods This paper describes a hybrid linguistic approach to DDI extraction that combines shallow parsing and syntactic simplification with pattern matching. Appositions and coordinate structures are interpreted based on shallow syntactic parsing provided by the UMLS MetaMap tool (MMTx). Subsequently, complex and compound sentences are broken down into clauses from which simple sentences are generated by a set of simplification rules. A pharmacist defined a set of domain-specific lexical patterns to capture the most common expressions of DDI in texts. These lexical patterns are matched with the generated sentences in order to extract DDIs. Results We have performed different experiments to analyze the performance of the different processes. The lexical patterns achieve a reasonable precision (67.30%), but very low recall (14.07%). The inclusion of appositions and coordinate structures helps to improve the recall (25.70%), however, precision is lower (48.69%). The detection of clauses does not improve the performance. Conclusions Information Extraction (IE) techniques can provide an interesting way of reducing the time spent by health care professionals on reviewing the literature. Nevertheless, no approach has been carried out to extract DDI from texts. To the best of our knowledge, this work proposes the first integral solution for the automatic extraction of DDI from biomedical texts. PMID:21489220

  19. Prediction of Drug Clearance and Drug-Drug Interactions in Microscale Cultures of Human Hepatocytes.

    PubMed

    Lin, Christine; Shi, Julianne; Moore, Amanda; Khetani, Salman R

    2016-01-01

    Accurate prediction of in vivo hepatic drug clearance using in vitro assays is important to properly estimate clinical dosing regimens. Clearance of low-turnover compounds is especially difficult to predict using short-lived suspensions of unpooled primary human hepatocytes (PHHs) and functionally declining PHH monolayers. Micropatterned cocultures (MPCCs) of PHHs and 3T3-J2 fibroblasts have been shown previously to display major liver functions for several weeks in vitro. In this study, we first characterized long-term activities of major cytochrome P450 enzymes in MPCCs created from unpooled cryopreserved PHH donors. MPCCs were then used to predict the clearance of 26 drugs that exhibit a wide range of turnover rates in vivo (0.05-19.5 ml/min per kilogram). MPCCs predicted 73, 92, and 96% of drug clearance values for all tested drugs within 2-fold, 3-fold, and 4-fold of in vivo values, respectively. There was good correlation (R(2) = 0.94, slope = 1.05) of predictions between the two PHH donors. On the other hand, suspension hepatocytes and conventional monolayers created from the same donor had significantly reduced predictive capacity (i.e., 30-50% clearance values within 4-fold of in vivo), and were not able to metabolize several drugs. Finally, we modulated drug clearance in MPCCs by inducing or inhibiting P450s. Rifampin-mediated CYP3A4 induction increased midazolam clearance by 73%, while CYP3A4 inhibition with ritonavir decreased midazolam clearance by 79%. Similarly, quinidine-mediated CYP2D6 inhibition reduced clearance of dextromethorphan and desipramine by 71 and 22%, respectively. In conclusion, MPCCs created using cryopreserved unpooled PHHs can be used for drug clearance predictions and to model drug-drug interactions.

  20. An attention-based effective neural model for drug-drug interactions extraction.

    PubMed

    Zheng, Wei; Lin, Hongfei; Luo, Ling; Zhao, Zhehuan; Li, Zhengguang; Zhang, Yijia; Yang, Zhihao; Wang, Jian

    2017-10-10

    Drug-drug interactions (DDIs) often bring unexpected side effects. The clinical recognition of DDIs is a crucial issue for both patient safety and healthcare cost control. However, although text-mining-based systems explore various methods to classify DDIs, the classification performance with regard to DDIs in long and complex sentences is still unsatisfactory. In this study, we propose an effective model that classifies DDIs from the literature by combining an attention mechanism and a recurrent neural network with long short-term memory (LSTM) units. In our approach, first, a candidate-drug-oriented input attention acting on word-embedding vectors automatically learns which words are more influential for a given drug pair. Next, the inputs merging the position- and POS-embedding vectors are passed to a bidirectional LSTM layer whose outputs at the last time step represent the high-level semantic information of the whole sentence. Finally, a softmax layer performs DDI classification. Experimental results from the DDIExtraction 2013 corpus show that our system performs the best with respect to detection and classification (84.0% and 77.3%, respectively) compared with other state-of-the-art methods. In particular, for the Medline-2013 dataset with long and complex sentences, our F-score far exceeds those of top-ranking systems by 12.6%. Our approach effectively improves the performance of DDI classification tasks. Experimental analysis demonstrates that our model performs better with respect to recognizing not only close-range but also long-range patterns among words, especially for long, complex and compound sentences.

  1. Drug-Drug Interaction Potentials of Tyrosine Kinase Inhibitors via Inhibition of UDP-Glucuronosyltransferases

    PubMed Central

    Zhang, Nan; Liu, Yong; Jeong, Hyunyoung

    2015-01-01

    Tyrosine kinase inhibitors (TKIs) are anticancer drugs that may be co-administered with other drugs. The aims of this study are to investigate the inhibitory effects of TKIs on UDP-glucuronosyltransferase (UGT) activities, and to quantitatively evaluate their potential to cause drug-drug interactions (DDIs). Inhibition kinetic profiles of a panel of UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17) by four TKIs (axitinib, imatinib, lapatinib and vandetanib) were characterized by using hepatic microsomes and recombinant proteins. Lapatinib exhibited potent competitive inhibition against UGT1A1 activity with a Ki of 0.5 μM. Imatinib was found to exhibit broad inhibition on several UGTs, particularly potent competitive inhibition against UGT2B17 with a Ki of 0.4 μM. The TKIs also exerted intermediate inhibition against several UGTs (i.e., UGT1A7 by lapatinib; UGT1A1 by imatinib; UGT1A4, 1A7 and 1A9 by axitinib; and UGT1A9 by vandetanib). Results from modeling for the quantitative prediction of DDI risk indicated that the coadministration of lapatinib or imatinib at clinical doses could result in a significant increase in AUC of drugs primarily cleared by UGT1A1 or 2B17. Lapatinib and imatinib may cause clinically significant DDIs when co-administered UGT1A1 or 2B17 substrates. PMID:26642944

  2. Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir.

    PubMed

    King, Jennifer R; Dutta, Sandeep; Cohen, Daniel; Podsadecki, Thomas J; Ding, Bifeng; Awni, Walid M; Menon, Rajeev M

    2016-02-01

    The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT

  3. Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir

    PubMed Central

    Dutta, Sandeep; Cohen, Daniel; Podsadecki, Thomas J.; Ding, Bifeng; Awni, Walid M.; Menon, Rajeev M.

    2015-01-01

    The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT

  4. Drug utilization, prescription errors and potential drug-drug interactions: an experience in rural Sri Lanka.

    PubMed

    Rathish, Devarajan; Bahini, Sivaswamy; Sivakumar, Thanikai; Thiranagama, Thilani; Abarajithan, Tharmarajah; Wijerathne, Buddhika; Jayasumana, Channa; Siribaddana, Sisira

    2016-06-25

    Prescription writing is a process which transfers the therapeutic message from the prescriber to the patient through the pharmacist. Prescribing errors, drug duplication and potential drug-drug interactions (pDDI) in prescriptions lead to medication error. Assessment of the above was made in prescriptions dispensed at State Pharmaceutical Corporation (SPC), Anuradhapura, Sri Lanka. A cross sectional study was conducted. Drugs were classified according to the WHO anatomical, therapeutic chemical classification system. A three point Likert scale, a checklist and Medscape online drug interaction checker were used to assess legibility, completeness and pDDIs respectively. Thousand prescriptions were collected. Majority were hand written (99.8 %) and from the private sector (73 %). The most frequently prescribed substance and subgroup were atorvastatin (4 %, n = 3668) and proton pump inhibitors (7 %, n = 3668) respectively. Out of the substances prescribed from the government and private sectors, 59 and 50 % respectively were available in the national list of essential medicines, Sri Lanka. Patients address (5 %), Sri Lanka Medical Council (SLMC) registration number (35 %), route (7 %), generic name (16 %), treatment symbol (48 %), diagnosis (41 %) and refill information (6 %) were seen in less than half of the prescriptions. Most were legible with effort (65 %) and illegibility was seen in 9 %. There was significant difference in omission and/or errors of generic name (P = 0.000), dose (P = 0.000), SLMC registration number (P = 0.000), and in evidence of pDDI (P = 0.009) with regards to the sector of prescribing. The commonest subgroup involved in duplication was non-steroidal anti-inflammatory drugs (NSAIDs) (43 %; 56/130). There were 1376 potential drug interactions (466/887 prescriptions). Most common pair causing pDDI was aspirin with losartan (4 %, n = 1376). Atorvastatin was the most frequently prescribed substance

  5. Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions.

    PubMed

    Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

    2016-02-24

    Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug-drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug-drug interactions.

  6. Clinical Drug-Drug Interaction Evaluations to Inform Drug Use and Enable Drug Access.

    PubMed

    Rekić, Dinko; Reynolds, Kellie S; Zhao, Ping; Zhang, Lei; Yoshida, Kenta; Sachar, Madhav; Piquette Miller, Micheline; Huang, Shiew-Mei; Zineh, Issam

    2017-09-01

    Clinical drug-drug interactions (DDIs) can occur when multiple drugs are taken by the same patient. Significant DDIs can result in clinical toxicity or treatment failure. Therefore, DDI assessment is an integral part of drug development and the benefit-risk assessment of new therapies. Regulatory agencies including the Food and Drug Administration, the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency of Japan have made recommendations in their DDI guidance documents on various methodologies (in vitro, in silico, and clinical) to assess DDI potential and inform patient management strategies. This commentary focuses on clinical DDI evaluation for the purpose of drug development and regulatory evaluation. Published by Elsevier Inc.

  7. Pregnane X receptor and natural products: beyond drug-drug interactions.

    PubMed

    Staudinger, Jeff L; Ding, Xunshan; Lichti, Kristin

    2006-12-01

    The pregnane X receptor (PXR, NR1I2) is a member of the nuclear receptor superfamily that is activated by a myriad of compounds and natural products in clinical use. Activation of PXR represents the basis for several clinically important drug-drug interactions. Although PXR activation has undesirable effects in patients on combination therapy, it also mediates the hepatoprotective effects exhibited by some herbal remedies. This review focuses on PXR activation by natural products and the potential therapeutic opportunities presented. In particular, the biological effects of St. John's Wort, gugulipid, kava kava, Coleus forskolii, Hypoxis, Sutherlandia, qing hao, wu wei zi, gan cao and other natural products are discussed. The impact of these natural products on drug metabolism and hepatoprotection is highlighted in the context of activation and antagonism of PXR.

  8. Pharmacokinetic drug-drug interaction and their implication in clinical management

    PubMed Central

    Palleria, Caterina; Di Paolo, Antonello; Giofrè, Chiara; Caglioti, Chiara; Leuzzi, Giacomo; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2013-01-01

    Drug-drug interactions (DDIs) are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline, PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications. PMID:24516494

  9. Target mediated drug disposition with drug-drug interaction, Part II: competitive and uncompetitive cases.

    PubMed

    Koch, Gilbert; Jusko, William J; Schropp, Johannes

    2017-02-01

    We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equation system arising from the QE or QSS approximation of the rapid binding assumptions. This manuscript is the second in a series to introduce and investigate DDI TMDD models and to apply the QE or QSS approximation.

  10. Renal drug transporters and their significance in drug-drug interactions.

    PubMed

    Yin, Jia; Wang, Joanne

    2016-09-01

    The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites. Renal drug transporters, which are primarily located in the renal proximal tubules, play an important role in tubular secretion and reabsorption of drug molecules in the kidney. Tubular secretion is characterized by high clearance capacities, broad substrate specificities, and distinct charge selectivity for organic cations and anions. In the past two decades, substantial progress has been made in understanding the roles of transporters in drug disposition, efficacy, toxicity and drug-drug interactions (DDIs). In the kidney, several transporters are involved in renal handling of organic cation (OC) and organic anion (OA) drugs. These transporters are increasingly recognized as the target for clinically significant DDIs. This review focuses on the functional characteristics of major human renal drug transporters and their involvement in clinically significant DDIs.

  11. Assessment of Drug-Drug Interactions among Renal Failure Patients of Nephrology Ward in a South Indian Tertiary Care Hospital.

    PubMed

    Rama, Mylapuram; Viswanathan, Gayathri; Acharya, Leelavathi D; Attur, R P; Reddy, P N; Raghavan, S V

    2012-01-01

    Polypharmacy is common in drug prescriptions of chronic kidney disease patients. A study of the prescription patterns of drugs with potential interactions would be of interest to prevent drug related adverse events. A prospective observational study of six months (Dec 2009-May 2010) was carried out among the chronic kidney disease patients admitted to the nephrology ward of a South Indian tertiary care hospital. The pattern and rates of drug-drug interactions seen in the prescriptions of these patients was studied. Among the 205 prescriptions included, a total of 474 interactions were reported, making 2.7 interactions per prescription with incidence rates of 76.09%. Around 19.62% of interactions were of major severity. Most common interactions were found between ascorbic acid and cyanocobalamine (12.45%), clonidine and metoprolol (3.80%) respectively. Hypo or hypertension (31.65%), decreased drug efficacy (29.11%) and hypo or hyperglycemia (14.14%), were the most commonly reported clinical outcomes of the drug interactions. Cardiovascular drugs (calcium channel blockers and beta blockers; 52%) constitute the major class of drugs involved in interactions. As most of the interactions had a delayed onset, long term follow-up is essential to predict the clinically significant outcomes of these interactions. Hence, drug interactions are commonly seen in the prescriptions of chronic kidney disease patients which can lead to serious adverse events if not detected early. Need for collaboration with a clinical pharmacist and electronic surveillance, which are absent in developing countries like India, is emphatic.

  12. Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach.

    PubMed

    Han, X; Quinney, S K; Wang, Z; Zhang, P; Duke, J; Desta, Z; Elmendorf, J S; Flockhart, D A; Li, L

    2015-09-01

    Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System. © 2015 The American Society for Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  13. Toward a complete dataset of drug-drug interaction information from publicly available sources.

    PubMed

    Ayvaz, Serkan; Horn, John; Hassanzadeh, Oktie; Zhu, Qian; Stan, Johann; Tatonetti, Nicholas P; Vilar, Santiago; Brochhausen, Mathias; Samwald, Matthias; Rastegar-Mojarad, Majid; Dumontier, Michel; Boyce, Richard D

    2015-06-01

    Although potential drug-drug interactions (PDDIs) are a significant source of preventable drug-related harm, there is currently no single complete source of PDDI information. In the current study, all publically available sources of PDDI information that could be identified using a comprehensive and broad search were combined into a single dataset. The combined dataset merged fourteen different sources including 5 clinically-oriented information sources, 4 Natural Language Processing (NLP) Corpora, and 5 Bioinformatics/Pharmacovigilance information sources. As a comprehensive PDDI source, the merged dataset might benefit the pharmacovigilance text mining community by making it possible to compare the representativeness of NLP corpora for PDDI text extraction tasks, and specifying elements that can be useful for future PDDI extraction purposes. An analysis of the overlap between and across the data sources showed that there was little overlap. Even comprehensive PDDI lists such as DrugBank, KEGG, and the NDF-RT had less than 50% overlap with each other. Moreover, all of the comprehensive lists had incomplete coverage of two data sources that focus on PDDIs of interest in most clinical settings. Based on this information, we think that systems that provide access to the comprehensive lists, such as APIs into RxNorm, should be careful to inform users that the lists may be incomplete with respect to PDDIs that drug experts suggest clinicians be aware of. In spite of the low degree of overlap, several dozen cases were identified where PDDI information provided in drug product labeling might be augmented by the merged dataset. Moreover, the combined dataset was also shown to improve the performance of an existing PDDI NLP pipeline and a recently published PDDI pharmacovigilance protocol. Future work will focus on improvement of the methods for mapping between PDDI information sources, identifying methods to improve the use of the merged dataset in PDDI NLP algorithms

  14. Similarity-based modeling in large-scale prediction of drug-drug interactions

    PubMed Central

    Vilar, Santiago; Uriarte, Eugenio; Santana, Lourdes; Lorberbaum, Tal; Hripcsak, George; Friedman, Carol; Tatonetti, Nicholas P

    2015-01-01

    Drug-drug interactions (DDIs) are a major cause of adverse drug effects and a public health concern, as they increase hospital care expenses and reduce patients’ quality of life. DDI detection is, therefore, an important objective in patient safety, one whose pursuit affects drug development and pharmacovigilance. In this article, we describe a protocol applicable on a large scale to predict novel DDIs based on similarity of drug interaction candidates to drugs involved in established DDIs. the method integrates a reference standard database of known DDIs with drug similarity information extracted from different sources, such as 2D and 3D molecular structure, interaction profile, target and side-effect similarities. the method is interpretable in that it generates drug interaction candidates that are traceable to pharmacological or clinical effects. We describe a protocol with applications in patient safety and preclinical toxicity screening. the time frame to implement this protocol is 5–7 h, with additional time potentially necessary, depending on the complexity of the reference standard DDI database and the similarity measures implemented. PMID:25122524

  15. Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6.

    PubMed

    Bahar, Muh Akbar; Setiawan, Didik; Hak, Eelko; Wilffert, Bob

    2017-05-01

    Currently, most guidelines on drug-drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug-gene interaction (DGI) where there are multiple biotransformation pathways, which is referred to as drug-drug-gene interaction (DDGI). In this systematic review, we report the impact of pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes - CYP2C9, CYP2C19 and CYP2D6 - are central. We observed that several DDI and DDGI are highly gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take pharmacogenetics into account when drug interactions in clinical practice are expected.

  16. Pharmacokinetic and Pharmacodynamic Analyses of Drug-Drug Interactions between Iguratimod and Warfarin.

    PubMed

    Yamamoto, Tetsuya; Hasegawa, Kyoko; Onoda, Makoto; Tanaka, Keiichi

    2016-01-01

    Iguratimod (IGU), a disease-modifying antirheumatic drug launched in September 2012, has been reported to carry a risk of severe hemorrhages through a suspected interaction with warfarin (WF) in the all-case surveillance and early postmarketing-phase vigilance. To elucidate possible mechanisms of adverse interaction between IGU and WF, we analyzed the effects of IGU on the pharmacodynamics and pharmacokinetics of WF in rats. IGU was orally administered to male Wistar rats once daily for 5 d at 10 or 30 mg/kg in combination with WF at an oral dose of 0.25 mg/kg. Coadministration of IGU 30 mg/kg enhanced the anticoagulant activity of WF; prolonged blood coagulation time (prothrombin time and activated partial thromboplastin time) and decreased levels of vitamin K (VK)-dependent blood coagulation factors (II, VII, IX, and X) were observed. On the other hand, the pharmacokinetic parameters of WF including maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24 h) were not affected by the combination with IGU. IGU alone did not change blood coagulation time at doses up to 100 mg/kg, while VK-dependent blood coagulation factors decreased slightly at 30 and 100 mg/kg. These results suggest that the pharmacodynamic effect of IGU on VK-dependent blood coagulation factors is involved in the mechanism of drug-drug interaction of IGU with WF.

  17. Information needs for making clinical recommendations about potential drug-drug interactions: a synthesis of literature review and interviews.

    PubMed

    Romagnoli, Katrina M; Nelson, Scott D; Hines, Lisa; Empey, Philip; Boyce, Richard D; Hochheiser, Harry

    2017-02-22

    Drug information compendia and drug-drug interaction information databases are critical resources for clinicians and pharmacists working to avoid adverse events due to exposure to potential drug-drug interactions (PDDIs). Our goal is to develop information models, annotated data, and search tools that will facilitate the interpretation of PDDI information. To better understand the information needs and work practices of specialists who search and synthesize PDDI evidence for drug information resources, we conducted an inquiry that combined a thematic analysis of published literature with unstructured interviews. Starting from an initial set of relevant articles, we developed search terms and conducted a literature search. Two reviewers conducted a thematic analysis of included articles. Unstructured interviews with drug information experts were conducted and similarly coded. Information needs, work processes, and indicators of potential strengths and weaknesses of information systems were identified. Review of 92 papers and 10 interviews identified 56 categories of information needs related to the interpretation of PDDI information including drug and interaction information; study design; evidence including clinical details, quality and content of reports, and consequences; and potential recommendations. We also identified strengths/weaknesses of PDDI information systems. We identified the kinds of information that might be most effective for summarizing PDDIs. The drug information experts we interviewed had differing goals, suggesting a need for detailed information models and flexible presentations. Several information needs not discussed in previous work were identified, including temporal overlaps in drug administration, biological plausibility of interactions, and assessment of the quality and content of reports. Richly structured depictions of PDDI information may help drug information experts more effectively interpret data and develop recommendations

  18. Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

    PubMed Central

    Wells, Charles; Petersen, Carolyn; Paccaly, Anne; Shoaf, Susan E.; Patil, Shiva; Geiter, Lawrence

    2016-01-01

    Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to

  19. Extracting Drug-Drug Interaction from the Biomedical Literature Using a Stacked Generalization-Based Approach

    PubMed Central

    He, Linna; Yang, Zhihao; Zhao, Zhehuan; Lin, Hongfei; Li, Yanpeng

    2013-01-01

    Drug-drug interaction (DDI) detection is particularly important for patient safety. However, the amount of biomedical literature regarding drug interactions is increasing rapidly. Therefore, there is a need to develop an effective approach for the automatic extraction of DDI information from the biomedical literature. In this paper, we present a Stacked Generalization-based approach for automatic DDI extraction. The approach combines the feature-based, graph and tree kernels and, therefore, reduces the risk of missing important features. In addition, it introduces some domain knowledge based features (the keyword, semantic type, and DrugBank features) into the feature-based kernel, which contribute to the performance improvement. More specifically, the approach applies Stacked generalization to automatically learn the weights from the training data and assign them to three individual kernels to achieve a much better performance than each individual kernel. The experimental results show that our approach can achieve a better performance of 69.24% in F-score compared with other systems in the DDI Extraction 2011 challenge task. PMID:23785452

  20. Extracting drug-drug interactions from literature using a rich feature-based linear kernel approach

    PubMed Central

    Kim, Sun; Yeganova, Lana; Wilbur, W. John

    2015-01-01

    Identifying unknown drug interactions is of great benefit in the early detection of adverse drug reactions. Despite existence of several resources for drug-drug interaction (DDI) information, the wealth of such information is buried in a body of unstructured medical text which is growing exponentially. This calls for developing text mining techniques for identifying DDIs. The state-of-the-art DDI extraction methods use Support Vector Machines (SVMs) with non-linear composite kernels to explore diverse contexts in literature. While computationally less expensive, linear kernel-based systems have not achieved a comparable performance in DDI extraction tasks. In this work, we propose an efficient and scalable system using a linear kernel to identify DDI information. The proposed approach consists of two steps: identifying DDIs and assigning one of four different DDI types to the predicted drug pairs. We demonstrate that when equipped with a rich set of lexical and syntactic features, a linear SVM classifier is able to achieve a competitive performance in detecting DDIs. In addition, the one-against-one strategy proves vital for addressing an imbalance issue in DDI type classification. Applied to the DDIExtraction 2013 corpus, our system achieves an F1 score of 0.670, as compared to 0.651 and 0.609 reported by the top two participating teams in the DDIExtraction 2013 challenge, both based on non-linear kernel methods. PMID:25796456

  1. Extracting drug-drug interactions from literature using a rich feature-based linear kernel approach.

    PubMed

    Kim, Sun; Liu, Haibin; Yeganova, Lana; Wilbur, W John

    2015-06-01

    Identifying unknown drug interactions is of great benefit in the early detection of adverse drug reactions. Despite existence of several resources for drug-drug interaction (DDI) information, the wealth of such information is buried in a body of unstructured medical text which is growing exponentially. This calls for developing text mining techniques for identifying DDIs. The state-of-the-art DDI extraction methods use Support Vector Machines (SVMs) with non-linear composite kernels to explore diverse contexts in literature. While computationally less expensive, linear kernel-based systems have not achieved a comparable performance in DDI extraction tasks. In this work, we propose an efficient and scalable system using a linear kernel to identify DDI information. The proposed approach consists of two steps: identifying DDIs and assigning one of four different DDI types to the predicted drug pairs. We demonstrate that when equipped with a rich set of lexical and syntactic features, a linear SVM classifier is able to achieve a competitive performance in detecting DDIs. In addition, the one-against-one strategy proves vital for addressing an imbalance issue in DDI type classification. Applied to the DDIExtraction 2013 corpus, our system achieves an F1 score of 0.670, as compared to 0.651 and 0.609 reported by the top two participating teams in the DDIExtraction 2013 challenge, both based on non-linear kernel methods. Published by Elsevier Inc.

  2. Effects of Shared Electronic Health Record Systems on Drug-Drug Interaction and Duplication Warning Detection

    PubMed Central

    Rinner, Christoph; Grossmann, Wilfried; Sauter, Simone Katja; Wolzt, Michael; Gall, Walter

    2015-01-01

    Shared electronic health records (EHRs) systems can offer a complete medication overview of the prescriptions of different health care providers. We use health claims data of more than 1 million Austrians in 2006 and 2007 with 27 million prescriptions to estimate the effect of shared EHR systems on drug-drug interaction (DDI) and duplication warnings detection and prevention. The Austria Codex and the ATC/DDD information were used as a knowledge base to detect possible DDIs. DDIs are categorized as severe, moderate, and minor interactions. In comparison to the current situation where only DDIs between drugs issued by a single health care provider can be checked, the number of warnings increases significantly if all drugs of a patient are checked: severe DDI warnings would be detected for 20% more persons, and the number of severe DDI warnings and duplication warnings would increase by 17%. We show that not only do shared EHR systems help to detect more patients with warnings but DDIs are also detected more frequently. Patient safety can be increased using shared EHR systems. PMID:26682218

  3. Effects of Shared Electronic Health Record Systems on Drug-Drug Interaction and Duplication Warning Detection.

    PubMed

    Rinner, Christoph; Grossmann, Wilfried; Sauter, Simone Katja; Wolzt, Michael; Gall, Walter

    2015-01-01

    Shared electronic health records (EHRs) systems can offer a complete medication overview of the prescriptions of different health care providers. We use health claims data of more than 1 million Austrians in 2006 and 2007 with 27 million prescriptions to estimate the effect of shared EHR systems on drug-drug interaction (DDI) and duplication warnings detection and prevention. The Austria Codex and the ATC/DDD information were used as a knowledge base to detect possible DDIs. DDIs are categorized as severe, moderate, and minor interactions. In comparison to the current situation where only DDIs between drugs issued by a single health care provider can be checked, the number of warnings increases significantly if all drugs of a patient are checked: severe DDI warnings would be detected for 20% more persons, and the number of severe DDI warnings and duplication warnings would increase by 17%. We show that not only do shared EHR systems help to detect more patients with warnings but DDIs are also detected more frequently. Patient safety can be increased using shared EHR systems.

  4. Potential P-glycoprotein-mediated drug-drug interactions of antimalarial agents in Caco-2 cells.

    PubMed

    Oga, Enoche F; Sekine, Shuichi; Shitara, Yoshihisa; Horie, Toshiharu

    2012-07-01

    Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells. Verapamil (100 μM) and quinidine (1 μM) were used as positive inhibition controls. Lumefantrine, amodiaquin, and artesunate all showed blockade of Rho-123 transport. Subsequently, the inhibitory effect of these antimalarials on the bi-directional passage of digoxin (DIG) was examined. All of the drugs decreased basal-to-apical (B-A) P-gp-mediated DIG transport at concentrations of 100 μM and 1 mM. These concentrations may reflect therapeutic doses for amodiaquin and artesunate. Therefore, clinically relevant DDIs may occur between certain antimalarials and P-gp substrates in general.

  5. Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction Between Clopidogrel and Dasabuvir.

    PubMed

    Shebley, M; Fu, W; Badri, P; Bow, Daj; Fischer, V

    2017-10-01

    Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-β-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data. Sensitivity analyses using these PBPK models suggested that CYP2C8 inhibition by clopidogrel acyl-β-D glucuronide may not be as potent as previously suggested. The dasabuvir and updated clopidogrel PBPK models predict a moderate increase of 1.5-1.9-fold for Cmax and 1.9-2.8-fold for AUC of dasabuvir when coadministered with clopidogrel. While the PBPK results suggest there is a potential for DDI between dasabuvir and clopidogrel, the magnitude is not expected to be clinically relevant. © 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  6. Label Propagation Prediction of Drug-Drug Interactions Based on Clinical Side Effects.

    PubMed

    Zhang, Ping; Wang, Fei; Hu, Jianying; Sorrentino, Robert

    2015-07-21

    Drug-drug interaction (DDI) is an important topic for public health, and thus attracts attention from both academia and industry. Here we hypothesize that clinical side effects (SEs) provide a human phenotypic profile and can be translated into the development of computational models for predicting adverse DDIs. We propose an integrative label propagation framework to predict DDIs by integrating SEs extracted from package inserts of prescription drugs, SEs extracted from FDA Adverse Event Reporting System, and chemical structures from PubChem. Experimental results based on hold-out validation demonstrated the effectiveness of the proposed algorithm. In addition, the new algorithm also ranked drug information sources based on their contributions to the prediction, thus not only confirming that SEs are important features for DDI prediction but also paving the way for building more reliable DDI prediction models by prioritizing multiple data sources. By applying the proposed algorithm to 1,626 small-molecule drugs which have one or more SE profiles, we obtained 145,068 predicted DDIs. The predicted DDIs will help clinicians to avoid hazardous drug interactions in their prescriptions and will aid pharmaceutical companies to design large-scale clinical trial by assessing potentially hazardous drug combinations. All data sets and predicted DDIs are available at http://astro.temple.edu/~tua87106/ddi.html.

  7. Drug-drug Interaction Discovery Using Abstraction Networks for “National Drug File – Reference Terminology” Chemical Ingredients

    PubMed Central

    Ochs, Christopher; Zheng, Ling; Gu, Huanying; Perl, Yehoshua; Geller, James; Kapusnik-Uner, Joan; Zakharchenko, Aleksandr

    2015-01-01

    The National Drug File – Reference Terminology (NDF-RT) is a large and complex drug terminology. NDF-RT provides important information about clinical drugs, e.g., their chemical ingredients, mechanisms of action, dosage form and physiological effects. Within NDF-RT such information is represented using tens of thousands of roles. It is difficult to comprehend large, complex terminologies like NDF-RT. In previous studies, we introduced abstraction networks to summarize the content and structure of terminologies. In this paper, we introduce the Ingredient Abstraction Network to summarize NDF-RT’s Chemical Ingredients and their associated drugs. Additionally, we introduce the Aggregate Ingredient Abstraction Network, for controlling the granularity of summarization provided by the Ingredient Abstraction Network. The Ingredient Abstraction Network is used to support the discovery of new candidate drug-drug interactions (DDIs) not appearing in First Databank, Inc.’s DDI knowledgebase. PMID:26958234

  8. Drug drug interaction extraction from biomedical literature using syntax convolutional neural network.

    PubMed

    Zhao, Zhehuan; Yang, Zhihao; Luo, Ling; Lin, Hongfei; Wang, Jian

    2016-11-15

    Detecting drug-drug interaction (DDI) has become a vital part of public health safety. Therefore, using text mining techniques to extract DDIs from biomedical literature has received great attentions. However, this research is still at an early stage and its performance has much room to improve. In this article, we present a syntax convolutional neural network (SCNN) based DDI extraction method. In this method, a novel word embedding, syntax word embedding, is proposed to employ the syntactic information of a sentence. Then the position and part of speech features are introduced to extend the embedding of each word. Later, auto-encoder is introduced to encode the traditional bag-of-words feature (sparse 0-1 vector) as the dense real value vector. Finally, a combination of embedding-based convolutional features and traditional features are fed to the softmax classifier to extract DDIs from biomedical literature. Experimental results on the DDIExtraction 2013 corpus show that SCNN obtains a better performance (an F-score of 0.686) than other state-of-the-art methods. The source code is available for academic use at http://202.118.75.18:8080/DDI/SCNN-DDI.zip CONTACT: yangzh@dlut.edu.cnSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

  9. Drug drug interaction extraction from biomedical literature using syntax convolutional neural network

    PubMed Central

    Zhao, Zhehuan; Yang, Zhihao; Luo, Ling; Lin, Hongfei; Wang, Jian

    2016-01-01

    Motivation: Detecting drug-drug interaction (DDI) has become a vital part of public health safety. Therefore, using text mining techniques to extract DDIs from biomedical literature has received great attentions. However, this research is still at an early stage and its performance has much room to improve. Results: In this article, we present a syntax convolutional neural network (SCNN) based DDI extraction method. In this method, a novel word embedding, syntax word embedding, is proposed to employ the syntactic information of a sentence. Then the position and part of speech features are introduced to extend the embedding of each word. Later, auto-encoder is introduced to encode the traditional bag-of-words feature (sparse 0–1 vector) as the dense real value vector. Finally, a combination of embedding-based convolutional features and traditional features are fed to the softmax classifier to extract DDIs from biomedical literature. Experimental results on the DDIExtraction 2013 corpus show that SCNN obtains a better performance (an F-score of 0.686) than other state-of-the-art methods. Availability and Implementation: The source code is available for academic use at http://202.118.75.18:8080/DDI/SCNN-DDI.zip. Contact: yangzh@dlut.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27466626

  10. Consensus Recommendations for Systematic Evaluation of Drug-Drug Interaction Evidence for Clinical Decision Support

    PubMed Central

    Scheife, Richard T.; Hines, Lisa E.; Boyce, Richard D.; Chung, Sophie P.; Momper, Jeremiah; Sommer, Christine D.; Abernethy, Darrell R.; Horn, John; Sklar, Stephen J.; Wong, Samantha K.; Jones, Gretchen; Brown, Mary; Grizzle, Amy J.; Comes, Susan; Wilkins, Tricia Lee; Borst, Clarissa; Wittie, Michael A.; Rich, Alissa; Malone, Daniel C.

    2015-01-01

    Background Healthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug-drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations. Objective To provide recommendations for systematic evaluation of evidence from the scientific literature, drug product labeling, and regulatory documents with respect to DDIs for clinical decision support. Methods A conference series was conducted to develop a structured process to improve the quality of DDI alerting systems. Three expert workgroups were assembled to address the goals of the conference. The Evidence Workgroup consisted of 15 individuals with expertise in pharmacology, drug information, biomedical informatics, and clinical decision support. Workgroup members met via webinar from January 2013 to February 2014. Two in-person meetings were conducted in May and September 2013 to reach consensus on recommendations. Results We developed expert-consensus answers to three key questions: 1) What is the best approach to evaluate DDI evidence?; 2) What evidence is required for a DDI to be applicable to an entire class of drugs?; and 3) How should a structured evaluation process be vetted and validated? Conclusion Evidence-based decision support for DDIs requires consistent application of transparent and systematic methods to evaluate the evidence. Drug information systems that implement these recommendations should be able to provide higher quality information about DDIs in drug compendia and clinical decision support tools. PMID:25556085

  11. A Topic-modeling Based Framework for Drug-drug Interaction Classification from Biomedical Text.

    PubMed

    Li, Dingcheng; Liu, Sijia; Rastegar-Mojarad, Majid; Wang, Yanshan; Chaudhary, Vipin; Therneau, Terry; Liu, Hongfang

    2016-01-01

    Classification of drug-drug interaction (DDI) from medical literatures is significant in preventing medication-related errors. Most of the existing machine learning approaches are based on supervised learning methods. However, the dynamic nature of drug knowledge, combined with the enormity and rapidly growing of the biomedical literatures make supervised DDI classification methods easily overfit the corpora and may not meet the needs of real-world applications. In this paper, we proposed a relation classification framework based on topic modeling (RelTM) augmented with distant supervision for the task of DDI from biomedical text. The uniqueness of RelTM lies in its two-level sampling from both DDI and drug entities. Through this design, RelTM take both relation features and drug mention features into considerations. An efficient inference algorithm for the model using Gibbs sampling is also proposed. Compared to the previous supervised models, our approach does not require human efforts such as annotation and labeling, which is its advantage in trending big data applications. Meanwhile, the distant supervision combination allows RelTM to incorporate rich existing knowledge resources provided by domain experts. The experimental results on the 2013 DDI challenge corpus reach 48% in F1 score, showing the effectiveness of RelTM.

  12. Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel.

    PubMed

    Cortés, Javier; Swain, Sandra M; Kudaba, Iveta; Hauschild, Maik; Patel, Taral; Grincuka, Elza; Masuda, Norikazu; McNally, Virginia; Ross, Graham; Brewster, Mike; Marier, Jean-François; Trinh, My My; Garg, Amit; Nijem, Ihsan; Visich, Jennifer; Lum, Bert L; Baselga, José

    2013-11-01

    Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.

  13. A Topic-modeling Based Framework for Drug-drug Interaction Classification from Biomedical Text

    PubMed Central

    Li, Dingcheng; Liu, Sijia; Rastegar-Mojarad, Majid; Wang, Yanshan; Chaudhary, Vipin; Therneau, Terry; Liu, Hongfang

    2016-01-01

    Classification of drug-drug interaction (DDI) from medical literatures is significant in preventing medication-related errors. Most of the existing machine learning approaches are based on supervised learning methods. However, the dynamic nature of drug knowledge, combined with the enormity and rapidly growing of the biomedical literatures make supervised DDI classification methods easily overfit the corpora and may not meet the needs of real-world applications. In this paper, we proposed a relation classification framework based on topic modeling (RelTM) augmented with distant supervision for the task of DDI from biomedical text. The uniqueness of RelTM lies in its two-level sampling from both DDI and drug entities. Through this design, RelTM take both relation features and drug mention features into considerations. An efficient inference algorithm for the model using Gibbs sampling is also proposed. Compared to the previous supervised models, our approach does not require human efforts such as annotation and labeling, which is its advantage in trending big data applications. Meanwhile, the distant supervision combination allows RelTM to incorporate rich existing knowledge resources provided by domain experts. The experimental results on the 2013 DDI challenge corpus reach 48% in F1 score, showing the effectiveness of RelTM. PMID:28269875

  14. A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

    PubMed

    Cherkaoui-Rbati, Mohammed H; Paine, Stuart W; Littlewood, Peter; Rauch, Cyril

    2017-01-01

    All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

  15. The prevalence of major potential drug-drug interactions at a University health centre pharmacy in Jamaica

    PubMed Central

    Kennedy-Dixon, Tracia-Gay; Gossell-Williams, Maxine; Hall, Jannel; Anglin-Brown, Blossom

    2015-01-01

    Objective: To identify major potential drug-drug interactions (DDIs) on prescriptions filled at the University Health Centre Pharmacy, Mona Campus, Jamaica. Methods: This investigation utilised a cross-sectional analysis on all prescriptions with more than one drug that were filled at the Health Centre Pharmacy between November 2012 and February 2013. Potential DDIs were identified using the online Drug Interactions Checker database of Drugs.com. Results: During the period of the study, a total of 2814 prescriptions were analysed for potential DDIs. The prevalence of potential DDIs found during the study period was 49.82%. Major potential DDIs accounted for 4.7 % of the total number of interactions detected, while moderate potential DDIs and minor potential DDIs were 80.8 % and 14.5 % respectively. The three most frequently occurring major potential DDIs were amlodipine and simvastatin (n=46), amiloride and losartan (n=27) and amiloride and lisinopril (n=16). Conclusion: This study has highlighted the need for educational initiatives to ensure that physicians and pharmacists collaborate in an effort to minimise the risks to the patients. These interactions are avoidable for the most part, as the use of online tools can facilitate the selection of therapeutic alternatives or guide decisions for closer patient monitoring and thus reduce the risks of adverse events. PMID:26759615

  16. [Evaluation of pharmacokinetic drug-drug-interactions. Critical considerations of the relevance of pharmacokinetic drug-drug interactions of proton pump inhibitors in self medication].

    PubMed

    Petersen, Karl-Uwe

    2011-08-01

    Mechanisms and evaluation of pharmacokinetic drug interactions are discussed in general, including mechanisms beyond the hepatic phase-I reactions, and especially for the example of proton pump inhibitors (PPI), preferentially omeprazole. Particular attention is paid to the use of PPI as self-prescribed drugs. The sequelae of pharmacokinetic drug interactions can be serious. However, only the evidence of clinical consequences will convert such an interaction from a laboratory finding into a possible adverse effect. Without this, interacting drugs can still be co-administered if the specific characteristics of the concerned drugs, quantitative aspects of the interaction, and especially severity and frequency of possible clinical correlates are taken into consideration. It is encouraging that the laboratory findings reported for the PPI--in vitro or ex vivo from volunteer studies--have hardly found equivalents in clinical consequences. As of today, this is also true of the widely discussed interaction with clopidogrel. Regarding the safety of use of PPI as self-prescribed drugs, it also needs to be emphasized that a sizable number of interactions reported for omeprazole and/or pantoprazole were observed at higher dose levels than the 20 mg licensed for self medication. In conjunction with the temporal limitation of PPI self-prescription (14 days), it can be expected that pharmacokinetic drug interactions will generally be no critical factor in the usage of PPI in self-medication. However clinically relevant interactions can occur, e.g. when PPI are combined with extracts from St. John's wort, methotrexat or some inhibitors of HIV-protease with pH-dependent absorption.

  17. Recommendations to improve the usability of drug-drug interaction clinical decision support alerts.

    PubMed

    Payne, Thomas H; Hines, Lisa E; Chan, Raymond C; Hartman, Seth; Kapusnik-Uner, Joan; Russ, Alissa L; Chaffee, Bruce W; Hartman, Christian; Tamis, Victoria; Galbreth, Brian; Glassman, Peter A; Phansalkar, Shobha; van der Sijs, Heleen; Gephart, Sheila M; Mann, Gordon; Strasberg, Howard R; Grizzle, Amy J; Brown, Mary; Kuperman, Gilad J; Steiner, Chris; Sullins, Amanda; Ryan, Hugh; Wittie, Michael A; Malone, Daniel C

    2015-11-01

    To establish preferred strategies for presenting drug-drug interaction (DDI) clinical decision support alerts. A DDI Clinical Decision Support Conference Series included a workgroup consisting of 24 clinical, usability, and informatics experts representing academia, health information technology (IT) vendors, healthcare organizations, and the Office of the National Coordinator for Health IT. Workgroup members met via web-based meetings 12 times from January 2013 to February 2014, and two in-person meetings to reach consensus on recommendations to improve decision support for DDIs. We addressed three key questions: (1) what, how, where, and when do we display DDI decision support? (2) should presentation of DDI decision support vary by clinicians? and (3) how should effectiveness of DDI decision support be measured? Our recommendations include the consistent use of terminology, visual cues, minimal text, formatting, content, and reporting standards to facilitate usability. All clinicians involved in the medication use process should be able to view DDI alerts and actions by other clinicians. Override rates are common but may not be a good measure of effectiveness. Seven core elements should be included with DDI decision support. DDI information should be presented to all clinicians. Finally, in their current form, override rates have limited capability to evaluate alert effectiveness. DDI clinical decision support alerts need major improvements. We provide recommendations for healthcare organizations and IT vendors to improve the clinician interface of DDI alerts, with the aim of reducing alert fatigue and improving patient safety. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Recommendations for Selecting Drug-Drug Interactions for Clinical Decision Support

    PubMed Central

    Tilson, Hugh; Hines, Lisa E.; McEvoy, Gerald; Weinstein, David M.; Hansten, Philip D.; Matuszewski, Karl; le Comte, Marianne; Higby-Baker, Stefanie; Hanlon, Joseph T.; Pezzullo, Lynn; Vieson, Kathleen; Helwig, Amy L.; Huang, Shiew-Mei; Perre, Anthony; Bates, David W.; Poikonen, John; Wittie, Michael A.; Grizzle, Amy J.; Brown, Mary; Malone, Daniel C.

    2016-01-01

    Purpose To recommend principles for including drug-drug interactions (DDIs) in clinical decision support. Methods A conference series was conducted to improve clinical decision support (CDS) for DDIs. The Content Workgroup met monthly by webinar from January 2013 to February 2014, with two in-person meetings to reach consensus. The workgroup consisted of 20 experts in pharmacology, drug information, and CDS from academia, government agencies, health information (IT) vendors, and healthcare organizations. Workgroup members addressed four key questions: (1) What process should be used to develop and maintain a standard set of DDIs?; (2) What information should be included in a knowledgebase of standard DDIs?; (3) Can/should a list of contraindicated drug pairs be established?; and (4) How can DDI alerts be more intelligently filtered? Results To develop and maintain a standard set of DDIs for CDS in the United States, we recommend a transparent, systematic, and evidence-driven process with graded recommendations by a consensus panel of experts and oversight by a national organization. We outline key DDI information needed to help guide clinician decision-making. We recommend judicious classification of DDIs as contraindicated, as only a small set of drug combinations are truly contraindicated. Finally, we recommend more research to identify methods to safely reduce repetitive and less relevant alerts. Conclusion A systematic ongoing process is necessary to select DDIs for alerting clinicians. We anticipate that our recommendations can lead to consistent and clinically relevant content for interruptive DDIs, and thus reduce alert fatigue and improve patient safety. PMID:27045070

  19. Clinical perspective on drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor rilpivirine.

    PubMed

    Crauwels, Herta; van Heeswijk, Rolf P G; Stevens, Marita; Buelens, Annemie; Vanveggel, Simon; Boven, Katia; Hoetelmans, Richard

    2013-01-01

    Rilpivirine (TMC278) is a non-nucleoside reverse transcriptase inhibitor approved in combination with other antiretrovirals for the treatment of HIV-1 infection in treatment-naive adults (Edurant(®) 25 mg once daily; Complera(®) [USA]/Eviplera(®) [EU] once daily single-tablet regimen). Rilpivirine should be administered with a meal to optimize bioavailability. Its solubility is pH dependent. Rilpivirine is primarily excreted via the feces with negligible renal elimination. Rilpivirine is predominantly metabolized by cytochrome P450 3A4. There is no clinically relevant effect of age, gender, bodyweight, race, estimated glomerular filtration rate, or hepatitis B/C coinfection status on rilpivirine pharmacokinetics in adults. Drug-drug interactions were investigated with cytochrome P450 3A substrates, inducers and inhibitors, drugs altering intragastric pH, antiretrovirals, and other often coadministered drugs. Rilpivirine 25 mg once daily does not have a clinically relevant effect on exposure of coadministered drugs. Coadministration with cytochrome P450 3A inhibitors (ketoconazole, ritonavir-boosted protease inhibitors, telaprevir) results in increased rilpivirine plasma concentrations, but these are not considered clinically relevant; no dose adjustments are required. Coadministration of rilpivirine with cytochrome P450 3A inducers (e.g. rifampin, rifabutin) or compounds increasing gastric pH (e.g. omeprazole, famotidine) results in decreased rilpivirine plasma concentrations, which may increase the risk of virologic failure and resistance development. Therefore, strong cytochrome P450 3A inducers and proton-pump inhibitors are contraindicated. Histamine-2 receptor antagonists and antacids can be coadministered with rilpivirine, provided doses are temporally separated. No dose adjustments are required when rilpivirine is coadministered with: acetaminophen, phosphodiesterase type 5 inhibitors (sildenafil, etc.), atorvastatin (and other statins), oral

  20. Drug-drug interactions and adverse drug reactions in polypharmacy among older adults: an integrative review.

    PubMed

    Rodrigues, Maria Cristina Soares; Oliveira, Cesar de

    2016-09-01

    to identify and summarize studies examining both drug-drug interactions (DDI) and adverse drug reactions (ADR) in older adults polymedicated. an integrative review of studies published from January 2008 to December 2013, according to inclusion and exclusion criteria, in MEDLINE and EMBASE electronic databases were performed. forty-seven full-text studies including 14,624,492 older adults (≥ 60 years) were analyzed: 24 (51.1%) concerning ADR, 14 (29.8%) DDI, and 9 studies (19.1%) investigating both DDI and ADR. We found a variety of methodological designs. The reviewed studies reinforced that polypharmacy is a multifactorial process, and predictors and inappropriate prescribing are associated with negative health outcomes, as increasing the frequency and types of ADRs and DDIs involving different drug classes, moreover, some studies show the most successful interventions to optimize prescribing. DDI and ADR among older adults continue to be a significant issue in the worldwide. The findings from the studies included in this integrative review, added to the previous reviews, can contribute to the improvement of advanced practices in geriatric nursing, to promote the safety of older patients in polypharmacy. However, more research is needed to elucidate gaps. identificar e sintetizar estudos que examinam as interações medicamentosas (IM) e reações adversas a medicamentos (RAM) em idosos polimedicados. revisão integrativa de estudos publicados de janeiro de 2008 a dezembro de 2013, de acordo com critérios de inclusão e exclusão, nas bases de dados eletrônicas MEDLINE e EMBASE. foram analisados 47 estudos de texto completo, incluindo 14,624,492 idosos (≥ 60 anos): 24 (51,1%) sobre RAM, 14 (29,8%) sobre IM e 9 estudos (19,1%) que investigaram tanto IM como RAM. Encontramos uma variedade de desenhos metodológicos. Os estudos revisados reforçaram que a polifarmácia é um processo multifatorial, e os preditores e a prescrição inadequada estão associados a

  1. Potential drug-drug interactions in medical intensive care unit of a tertiary care hospital in Pakistan.

    PubMed

    Ismail, Mohammad; Khan, Farmanullah; Noor, Sidra; Haider, Iqbal; Haq, Inam-Ul; Ali, Zahid; Shah, Zahir; Hassam, Mohsin

    2016-10-01

    Background Patients admitted to intensive care unit (ICU) present with severe and life-threatening illnesses. Most of them suffer from various comorbidities. They usually receive complex pharmacotherapy with large number of medicines which increase the risk of drug-drug interactions (DDIs). Objective The present report aimed to investigate prevalence and levels of potential DDIs (pDDIs) in medical ICU. Methods Medications profiles of 416 patients were checked for pDDIs using Micromedex Drug-Reax(®). Prevalence, levels of severity and levels of documentation were reported. Results Of total 416 patients, 310 were exposed to pDDIs (overall prevalence = 74.5 %). Likewise, a prevalence rate of 13.9 % was recorded for contraindicated pDDIs, 52.2 % for major pDDI and 58.4 % for moderate pDDI. This study reported 740 interacting drug pairs that were presented in total 1686 pDDIs. Of 1686 pDDIs, 4.3 % were of contraindicated severity, 33.8 % of major severity and 49.6 % of moderate severity, whereas 45.5 % were of fair scientific evidence and 41.4 % of good scientific evidence. Conclusion In this study, pDDIs were found highly prevalent in ICU patients at a rate of 74.5 %. Most of the pDDIs had moderate severity; however, substantial number of interactions (38.1 %) had major and contraindicated severity.

  2. Extraction of pharmacokinetic evidence of drug-drug interactions from the literature.

    PubMed

    Kolchinsky, Artemy; Lourenço, Anália; Wu, Heng-Yi; Li, Lang; Rocha, Luis M

    2015-01-01

    Drug-drug interaction (DDI) is a major cause of morbidity and mortality and a subject of intense scientific interest. Biomedical literature mining can aid DDI research by extracting evidence for large numbers of potential interactions from published literature and clinical databases. Though DDI is investigated in domains ranging in scale from intracellular biochemistry to human populations, literature mining has not been used to extract specific types of experimental evidence, which are reported differently for distinct experimental goals. We focus on pharmacokinetic evidence for DDI, essential for identifying causal mechanisms of putative interactions and as input for further pharmacological and pharmacoepidemiology investigations. We used manually curated corpora of PubMed abstracts and annotated sentences to evaluate the efficacy of literature mining on two tasks: first, identifying PubMed abstracts containing pharmacokinetic evidence of DDIs; second, extracting sentences containing such evidence from abstracts. We implemented a text mining pipeline and evaluated it using several linear classifiers and a variety of feature transforms. The most important textual features in the abstract and sentence classification tasks were analyzed. We also investigated the performance benefits of using features derived from PubMed metadata fields, various publicly available named entity recognizers, and pharmacokinetic dictionaries. Several classifiers performed very well in distinguishing relevant and irrelevant abstracts (reaching F1≈0.93, MCC≈0.74, iAUC≈0.99) and sentences (F1≈0.76, MCC≈0.65, iAUC≈0.83). We found that word bigram features were important for achieving optimal classifier performance and that features derived from Medical Subject Headings (MeSH) terms significantly improved abstract classification. We also found that some drug-related named entity recognition tools and dictionaries led to slight but significant improvements, especially in

  3. Time-dependent drug-drug interaction alerts in care provider order entry: software may inhibit medication error reductions.

    PubMed

    van der Sijs, Heleen; Lammers, Laureen; van den Tweel, Annemieke; Aarts, Jos; Berg, Marc; Vulto, Arnold; van Gelder, Teun

    2009-01-01

    Time-dependent drug-drug interactions (TDDIs) are drug combinations that result in a decreased drug effect due to coadministration of a second drug. Such interactions can be prevented by separately administering the drugs. This study attempted to reduce drug administration errors due to overridden TDDIs in a care provider order entry (CPOE) system. In four periods divided over two studies, logged TDDIs were investigated by reviewing the time intervals prescribed in the CPOE and recorded on the patient chart. The first study showed significant drug administration error reduction from 56.4 to 36.2% (p<0.05), whereas the second study was not successful (46.7 and 45.2%; p>0.05). Despite interventions, drug administration errors still occurred in more than one third of cases and prescribing errors in 79-87%. Probably the low alert specificity, the unclear alert information content, and the inability of the software to support safe and efficient TDDI alert handling all diminished correct prescribing, and consequently, insufficiently reduced drug administration errors.

  4. Evaluating the roles of autophagy and lysosomal trafficking defects in intracellular distribution-based drug-drug interactions involving lysosomes.

    PubMed

    Logan, Randall; Kong, Alex; Krise, Jeffrey P

    2013-11-01

    Many currently approved drugs possess weakly basic properties that make them substrates for extensive sequestration in acidic intracellular compartments such as lysosomes through an ion trapping-type mechanism. Lysosomotropic drugs often have unique pharmacokinetic properties that stem from the extensive entrapment in lysosomes, including an extremely large volume of distribution and a long half-life. Accordingly, pharmacokinetic drug-drug interactions can occur when one drug modifies lysosomal volume such that the degree of lysosomal sequestration of secondarily administered drugs is significantly altered. In this work, we have investigated potential mechanisms for drug-induced alterations in lysosomal volume that give rise to drug-drug interactions involving lysosomes. We show that eight hydrophobic amines, previously characterized as perpetrators in this type of drug-drug interaction, cause a significant expansion in lysosomal volume that was correlated with both the induction of autophagy and with decreases in the efficiency of lysosomal egress. We also show that well-known chemical inducers of autophagy caused an increase in apparent lysosomal volume and an increase in secondarily administered lysosomotropic drugs without negatively impacting vesicle-mediated lysosomal egress. These results could help rationalize how the induction of autophagy could cause variability in the pharmacokinetic properties of lysosomotropic drugs.

  5. Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein.

    PubMed

    Ledwitch, Kaitlyn V; Barnes, Robert W; Roberts, Arthur G

    2016-01-28

    Drug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.

  6. Drug-drug interactions and adverse drug reactions in polypharmacy among older adults: an integrative review 1

    PubMed Central

    Rodrigues, Maria Cristina Soares; de Oliveira, Cesar

    2016-01-01

    ABSTRACT Objective: to identify and summarize studies examining both drug-drug interactions (DDI) and adverse drug reactions (ADR) in older adults polymedicated. Methods: an integrative review of studies published from January 2008 to December 2013, according to inclusion and exclusion criteria, in MEDLINE and EMBASE electronic databases were performed. Results: forty-seven full-text studies including 14,624,492 older adults (≥ 60 years) were analyzed: 24 (51.1%) concerning ADR, 14 (29.8%) DDI, and 9 studies (19.1%) investigating both DDI and ADR. We found a variety of methodological designs. The reviewed studies reinforced that polypharmacy is a multifactorial process, and predictors and inappropriate prescribing are associated with negative health outcomes, as increasing the frequency and types of ADRs and DDIs involving different drug classes, moreover, some studies show the most successful interventions to optimize prescribing. Conclusions: DDI and ADR among older adults continue to be a significant issue in the worldwide. The findings from the studies included in this integrative review, added to the previous reviews, can contribute to the improvement of advanced practices in geriatric nursing, to promote the safety of older patients in polypharmacy. However, more research is needed to elucidate gaps. PMID:27598380

  7. pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development.

    PubMed

    Zhang, L; Wu, F; Lee, S C; Zhao, H; Zhang, L

    2014-08-01

    Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated.

  8. Drug-Drug Interactions and Diagnostics for Drug Users With HIV and HIV/HCV Coinfections: Introduction.

    PubMed

    Khalsa, Jag H; Talal, Andrew H; Morse, Gene

    2017-03-01

    Substance use and pharmacologic treatment of co-occurring infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are associated with many adverse consequences including pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs). The National Institute on Drug Abuse sponsored a 2-day conference on DDIs at which clinicians/scientists from government, academia, and the pharmaceutical industry presented the most current research findings to formulate a comprehensive overview of DDIs. Specific topics discussed included drug metabolism; drug interactions between medications used in the treatment of HIV, HCV, and substance use disorders; intrahepatic concentrations and methods of assessment of drugs in liver disease of varying etiologies and degrees of impairment; and minimally invasive sampling techniques for the assessment of intrahepatic drug concentrations, viral replication, and changes in gene expression in response to treatment. Finally, the speakers identified research targets and priorities on DDIs. Areas of emphasis included development of diagnostic assays for drug concentration assessment in different organs, an enhanced understanding of factors responsible for alterations in drug metabolism and excretion, and establishment of clinical trials and work groups to study DDIs. Our long-term objective is to broaden investigation in the field of DDIs in substance users. © 2017, The American College of Clinical Pharmacology.

  9. Biological products for the treatment of psoriasis: therapeutic targets, pharmacodynamics and disease-drug-drug interaction implications.

    PubMed

    Wang, Jie; Wang, Yow-Ming C; Ahn, Hae-Young

    2014-09-01

    Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocytes. Currently approved biological products for psoriasis treatment fall into two main classes: cytokine modulators and biologics targeting T cells. In psoriatic patients, elevated levels of proinflammatory cytokines are observed. Elevated proinflammatory cytokines can suppress some cytochrome P450 (CYP) enzymes, and the treatment of psoriasis with biological products can reduce proinflammatory cytokine levels. Therefore, the exposure of CYP substrate drugs is anticipated to be affected by the psoriasis disease resulting in a higher exposure than in healthy state (named disease-drug interaction) as well as by the biological treatments due to disease improvements resulting in a decrease in exposure (named disease-drug-drug interaction, disease-DDI). However, the quantitative impact on CYP substrate exposure due to disease or due to treatment with biological products remains to be evaluated. The objective of the current review is to provide an overview of the therapeutic targets and cytokine-related pharmacodynamic effects of biological products in psoriasis treatment with a particular focus on their implications for disease-DDI. The clinical study design considerations for psoriasis disease-DDI evaluation are also discussed.

  10. In vitro drug-drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes.

    PubMed

    Chen, Nancy; Cui, Donghui; Wang, Qing; Wen, Zhiming; Finkelman, Richard D; Welty, Devin

    2017-07-21

    1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P450 (CYP) 3A and the efflux transporter P-glycoprotein (P-gp). This study aimed to evaluate the potential of budesonide to act as a perpetrator or a victim of transporter- or CYP-mediated drug-drug interactions (DDIs). 2. In vitro studies were conducted for P-gp, breast cancer resistance protein and organic anion and cation transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2) in transporter-transfected cells. Changes in mRNA expression in human hepatocytes and enzyme activity in human liver microsomes by budesonide were determined for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A. 3. The data indicated that budesonide is a substrate of P-gp but is not a substrate or an inhibitor of the other transporters investigated. Budesonide is neither an inducer nor an inhibitor of major CYP enzymes. The effect of P-gp on budesonide disposition is anticipated to be low owing to CYP3A-mediated clearance. 4. Collectively, our data indicate there is a low risk of budesonide perpetrating clinical DDIs mediated by the transporters or CYPs studied.

  11. Population pharmacokinetic analysis of drug-drug interactions among risperidone, bupropion, and sertraline in CF1 mice.

    PubMed

    Wang, Jun-Sheng; DeVane, C Lindsay; Gibson, B Bryan; Donovan, Jennifer L; Markowitz, John S; Zhu, Hao-Jie

    2006-01-01

    Accumulating evidence indicates that modulation of the activity of cytochrome P450 (CYP) enzymes and the multidrug resistance transporter P-glycoprotein (P-gp) is responsible for many drug-drug interactions. The potential interaction of risperidone (RISP), which is metabolized by 2D6 and transported across the blood brain barrier (BBB) by P-gp, was studied in combination with bupropion (BUP) and also with sertraline (SERT). BUP, SERT, and RISP were administered intraperitoneally into CF1 mice at doses of 100, 10, and 1 microg/g mouse, respectively. Plasma and brain samples were collected at timed intervals from 0.5 to 6 h. A pharmacokinetic analysis was performed using both traditional compartmental modeling and a population pharmacokinetic approach. BUP increased the RISP plasma (5.9-fold, P<0.01) and brain (2.2-fold, P<0.01) area under the drug concentration vs time curve (AUC), but did not alter the brain-to-plasma concentration ratio. SERT did not significantly change the plasma AUC of RISP and 9-hydroxy-RISP, but increased the brain AUC of RISP and 9-hydroxy-RISP 1.5-fold (P<0.05) and 5-fold (P<0.01), respectively. RISP did not produce significant alterations of plasma or brain concentrations of BUP. It increased the plasma AUC and elimination half-life (T1/2e) of desmethyl-SERT 12.5-fold (P<0.01) and 107-fold (P<0.01), respectively. These results suggest that pharmacokinetic interactions exist among these three psychoactive drugs involving inhibition of drug metabolizing enzymes and/or P-gp and other drug transporters present in the BBB. The mechanisms and consequences of these interactions require further study in humans to establish clinical relevance.

  12. Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein.

    PubMed

    Robertson, Sarah M; Luo, Xia; Dubey, Neeraj; Li, Chonghua; Chavan, Ajit B; Gilmartin, Geoffrey S; Higgins, Mark; Mahnke, Lisa

    2015-01-01

    Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

  13. Drug-drug interactions related to altered absorption and plasma protein binding: theoretical and regulatory considerations, and an industry perspective.

    PubMed

    Hochman, Jerome; Tang, Cuyue; Prueksaritanont, Thomayant

    2015-03-01

    Drug-drug interactions (DDIs) related to altered drug absorption and plasma protein binding have received much less attention from regulatory agencies relative to DDIs mediated via drug metabolizing enzymes and transporters. In this review, a number of theoretical bases and regulatory framework are presented for these DDI aspects. Also presented is an industry perspective on how to approach these issues in support of drug development. Overall, with the exception of highly permeable and highly soluble (BCS 1) drugs, DDIs related to drug-induced changes in gastrointestinal (GI) physiology can be substantial, thus warranting more attentions. For a better understanding of absorption-associated DDI potential in a clinical setting, mechanistic studies should be conducted based on holistic integration of the pharmaceutical profiles (e.g., pH-dependent solubility) and pharmacological properties (e.g., GI physiology and therapeutic margin) of drug candidates. Although majority of DDI events related to altered plasma protein binding are not expected to be of clinical significance, exceptions exist for a subset of compounds with certain pharmacokinetic and pharmacological properties. Knowledge of the identity of binding proteins and the binding extent in various clinical setting (including disease states) can be valuable in aiding clinical DDI data interpretations, and ensuring safe and effective use of new drugs.

  14. Comparison of the Drug-Drug Interactions Potential of Erlotinib and Gefitinib via Inhibition of UDP-Glucuronosyltransferases

    PubMed Central

    Liu, Yong; Ramírez, Jacqueline; House, Larry

    2010-01-01

    We aimed to investigate and compare the effects of erlotinib and gefitinib on UDP-glucuronosyltransferase (UGT) activities and to quantitatively evaluate their drug-drug interaction (DDI) potential due to UGT inhibition. The inhibitory effects of erlotinib and gefitinib on UGTs were determined using high-performance liquid chromatography by measuring the formation rates for 4-methylumbelliferone (4-MU) glucuronide, imipramine N-glucuronide, and bilirubin glucuronides using recombinant human UGT isoforms and human liver microsomes (HLMs) in the absence or presence of erlotinib and gefitinib. Inhibition kinetic studies were conducted. Area under the curve (AUC) ratios were used to predict the risk of potential DDI in vivo. Erlotinib exhibited selective potent competitive inhibition against 4-MU glucuronidation by UGT1A1, and gefitinib demonstrated a wide range of inhibition against UGT-mediated 4-MU glucuronidation, particularly against UGT1A1, UGT1A7, UGT1A9, and UGT2B7. Erlotinib also exerted potent mixed inhibition against bilirubin glucuronidation in HLMs. We estimated that coadministration of erlotinib at 100 mg/day or higher doses may result in at least a 30% increase in the AUC of drugs predominantly cleared by UGT1A1. Thus, the coadministration of erlotinib with drugs primarily cleared by UGT1A1 may result in potential DDI. In contrast, gefitinib is unlikely to cause a clinically significant DDI through inhibition of glucuronidation. PMID:19850672

  15. Characterization of the mechanism of drug-drug interactions from PubMed using MeSH terms.

    PubMed

    Lu, Yin; Figler, Bryan; Huang, Hong; Tu, Yi-Cheng; Wang, Ju; Cheng, Feng

    2017-01-01

    Identifying drug-drug interaction (DDI) is an important topic for the development of safe pharmaceutical drugs and for the optimization of multidrug regimens for complex diseases such as cancer and HIV. There have been about 150,000 publications on DDIs in PubMed, which is a great resource for DDI studies. In this paper, we introduced an automatic computational method for the systematic analysis of the mechanism of DDIs using MeSH (Medical Subject Headings) terms from PubMed literature. MeSH term is a controlled vocabulary thesaurus developed by the National Library of Medicine for indexing and annotating articles. Our method can effectively identify DDI-relevant MeSH terms such as drugs, proteins and phenomena with high accuracy. The connections among these MeSH terms were investigated by using co-occurrence heatmaps and social network analysis. Our approach can be used to visualize relationships of DDI terms, which has the potential to help users better understand DDIs. As the volume of PubMed records increases, our method for automatic analysis of DDIs from the PubMed database will become more accurate.

  16. Potential drug-drug interactions in hospitalized patients with chronic heart failure and chronic obstructive pulmonary disease

    PubMed Central

    Roblek, Tina; Trobec, Katja; Mrhar, Ales

    2014-01-01

    Introduction Polypharmacy is common in patients with chronic heart failure (HF) and/or chronic obstructive pulmonary disease (COPD), but little is known about the prevalence and significance of drug-drug interactions (DDIs). This study evaluates DDIs in hospitalized patients. Material and methods We retrospectively screened medical charts over a 6-month period for diagnosis of chronic HF and/or COPD. Potential DDIs were evaluated using Lexi-Interact software. Results Seven hundred and seventy-eight patients were included in the study (median age 75 years, 61% men). The median number of drugs on admission and discharge was 6 (interquartile range (IQR) 4–9) and 7 (IQR 5–), respectively (p = 0.10). We recorded 6.5 ±5.7 potential DDIs per patient on admission and 7.2 ±5.6 on discharge (p = 0.2). From admission to discharge, type-C and type-X potential DDIs increased (p < 0.05 for both). Type X interactions were rare (< 1%), with the combination of a β-blocker and a β2 agonist being the most common (64%). There were significantly more type-C and type-D potential DDIs in patients with chronic HF as compared to patients with COPD (p < 0.001). Patients with concomitant chronic HF and COPD had more type-C and type-X potential DDIs when compared to those with individual disease (p < 0.005). An aldosterone antagonist and ACE inhibitor/ARB were prescribed to 3% of chronic HF patients with estimated glomerular filtration rate < 30 ml/(min × 1.73 m2). Conclusions The DDIs are common in patients with chronic HF and/or COPD, but only a few appear to be of clinical significance. The increase in potential DDIs from admission to discharge may reflect better guideline implementation rather than poor clinical practice. PMID:25395943

  17. High-Throughput Cytochrome P450 Cocktail Inhibition Assay for Assessing Drug-Drug and Drug-Botanical Interactions

    PubMed Central

    Li, Guannan; Huang, Ke; Nikolic, Dejan

    2015-01-01

    Detection of drug-drug interactions is essential during the early stages of drug discovery and development, and the understanding of drug-botanical interactions is important for the safe use of botanical dietary supplements. Among the different forms of drug interactions that are known, inhibition of cytochrome P450 (P450) enzymes is the most common cause of drug-drug or drug-botanical interactions. Therefore, a rapid and comprehensive mass spectrometry–based in vitro high-throughput P450 cocktail inhibition assay was developed that uses 10 substrates simultaneously against nine CYP isoforms. Including probe substrates for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and two probes targeting different binding sites of CYP3A4/5, this cocktail simultaneously assesses at least as many P450 enzymes as previous assays while remaining among the fastest due to short incubation times and rapid analysis using ultrahigh pressure liquid chromatography–tandem mass spectrometry. The method was validated using known inhibitors of each P450 enzyme and then shown to be useful not only for single-compound testing but also for the evaluation of potential drug-botanical interactions using the botanical dietary supplement licorice (Glycyrrhiza glabra) as an example. PMID:26285764

  18. High-Throughput Cytochrome P450 Cocktail Inhibition Assay for Assessing Drug-Drug and Drug-Botanical Interactions.

    PubMed

    Li, Guannan; Huang, Ke; Nikolic, Dejan; van Breemen, Richard B

    2015-11-01

    Detection of drug-drug interactions is essential during the early stages of drug discovery and development, and the understanding of drug-botanical interactions is important for the safe use of botanical dietary supplements. Among the different forms of drug interactions that are known, inhibition of cytochrome P450 (P450) enzymes is the most common cause of drug-drug or drug-botanical interactions. Therefore, a rapid and comprehensive mass spectrometry-based in vitro high-throughput P450 cocktail inhibition assay was developed that uses 10 substrates simultaneously against nine CYP isoforms. Including probe substrates for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and two probes targeting different binding sites of CYP3A4/5, this cocktail simultaneously assesses at least as many P450 enzymes as previous assays while remaining among the fastest due to short incubation times and rapid analysis using ultrahigh pressure liquid chromatography-tandem mass spectrometry. The method was validated using known inhibitors of each P450 enzyme and then shown to be useful not only for single-compound testing but also for the evaluation of potential drug-botanical interactions using the botanical dietary supplement licorice (Glycyrrhiza glabra) as an example. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Comparison of two databases to detect potential drug-drug interactions between prescriptions of HIV/AIDS patients in critical care.

    PubMed

    Ramos, G V; Guaraldo, L; Japiassú, A M; Bozza, F A

    2015-02-01

    Adverse drug events (ADE), common and underestimated in ICU patients, have direct consequences on length of stay, mortality and hospital costs. Critically ill patients with HIV/AIDS are at a high risk of ADE because of their need for multiple drug therapies. ADE can be prevented, especially by the identification of potentially harmful drug-drug interactions (DDIs). Electronic databases are useful tools for the investigation of DDIs to avoid potential ADEs, thereby increasing patient safety. The purpose of this study was to compare the classification and severity rating of potential adverse drug interactions seen in the prescriptions for patients with HIV/AIDS in two databases, one with free access (Drugs.com(™)) and another requiring payment for access (Micromedex(®)). A cross-sectional retrospective study of the prescriptions issued for 40 ICU HIV/AIDS patients on mechanical ventilation, admitted for more than 48 h, in a referral hospital for infectious diseases in Rio de Janeiro, Brazil, was undertaken. One prescription was reviewed each week for each patient from the second day after admission. A list of all drug-drug interactions was generated for each patient using the two drug-drug interactions databases. The weighted kappa index was estimated to assess the agreement between the classifications of DDIs identified by both databases and qualitative assessment made of any discordant classification of recorded drug-drug interactions. Of the 106 prescriptions analysed, Micromedex(®) and Drugs.com identified 347 and 615 potential DDIs, respectively. A predominance of moderate interactions and pharmacokinetic interactions was observed. The agreement between the databases regarding the severity rating was only 68.3%. The weighted kappa of 0.44 is considered moderate. Better agreement (82.4%) was observed in the classification of mechanism of interaction, with a weighted kappa of 0.61. DDIs are common between the prescriptions of patients with HIV/AIDS admitted to

  20. 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

  1. Information Technology-Based Interventions to Improve Drug-Drug Interaction Outcomes: A Systematic Review on Features and Effects.

    PubMed

    Nabovati, Ehsan; Vakili-Arki, Hasan; Taherzadeh, Zhila; Saberi, Mohammad Reza; Medlock, Stephanie; Abu-Hanna, Ameen; Eslami, Saeid

    2017-01-01

    The purpose of this systematic review was to identify features and effects of information technology (IT)-based interventions on outcomes related to drug-drug interactions (DDI outcomes). A literature search was conducted in Medline, EMBASE, and the Cochrane Library for published English-language studies. Studies were included if a main outcome was related to DDIs, the intervention involved an IT-based system, and the study design was experimental or observational with controls. Study characteristics, including features and effects of IT-based interventions, were extracted. Nineteen studies comprising five randomized controlled trials (RCT), five non-randomized controlled trials (NRCT) and nine observational studies with controls (OWC) were included. Sixty-four percent of prescriber-directed interventions, and all non-prescriber interventions, were effective. Each of the following characteristics corresponded to groups of studies of which a majority were effective: automatic provision of recommendations within the providers' workflow, intervention at the time of decision-making, integration into other systems, and requiring the reason for not following the recommendations. Only two studies measured clinical outcomes: an RCT that showed no significant improvement and an OWC that showed improvement, but did not statistically assess the effect. Most studies that measured surrogate outcomes (e.g. potential DDIs) and other outcomes (e.g. adherence to alerts) showed improvements. IT-based interventions improve surrogate clinical outcomes and adherence to DDI alerts. However, there is lack of robust evidence about their effectiveness on clinical outcomes. It is recommended that researchers consider the identified features of effective interventions in the design of interventions and evaluate the effectiveness on DDI outcomes, particularly clinical outcomes.

  2. Discovering drug-drug interactions: a text-mining and reasoning approach based on properties of drug metabolism.

    PubMed

    Tari, Luis; Anwar, Saadat; Liang, Shanshan; Cai, James; Baral, Chitta

    2010-09-15

    Identifying drug-drug interactions (DDIs) is a critical process in drug administration and drug development. Clinical support tools often provide comprehensive lists of DDIs, but they usually lack the supporting scientific evidences and different tools can return inconsistent results. In this article, we propose a novel approach that integrates text mining and automated reasoning to derive DDIs. Through the extraction of various facts of drug metabolism, not only the DDIs that are explicitly mentioned in text can be extracted but also the potential interactions that can be inferred by reasoning. Our approach was able to find several potential DDIs that are not present in DrugBank. We manually evaluated these interactions based on their supporting evidences, and our analysis revealed that 81.3% of these interactions are determined to be correct. This suggests that our approach can uncover potential DDIs with scientific evidences explaining the mechanism of the interactions.

  3. Physiologically Based Pharmacokinetic (Pbpk) Model of the Cyp2d6 Probe Atomoxetine: Extrapolation to Special Populations and Drug-Drug Interactions.

    PubMed

    Huang, Weize; Nakano, Mariko; Sager, Jennifer E; Ragueneau-Majlessi, Isabelle; Isoherranen, Nina

    2017-08-31

    Physiologically based pharmacokinetic (PBPK) modeling of drug disposition and drug-drug interactions has become a key component of drug development. PBPK modeling has also been considered as an approach to predict drug disposition in special populations. However, whether models developed and validated in healthy populations can be extrapolated to special populations is not well established. The goal of this study was to determine whether a drug specific PBPK model validated using healthy populations could be used to predict drug disposition in specific populations and in organ impairment. A full PBPK model of atomoxetine was developed using a training set of PK data from CYP2D6 genotyped individuals. The model was validated using drug-specific acceptance criteria and a test set of 14 healthy subject PK studies. Population PBPK models were then challenged by simulating the effects of ethnicity, drug-drug interactions, pediatrics and renal and hepatic impairment on atomoxetine PK. Atomoxetine disposition was successfully predicted in 100% of healthy subject studies, 88% of studies in Asians, 79% of drug-drug interaction (DDI) studies, and 100% of pediatric studies. However, atomoxetine AUC was overpredicted by 3-4 fold in end stage renal disease and hepatic impairment. The results show that validated PBPK models can be extrapolated to different ethnicities, DDIs, and pediatrics but not to renal and hepatic impairment patients, likely due to incomplete understanding of the physiological changes in these conditions. These results show that systematic modeling efforts can be used to further refine population models to improve the predictive value in this area. The American Society for Pharmacology and Experimental Therapeutics.

  4. Lack of a pharmacokinetic drug-drug interaction with venlafaxine extended-release/indinavir and desvenlafaxine extended-release/indinavir.

    PubMed

    Jann, Michael W; Spratlin, Vicky; Momary, Kathryn; Zhang, Hailing; Turner, David; Penzak, Scott R; Wright, Alan; VanDenBerg, Chad

    2012-05-01

    To assess the effects of venlafaxine extended-release (XR) capsules and desvenlafaxine extended-release (XR) tablets upon indinavir pharmacokinetic properties when co-administrated to healthy volunteers. This was an open-label, two-period, fixed-dose study conducted at the clinical research unit located on a university campus. Twenty-four healthy volunteers enrolled in the study (mean age 28.3 ± 8.0 years). Each subject received a single dose of indinavir 800 mg on day 1. Subsequently, subjects were then randomly assigned to either the venlafaxine XR group (N = 12) or the desvenlafaxine XR group (N = 12). Starting on day 2, venlafaxine XR was dosed at 37.5 mg/day for 4 days and increased to 75 mg/day for 6 days. Desvenlafaxine XR was dosed at 50 mg/day for 10 days. On day 12, indivanvir 800 mg was co-administered to both the venlafaxine XR and the desvenlafaxine XR groups. The pharmacokinetics of indinavir were determined both before and at the end of antidepressant dosing. Plasma indinavir, venlafaxine, and desvenlafaxine concentrations were assayed by high-performance liquid chromatography with ultra-violet (UV) detection. Indinavir pharmacokinetic parameters were calculated by noncompartmental analysis using validated computer software. Venlafaxine XR and desvenlafaxine XR did not produce any significant changes in indinavir disposition. Both antidepressants were well tolerated by the subjects with only minor adverse side effects. No pharmacokinetic drug-drug interaction was demonstrated between venlafaxine XR and indinavir or between desvenlafaxine XR and indinvair. The lack of interaction could be due to the venlafaxine and desvenlafaxine extended-release formulation.

  5. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios.

    PubMed

    Williams, J Andrew; Hyland, Ruth; Jones, Barry C; Smith, Dennis A; Hurst, Susan; Goosen, Theunis C; Peterkin, Vincent; Koup, Jeffrey R; Ball, Simon E

    2004-11-01

    Glucuronidation is a listed clearance mechanism for 1 in 10 of the top 200 prescribed drugs. The objective of this article is to encourage those studying ligand interactions with UDP-glucuronosyltransferases (UGTs) to adequately consider the potential consequences of in vitro UGT inhibition in humans. Spurred on by interest in developing potent and selective inhibitors for improved confidence around UGT reaction phenotyping, and the increased availability of recombinant forms of human UGTs, several recent studies have reported in vitro inhibition of UGT enzymes. In some cases, the observed potency of UGT inhibitors in vitro has been interpreted as having potential relevance in humans via pharmacokinetic drug-drug interactions. Although there are reported examples of clinically relevant drug-drug interactions for UGT substrates, exposure increases of the aglycone are rarely greater than 100% in the presence of an inhibitor relative to its absence (i.e., AUCi/AUC < or = 2). This small magnitude in change is in contrast to drugs primarily cleared by cytochrome P450 enzymes, where exposures have been reported to increase as much as 35-fold on coadministration with an inhibitor (e.g., ketoconazole inhibition of CYP3A4-catalyzed terfenadine metabolism). In this article the evidence for purported clinical relevance of potent in vitro inhibition of UGT enzymes will be assessed, taking the following into account: in vitro data on the enzymology of glucuronide formation from aglycone, pharmacokinetic principles based on empirical data for inhibition of metabolism, and clinical data on the pharmacokinetic drug-drug interactions of drugs primarily cleared by glucuronidation.

  6. Improving Detection of Arrhythmia Drug-Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity-Based Modeling.

    PubMed

    Vilar, Santiago; Lorberbaum, Tal; Hripcsak, George; Tatonetti, Nicholas P

    2015-01-01

    Identification of Drug-Drug Interactions (DDIs) is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs), decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure), adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR). Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate.

  7. Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents.

    PubMed

    Murray, Michael

    2006-07-01

    Cytochrome P450 (CYP) drug oxidases play a pivotal role in the elimination of antipsychotic agents, and therefore influence the toxicity and efficacy of these drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes with antipsychotic agents. In particular, aspects of CYP pharmacogenetics, and the processes of CYP induction and inhibition all influence in-vivo rates of drug elimination. Certain CYPs that mediate the oxidation of antipsychotic drugs exhibit genetic variants that may influence in-vivo activity. Thus, single nucleotide polymorphisms (SNPs) in CYP genes have been shown to encode enzymes that have decreased drug oxidation capacity. Additionally, psychopharmacotherapy has the potential for drug-drug inhibitory interactions involving CYPs, as well as drug-mediated CYP induction. Literature evidence supports a role for CYP1A2 in the clearance of the atypical antipsychotics clozapine and olanzapine; CYP1A2 is inducible by certain drugs and environmental chemicals. Recent studies have suggested that specific CYP1A2 variants possessing individual SNPs, and possibly also SNP combinations (haplotypes), in the 5'-regulatory regions may respond differently to inducing chemicals. CYP2D6 is an important catalyst of the oxidation of chlorpromazine, thioridazine, risperidone and haloperidol. Certain CYP2D6 allelic variants that encode enzymes with decreased drug oxidation capacity are more common in particular ethnic groups, which may lead to adverse effects with standard doses of psychoactive drugs. Thus, genotyping may be useful for dose optimization with certain psychoactive drugs that are substrates for CYP2D6. However, genotyping for inducible CYPs is unlikely to be sufficient to direct therapy with all antipsychotic agents. In-vivo CYP phenotyping with cocktails of drug substrates may assist at the commencement of therapy, but this approach could be complicated by pharmacokinetic interactions if applied when an

  8. Drug-drug interactions between immunosuppressants and antidiabetic drugs in the treatment of post-transplant diabetes mellitus.

    PubMed

    Vanhove, Thomas; Remijsen, Quinten; Kuypers, Dirk; Gillard, Pieter

    2016-09-14

    Post-transplant diabetes mellitus is a frequent complication of solid organ transplantation that generally requires treatment with lifestyle interventions and antidiabetic medication. A number of demonstrated and potential pharmacokinetic drug-drug interactions (DDIs) exist between commonly used immunosuppressants and antidiabetic drugs, which are comprehensively summarized in this review. Cyclosporine (CsA) itself inhibits the cytochrome P450 (CYP) 3A4 enzyme and a variety of drug transporters. As a result, it increases exposure to repaglinide and sitagliptin, will likely increase the exposure to nateglinide, glyburide, saxagliptin, vildagliptin and alogliptin, and could theoretically increase the exposure to gliquidone and several sodium-glucose transporter (SGLT)-2 inhibitors. Currently available data, although limited, suggest that these increases are modest and, particularly with regard to gliptins and SGLT-2 inhibitors, unlikely to result in hypoglycemia. The interaction with repaglinide is more pronounced but does not preclude concomitant use if repaglinide dose is gradually titrated. Mycophenolate mofetil and azathioprine do not engage in DDIs with any antidiabetic drug. Although calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibitors (mTORi) are intrinsically prone to DDIs, their disposition is not influenced by metformin, pioglitazone, sulfonylureas (except possibly glyburide) or insulin. An effect of gliptins on the disposition of CNIs and mTORi is unlikely, but has not been definitively ruled out. Based on their disposition profiles, glyburide and canagliflozin could affect CNI and mTORi disposition although this requires further study. Finally, delayed gastric emptying as a result of glucagon-like peptide-1 agonists seems to have a limited, but not necessarily negligible effect on CNI disposition.

  9. Prediction of Drug-Drug Interactions Arising from CYP3A induction Using a Physiologically Based Dynamic Model

    PubMed Central

    Mukadam, Sophie; Gardner, Iain; Okialda, Krystle; Wong, Susan; Hatley, Oliver; Tay, Suzanne; Rowland-Yeo, Karen; Jamei, Masoud; Rostami-Hodjegan, Amin; Kenny, Jane R.

    2016-01-01

    Using physiologically based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine the most appropriate model refinement. When the maximal fold induction (Indmax) for rifampicin was increased (from 8 to 16) in both the liver and the gut, or when the Indmax was increased in the gut but not in liver, there was a decrease in bias and increased precision compared with the base model (Indmax = 8) [geometric mean fold error (GMFE) 2.12 vs. 1.48 and 1.77, respectively]. Induction parameters (mRNA and activity), determined for rifampicin, carbamazepine, phenytoin, and phenobarbital in hepatocytes from four donors, were then used to evaluate use of the refined rifampicin model for calibration. Calibration of mRNA and activity data for other inducers using the refined rifampicin model led to more accurate DDI predictions compared with the initial model (activity GMFE 1.49 vs. 1.68; mRNA GMFE 1.35 vs. 1.46), suggesting that robust in vivo reference values can be used to overcome interdonor and laboratory-to-laboratory variability. Use of uncalibrated data also performed well (GMFE 1.39 and 1.44 for activity and mRNA). As a result of experimental variability (i.e., in donors and protocols), it is prudent to fully characterize in vitro induction with prototypical inducers to give an understanding of how that particular system extrapolates to the in vivo situation when using an uncalibrated approach. PMID:27026679

  10. Targeted screen for human UDP-glucuronosyltransferases inhibitors and the evaluation of potential drug-drug interactions with zafirlukast.

    PubMed

    Oda, Shingo; Fujiwara, Ryoichi; Kutsuno, Yuki; Fukami, Tatsuki; Itoh, Tomoo; Yokoi, Tsuyoshi; Nakajima, Miki

    2015-06-01

    Inhibition of drug metabolizing enzymes is a major mechanism in drug-drug interactions (DDIs). A number of cases of DDIs via inhibition of UDP-glucuronosyltranseferases (UGTs) have been reported, although the changes in pharmacokinetics are relatively small in comparison with drugs that are metabolized by cytochrome P450s. Most of the past studies have investigated hepatic UGTs, although recent studies have revealed a significant contribution of UGTs in the small intestine to drug clearance. To evaluate potential DDIs caused by inhibition of intestinal UGTs, we assessed inhibitory effects of 578 compounds, including drugs, xenobiotics, and endobiotics, on human UGT1A8 and UGT1A10, which are major contributors to intestinal glucuronidation. We identified 29 inhibitors by monitoring raloxifene glucuronidation with recombinant UGTs. All of the inhibitors potently inhibited UGT1A1 activity, as well. We found that zafirlukast is a potent general inhibitor of UGT1As and a moderate inhibitor of UGT2Bs because it monitors 4-methylumbelliferone glucuronidation by recombinant UGTs. However, zafirlukast did not potently inhibit diclofenac glucuronidation, suggesting that the inhibitory effects might be substrate specific. Inhibitory effects of zafirlukast on some UGT substrates were further investigated in human liver and human small intestine microsomes in order to evaluate potential DDIs. The R values (the ratios of intrinsic clearance with and without an inhibitor) revealed that zafirlukast has potential to cause clinical DDIs in the small intestine. Although we could not identify specific UGT1A8 and UGT1A10 inhibitors, zafirlukast was identified as a general inhibitor for UGTs in vitro. The present study suggests that the inhibition of UGT in the small intestine would be an underlying mechanism for DDIs.

  11. First case of stress cardiomyopathy as a result of methadone withdrawal secondary to drug-drug interaction.

    PubMed

    Lemesle, Frédéric; Lemesle, Florence; Nicola, Walid; Pierre Jonville-Béra, Annie

    2010-03-01

    We describe the first case of stress cardiomyopathy secondary to a drug-drug interaction. A 44-year-old man was admitted for acute agitation, hallucinations, tachycardia, and fever within 2 hours of ingestion of naltrexone prescribed to stop alcohol consumption. He had been receiving methadone (120 mg/d) for several months for a history of heroin use; thus, acute opiate withdrawal syndrome secondary to naltrexone treatment was diagnosed. Because electrocardiography showed diffuse ST-segment elevation, a transthoracic echocardiography was performed. It revealed apical akinesia of the left ventricle with a reduction in systolic function. The echocardiogram showed an ejection fraction of 35%, apical and midventricular wall motion abnormalities of the left ventricle, and a cardiac output of 4 L/min without coronary stenosis. The patient was transferred to the cardiologic intensive care unit with a diagnosis of transient left ventricular apical ballooning syndrome secondary to acute opiate withdrawal syndrome. It is likely that opioid withdrawal, inducing a marked increase in catecholamine plasma concentrations, contributed to the development of stress cardiomyopathy. To our knowledge, this is the first case of stress cardiomyopathy described after abrupt opiate withdrawal secondary to a drug-drug interaction.

  12. Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions-an Industry Perspective.

    PubMed

    Bohnert, Tonika; Patel, Aarti; Templeton, Ian; Chen, Yuan; Lu, Chuang; Lai, George; Leung, Louis; Tse, Susanna; Einolf, Heidi J; Wang, Ying-Hong; Sinz, Michael; Stearns, Ralph; Walsky, Robert; Geng, Wanping; Sudsakorn, Sirimas; Moore, David; He, Ling; Wahlstrom, Jan; Keirns, Jim; Narayanan, Rangaraj; Lang, Dieter; Yang, Xiaoqing

    2016-08-01

    Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

  13. Incidence of Potential Drug-Drug Interactions in a Limited and Stereotyped Prescription Setting - Comparison of Two Free Online Pharmacopoeias

    PubMed Central

    Kannan, Bhaskar; Nagella, Amrutha Bindu; Sathia Prabhu, A; Sasidharan, Gopalakrishnan M; Ramesh, A S

    2016-01-01

    Background: Drug-drug interactions (DDIs) are very common adverse events in health care delivery settings. The use of electronic pharmacopeias can potentially reduce the incidence of DDIs, but they are often thought to be cumbersome to use. This study is aimed at studying the incidence of potential DDIs in a surgical department, where a limited number of drugs are used in stereotyped combinations. We also compared two popular drug compendia in detecting potential DDIs. Methods: The prescriptions of selected patients were entered into Epocrates® and Medscape® for Android smartphones. Potential DDIs were generated and their categories were noted. The warnings generated by Epocrates® were compared with those generated by Medscape® and an agreement index was calculated. Results: Three hundred and thirty-one patients were included for analysis who had received a total of 2,878 drug orders. The incidence of potential DDIs was very high - 89% of all prescriptions. Phenytoin was the drug most commonly implicated, followed by furosemide. Of the DDIs detected, 0.14% were potentially serious and the drug combinations were contraindicated. There was a significant discrepancy between the categories of potential DDIs detected by Epocrates® and Medscape®. No clinically significant DDI was detected in any patient in this cohort. Conclusions: Despite routinely using only a limited number of drugs in stereotyped combinations, prescriptions in surgical departments may not be immune from a significant incidence of DDIs. The use of free apps could reduce the incidence of DDIs, enhance patient safety, and also aid in educating trainees. PMID:28018756

  14. The inhibition of human multidrug and toxin extrusion 1 is involved in the drug-drug interaction caused by cimetidine.

    PubMed

    Matsushima, Soichiro; Maeda, Kazuya; Inoue, Katsuhisa; Ohta, Kin-ya; Yuasa, Hiroaki; Kondo, Tsunenori; Nakayama, Hideki; Horita, Shigeru; Kusuhara, Hiroyuki; Sugiyama, Yuichi

    2009-03-01

    Cimetidine is known to cause drug-drug interactions (DDIs) with organic cations in the kidney, and a previous clinical study showed that coadministration of cimetidine or probenecid with fexofenadine (FEX) decreased its renal clearance. FEX was taken up into human kidney by human organic anion transporter (hOAT) 3 (SLC22A8), but the mechanism of its luminal efflux has not been clarified. The present study examined the molecular mechanism of these DDIs. Saturable uptake of FEX was observed in human kidney slices, with K(m) and V(max) values of 157+/-7 microM and 418+/-16 nmol/15 min/g kidney, respectively. Cimetidine only slightly inhibited its uptake even at 100 microM, far greater than its clinically relevant concentration, whereas 10 microM probenecid markedly inhibited its uptake. As candidate transporters for the luminal efflux of FEX, we focused on human multidrug and toxin extrusions MATE1 (SLC47A1) and MATE2-K (SLC47A2). Saturable uptake of FEX could be observed in human embryonic kidney 293 cells expressing human MATE1 (hMATE1), whereas hMATE2-K-specific uptake of FEX was too small to conduct its further kinetic analysis. The hMATE1-mediated uptake clearance of FEX was inhibited by cimetidine in a concentration-dependent manner, and it was decreased to 60% of the control value in the presence of 3 microM cimetidine. Taken together, our results suggest that the DDI of FEX with probenecid can be explained by the inhibition of renal uptake mediated by hOAT3, whereas the DDI with cimetidine is mainly caused by the inhibition of hMATE1-mediated efflux of FEX rather than the inhibition of its renal uptake process.

  15. In vivo evaluation of drug-drug interaction via mechanism-based inhibition by macrolide antibiotics in cynomolgus monkeys.

    PubMed

    Ogasawara, Akihito; Negishi, Isao; Kozakai, Kazumasa; Kume, Toshiyuki

    2009-11-01

    Irreversible inhibition, characterized as mechanism-based inhibition (MBI), of cytochrome P450 in drugs has to be avoided for their safe use. A comprehensive assessment of drug-drug interaction (DDI) potential is important during the drug discovery process. In the present study, we evaluated the effects of macrolide antibiotics, erythromycin (ERM), clarithromycin (CAM), and azithromycin (AZM), which are mechanism-based inhibitors of CYP3A, on biotransformation of midazolam (MDZ) in monkeys. These macrolides inhibited the formation of 1'-hydroxymidazolam in monkey microsomes as functions of incubation time and macrolide concentration. Furthermore, the inactivation potentials of macrolides (k(inact)/K(I): CAM congruent with ERM > AZM) were as effective as that observed in human samples. In in vivo studies, MDZ was administered orally (1 mg/kg) without or with multiple oral dosing of macrolides (15 mg/kg, twice a day on days 1-3). On day 3, the area under the plasma concentration-time curve (AUC) of MDZ increased 7.0-, 9.9-, and 2.0-fold with ERM, CAM, and AZM, respectively, compared with MDZ alone. Furthermore, the effects of ERM and CAM on the pharmacokinetics of MDZ were also observed on the day (day 4) after completion of macrolide treatments (AUC changes: 7.3- and 7.3-fold, respectively). Because the plasma concentrations of macrolides immediately before MDZ administration on day 4 were much lower than the IC(50) values for reversible CYP3A inhibition, the persistent effects may be predominantly caused by CYP3A inactivation. These results suggest that the monkey might be a suitable animal model to predict DDIs caused by MBI of CYP3A.

  16. Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

    PubMed

    Lin, Wen; Ji, Tao; Einolf, Heidi; Ayalasomayajula, Surya; Lin, Tsu-Han; Hanna, Imad; Heimbach, Tycho; Breen, Christopher; Jarugula, Venkateswar; He, Handan

    2017-01-13

    Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.

  17. Comparison of three commercial knowledge bases for detection of drug-drug interactions in clinical decision support.

    PubMed

    Fung, Kin Wah; Kapusnik-Uner, Joan; Cunningham, Jean; Higby-Baker, Stefanie; Bodenreider, Olivier

    2017-07-01

    To compare 3 commercial knowledge bases (KBs) used for detection and avoidance of potential drug-drug interactions (DDIs) in clinical practice. Drugs in the DDI tables from First DataBank (FDB), Micromedex, and Multum were mapped to RxNorm. The KBs were compared at the clinical drug, ingredient, and DDI rule levels. The KBs were evaluated against a reference list of highly significant DDIs from the Office of the National Coordinator for Health Information Technology (ONC). The KBs and the ONC list were applied to a prescription data set to simulate their use in clinical decision support. The KBs contained 1.6 million (FDB), 4.5 million (Micromedex), and 4.8 million (Multum) clinical drug pairs. Altogether, there were 8.6 million unique pairs, of which 79% were found only in 1 KB and 5% in all 3 KBs. However, there was generally more agreement than disagreement in the severity rankings, especially in the contraindicated category. The KBs covered 99.8-99.9% of the alerts of the ONC list and would have generated 25 (FDB), 145 (Micromedex), and 84 (Multum) alerts per 1000 prescriptions. The commercial KBs differ considerably in size and quantity of alerts generated. There is less variability in severity ranking of DDIs than suggested by previous studies. All KBs provide very good coverage of the ONC list. More work is needed to standardize the editorial policies and evidence for inclusion of DDIs to reduce variation among knowledge sources and improve relevance. Some DDIs considered contraindicated in all 3 KBs might be possible candidates to add to the ONC list.

  18. Development and validation of a survey instrument for assessing prescribers' perception of computerized drug-drug interaction alerts.

    PubMed

    Zheng, Kai; Fear, Kathleen; Chaffee, Bruce W; Zimmerman, Christopher R; Karls, Edward M; Gatwood, Justin D; Stevenson, James G; Pearlman, Mark D

    2011-12-01

    To develop a theoretically informed and empirically validated survey instrument for assessing prescribers' perception of computerized drug-drug interaction (DDI) alerts. The survey is grounded in the unified theory of acceptance and use of technology and an adapted accident causation model. Development of the instrument was also informed by a review of the extant literature on prescribers' attitude toward computerized medication safety alerts and common prescriber-provided reasons for overriding. To refine and validate the survey, we conducted a two-stage empirical validation study consisting of a pretest with a panel of domain experts followed by a field test among all eligible prescribers at our institution. The resulting survey instrument contains 28 questionnaire items assessing six theoretical dimensions: performance expectancy, effort expectancy, social influence, facilitating conditions, perceived fatigue, and perceived use behavior. Satisfactory results were obtained from the field validation; however, a few potential issues were also identified. We analyzed these issues accordingly and the results led to the final survey instrument as well as usage recommendations. High override rates of computerized medication safety alerts have been a prevalent problem. They are usually caused by, or manifested in, issues of poor end user acceptance. However, standardized research tools for assessing and understanding end users' perception are currently lacking, which inhibits knowledge accumulation and consequently forgoes improvement opportunities. The survey instrument presented in this paper may help fill this methodological gap. We developed and empirically validated a survey instrument that may be useful for future research on DDI alerts and other types of computerized medication safety alerts more generally.

  19. Drug-drug interactions in inpatient and outpatient settings in Iran: a systematic review of the literature

    PubMed Central

    2014-01-01

    Drug-drug interactions (DDIs) are an important type of adverse drug events. Yet overall incidence and pattern of DDIs in Iran has not been well documented and little information is available about the strategies that have been used for their prevention. The purpose of this study was to systematically review the literature on the incidence and pattern of DDIs in Iran as well as the used strategies for their prevention. PubMed, Scopus, electronic Persian databases, and Google Scholar were searched to identify published studies on DDIs in Iran. Additionally, the reference lists of all retrieved articles were reviewed to identify additional relevant articles. Eligible studies were those that analyzed original data on the incidence of DDIs in inpatient or outpatient settings in Iran. Articles about one specific DDI and drug interactions with herbs, diseases, and nutrients were excluded. The quality of included studies was assessed using quality assessment criteria. Database searches yielded 1053 potentially eligible citations. After removing duplicates, screening titles and abstracts, and reading full texts, 34 articles were found to be relevant. The quality assessment of the included studies showed a relatively poor quality. In terms of study setting, 18 and 16 studies have been conducted in inpatient and outpatient settings, respectively. All studies focused on potential DDIs while no study assessed actual DDIs. The median incidence of potential DDIs in outpatient settings was 8.5% per prescription while it was 19.2% in inpatient settings. The most indicated factor influencing DDIs incidence was patient age. The most involved drug classes in DDIs were beta blockers, angiotensin-converting-enzyme inhibitors (ACEIs), diuretic agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Thirty-one studies were observational and three were experimental in which the strategies to reduce DDIs were applied. Although almost all studies concluded that the incidence of potential

  20. No Pharmacokinetic Drug-Drug Interaction Between Prasugrel and Vorapaxar Following Multiple-Dose Administration in Healthy Volunteers.

    PubMed

    Anderson, Matt S; Kosoglou, Teddy; Statkevich, Paul; Li, Jing; Rotonda, Jennifer; Meehan, Alan G; Cutler, David L

    2017-04-12

    Vorapaxar is a first-in-class antagonist of the protease-activated receptor-1, the primary thrombin receptor on human platelets, which mediates the downstream effects of thrombin in hemostasis and thrombosis. Prasugrel is a platelet inhibitor that acts as a P2Y12 receptor antagonist through an active metabolite, R-138727. This study investigated the interaction of these 2 platelet antagonists when coadministered. This was a randomized, open-label, multiple-dose study in 54 healthy volunteers consisting of a fixed-sequence crossover and a parallel group design. In sequence 1, 36 subjects received prasugrel 60 mg on day 1 and then prasugrel 10 mg once daily on days 2 to 7, followed by vorapaxar 40 mg and prasugrel 10 mg on day 8 and then vorapaxar 2.5 mg and prasugrel 10 mg orally once daily on days 9 to 28. In sequence 2, 18 subjects received vorapaxar 40 mg on day 1 and then vorapaxar 2.5 mg once daily on days 2 to 21. The geometric mean ratios (90% confidence intervals) for AUCτ and Cmax of coadministration/monotherapy for vorapaxar (0.93 ng·h/mL[0.85-1.02 ng·h/mL] and 0.95 ng/mL [0.86-1.05 ng/mL]) and R-138727 (0.91 ng·h/mL [0.85- 0.99 ng·h/mL] and 1.02 ng/mL [0.89-1.17 ng/mL]) were within prespecified bounds, demonstrating the absence of a pharmacokinetic interaction between vorapaxar and prasugrel. There was no specific safety or tolerability risk associated with multiple-dose coadministration of vorapaxar and prasugrel. In conclusion, in this study in healthy volunteers, there was no pharmacokinetic drug-drug interaction between vorapaxar and prasugrel. Multiple-dose coadministration of the 2 drugs was generally well tolerated.

  1. Development and application of a UPLC-MS/MS method for simultaneous determination of fenofibric acid and berberine in rat plasma: application to the drug-drug pharmacokinetic interaction study of fenofibrate combined with berberine after oral administration in rats.

    PubMed

    Li, Guofei; Yang, Fan; Liu, Mei; Su, Xianying; Zhao, Mingming; Zhao, Limei

    2016-07-01

    With the purpose of carrying out pharmacokinetic interaction studies ofnberberine (BBR) and fenofibrate (FBT), an UPLC-MS/MS method has been developed and validated. The analytes, BBR and fenofibric acid (FBA, metabolite of FBT) and the internal standard, tetrahydropalmatine, were extracted with dichloromethane-diethyl ether (3:2, v/v) and separated on an Agilent Eclipse XDB C18 column using a mobile phase composed of acetonitrile and water. With positive ion electrospray ionization, the analytes were monitored on a triple quadrupole mass spectrometer in multiple reaction monitoring mode. Linear calibration curves were obtained over the concentration ranges of 0.1-100.0 ng/mL for BBR and 10.0-50,000.0 ng/mL for FBA. For BBR and FBA, the intra- and inter-day precisions were <11.5 and 11.9%, respectively. The accuracy was within 11.7% and 11.3%. The mean recoveries of BBR at three concentrations of 0.2, 20.0, 80.0 ng/mL were >85.6%, and those of FBA at three concentrations of 20.0, 2500.0, 40,000.0 ng/mL were >87.9%. Consequently, the proposed method was applied to the pharmacokinetic interaction study of FBT combined with BBR after oral administration in rats and was proved to be sensitive, specific and reliable to analyze BBR and FBA in biological samples simultaneously. Copyright © 2016 John Wiley & Sons, Ltd.

  2. Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions.

    PubMed

    Russo, Emilio; Scicchitano, Francesca; Whalley, Benjamin J; Mazzitello, Carmela; Ciriaco, Miriam; Esposito, Stefania; Patanè, Marinella; Upton, Roy; Pugliese, Michela; Chimirri, Serafina; Mammì, Maria; Palleria, Caterina; De Sarro, Giovambattista

    2014-05-01

    Hypericum perforatum (HP) belongs to the Hypericaceae family and is one of the oldest used and most extensively investigated medicinal herbs. The medicinal form comprises the leaves and flowering tops of which the primary ingredients of interest are naphthodianthrones, xanthones, flavonoids, phloroglucinols (e.g. hyperforin), and hypericin. Although several constituents elicit pharmacological effects that are consistent with HP's antidepressant activity, no single mechanism of action underlying these effects has thus far been found. Various clinical trials have shown that HP has a comparable antidepressant efficacy as some currently used antidepressant drugs in the treatment of mild/moderate depression. Interestingly, low-hyperforin-content preparations are effective in the treatment of depression. Moreover, HP is also used to treat certain forms of anxiety. However, HP can induce various cytochrome P450s isozymes and/or P-glycoprotein, of which many drugs are substrates and which are the main origin of HP-drug interactions. Here, we analyse the existing evidence describing the clinical consequence of HP-drug interactions. Although some of the reported interactions are based on findings from in vitro studies, the clinical importance of which remain to be demonstrated, others are based on case reports where causality can, in some cases, be determined to reveal clinically significant interactions that suggest caution, consideration, and disclosure of potential interactions prior to informed use of HP.

  3. Evaluation of the potential for pharmacokinetic drug-drug interaction between armodafinil and carbamazepine in healthy adults.

    PubMed

    Darwish, Mona; Bond, Mary; Yang, Ronghua; Hellriegel, Edward T; Robertson, Philmore

    2015-02-01

    Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as adjunctive therapy for the treatment of major depressive episodes associated with bipolar I disorder. Armodafinil and the mood stabilizer carbamazepine are both inducers of and substrates for cytochrome P450 (CYP3A4). This study was designed to evaluate the bidirectional carbamazepine-armodafinil pharmacokinetic drug-drug interaction. This was an open-label, single-center study conducted in healthy adult men. Subjects assigned to group 1 received a dose of carbamazepine (200 mg) alone and a dose after pretreatment with daily dosing of armodafinil (titrated to 250 mg/d). Subjects assigned to group 2 received a dose of armodafinil (250 mg) alone and a dose after pretreatment with carbamazepine BID (titrated to 400 mg/d). Pharmacokinetic parameters for carbamazepine, armodafinil, and their major circulating metabolites were determined when dosed alone and after pretreatment with the other drug. The safety and tolerability of armodafinil and carbamazepine were also assessed throughout the study. Eighty-one subjects enrolled in the study (group 1 = 40; group 2 = 41), of whom 79 (group 1 = 40; group 2 = 39) were evaluable for pharmacokinetic analysis and 80 (group 1 = 40; group 2 = 40) were evaluable for safety analysis. In group 1, pretreatment with armodafinil reduced systemic exposure to carbamazepine by 12% for Cmax and 25% for AUC (based on comparison of geometric means). Similarly, in group 2, pretreatment with carbamazepine reduced systemic exposure to armodafinil by 11% for Cmax and 37% for AUC. Systemic exposure to the metabolites of these agents that are formed via CYP3A4 were increased after pretreatment in each group. There were no new or unexpected adverse events. Systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; systemic exposure to the

  4. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort.

    PubMed

    Lewis, J M; Stott, K E; Monnery, D; Seden, K; Beeching, N J; Chaponda, M; Khoo, S; Beadsworth, M B J

    2016-02-01

    Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety.

  5. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

    PubMed

    Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

    2015-04-01

    Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed.

  6. Improving Detection of Arrhythmia Drug-Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity-Based Modeling

    PubMed Central

    Vilar, Santiago; Lorberbaum, Tal; Hripcsak, George; Tatonetti, Nicholas P.

    2015-01-01

    Identification of Drug-Drug Interactions (DDIs) is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs), decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure), adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR). Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate. PMID:26068584

  7. Evaluation of change in the skin concentration of tazarotene and betamethasone dipropionate based on drug-drug interaction for transdermal drug delivery in miniature pig.

    PubMed

    Yu, Biao; Ma, Pengcheng; Yuan, Linwen; Chen, Dingding; Yang, Jin

    2015-05-01

    1. The present study was designed to investigate drug-drug interaction in a new combination cream which contains both tazarotene (TZRT) and betamethasone dipropionate (BTMSDP) by comparing the pharmacokinetic (PK) behaviors of TZRT, BTMSDP, and their major metabolites, tazarotenic acid (TZRTAC) and betamethasone (BTMS) with those in the commonly prescribed TZRT gel and BTMSDP cream. 2. The trial was performed on six Bama mini-pigs. The different regions on the back side of each pig were randomly assigned to one of three treatment groups: TZRT 0.05% gel, BTMSDP 0.05% cream, and combination cream. The stratum corneum and epidermis-dermis samples were collected at various times after drug administration and analyzed for TZRT, TZRTAC, BTMSDP, and BTMS by LC-MS/MS. Compared with TZRT gel alone, TZRT + BTMSDP did not significantly change the PK profiles of TZRT; neither did BTMSDP + TZRT significantly change the PK profiles of BTMSDP, compared with the BTMSDP cream alone. In addition, the concentrations of TZRTAC and BTMS in most samples were below the lower limit of quantitation (LLOQ). 3. The results suggest that there was no significant drug-drug interaction trend between TZRT and BTMSDP in the process of transdermal permeation of combination cream into the stratum corneum and epidermis-dermis of mini-pigs.

  8. Clinical drug-drug interactions of bosentan, a potent endothelial receptor antagonist, with various drugs: Physiological role of enzymes and transporters.

    PubMed

    Srinivas, Nuggehally R

    2016-07-01

    Bosentan, an endothelin-1 (ET) receptor antagonist is an important drug for the effective management of patients with pulmonary arterial hypertension. Bosentan has a rather complicated pharmacokinetics in humans involving multiple physiological components that have a profound influence on its drug disposition. Bosentan is mainly metabolized by cytochrome P450 (CYP) 3A4 and 2C9 enzymes with the involvement of multiple transporters that control its hepatic uptake and biliary excretion. The involvement of phase 2 metabolism of bosentan is a key to have an enhanced biliary excretion of the drug-related products. While bosentan exhibits high protein binding restricting the drug from extensive distribution and significant urinary excretion, bosentan induces its own metabolism by an increased expression of CYP3A4 on repeated dosing. Due to the above properties, bosentan has the potential to display drug-drug interaction with the co-administered drugs, either being a perpetrator or a victim. The intent of this review is manifold: a) to summarize the physiological role of CYP enzymes and hepatic-biliary transporters; b) to discuss the mechanism(s) involved in the purported liver injury caused by bosentan; c) to tabulate the numerous clinical drug-drug interaction studies involving the physiological interplay with CYP and/or transporters; d) to provide some perspectives on dosing strategy of bosentan.

  9. Drug-drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems.

    PubMed

    Kumar, Santosh; Rao, P S S; Earla, Ravindra; Kumar, Anil

    2015-03-01

    Substance abuse is a common problem among HIV-infected individuals. Importantly, addictions as well as moderate use of alcohol, smoking, or other illicit drugs have been identified as major reasons for non-adherence to antiretroviral therapy (ART) among HIV patients. The literature also suggests a decrease in the response to ART among HIV patients who use these substances, leading to failure to achieve optimal virological response and increased disease progression. This review discusses the challenges with adherence to ART as well as observed drug interactions and known toxicities with major drugs of abuse, such as alcohol, smoking, methamphetamine, cocaine, marijuana, and opioids. The lack of adherence and drug interactions potentially lead to decreased efficacy of ART drugs and increased ART, and drugs of abuse-mediated toxicity. As CYP is the common pathway in metabolizing both ART and drugs of abuse, we discuss the possible involvement of CYP pathways in such drug interactions. We acknowledge that further studies focusing on common metabolic pathways involving CYP and advance research in this area would help to potentially develop novel/alternate interventions and drug dose/regimen adjustments to improve medication outcomes in HIV patients who consume drugs of abuse.

  10. Semi-mechanistic physiologically-based pharmacokinetic modeling of clinical glibenclamide pharmacokinetics and drug-drug-interactions.

    PubMed

    Greupink, Rick; Schreurs, Marieke; Benne, Marina S; Huisman, Maarten T; Russel, Frans G M

    2013-08-16

    We studied if the clinical pharmacokinetics and drug-drug interactions (DDIs) of the sulfonylurea-derivative glibenclamide can be simulated via a physiologically-based pharmacokinetic modeling approach. To this end, a glibenclamide PBPK-model was build in Simcyp using in vitro physicochemical and biotransformation data of the drug, and was subsequently optimized using plasma disappearance data observed after i.v. administration. The model was validated against data observed after glibenclamide oral dosing, including DDIs. We found that glibenclamide pharmacokinetics could be adequately modeled if next to CYP metabolism an active hepatic uptake process was assumed. This hepatic uptake process was subsequently included in the model in a non-mechanistic manner. After an oral dose of 0.875 mg predicted Cmax and AUC were 39.7 (95% CI:37.0-42.7)ng/mL and 108 (95% CI: 96.9-120)ng/mLh, respectively, which is in line with observed values of 43.6 (95% CI: 37.7-49.5)ng/mL and 133 (95% CI: 107-159)ng/mLh. For a 1.75 mg oral dose, the predicted and observed values were 82.5 (95% CI:76.6-88.9)ng/mL vs 91.1 (95% CI: 67.9-115.9) for Cmax and 224 (95% CI: 202-248) vs 324 (95% CI: 197-451)ng/mLh for AUC, respectively. The model correctly predicted a decrease in exposure after rifampicin pre-treatment. An increase in glibenclamide exposure after clarithromycin co-treatment was predicted, but the magnitude of the effect was underestimated because part of this DDI is the result of an interaction at the transporter level. Finally, the effects of glibenclamide and fluconazol co-administration were simulated. Our simulations indicated that co-administration of this potent CYP450 inhibitor will profoundly increase glibenclamide exposure, which is in line with clinical observations linking the glibenclamide-fluconazol combination to an increased risk of hypoglycemia. In conclusion, glibenclamide pharmacokinetics and its CYP-mediated DDIs can be simulated via PBPK-modeling. In addition, our

  11. Assessment of the Drug-Drug Interaction Potential Between Theacrine and Caffeine in Humans.

    PubMed

    He, Hui; Ma, Dejian; Crone, Laura Brooks; Butawan, Matthew; Meibohm, Bernd; Bloomer, Richard J; Yates, Charles R

    2017-09-01

    Objective: Theacrine, a methylurate class purine alkaloid, triggers diverse pharmacologic responses, including psychostimulatory activity by modulation of adenosinergic and dopaminergic pathways. In a double-blind, placebo-controlled study, theacrine increased energy, concentration, and mood, while reducing fatigue. Because caffeine, a methylxanthine purine alkaloid, is frequently coadministered with theacrine, we sought to determine if a pharmacokinetic and/or pharmacodynamic interaction existed between theacrine and caffeine. Methods: Eight healthy adults received theacrine, as TeaCrine(®) (25 or 125 mg), caffeine (150 mg), or a combination of theacrine (125 mg) and caffeine (150 mg) in a randomized, double-blind crossover study. Blood samples were collected over a 24-hour period and analyzed by Liquid chromatrography-mass spectrometry/mass spectrometry (LC-MS/MS) for theacrine, caffeine, and paraxanthine. Pharmacodynamic response markers, heart rate and blood pressure, were recorded. Results: Theacrine pharmacokinetics was similar following administration of theacrine alone. Caffeine coadministration increased maximum plasma concentration and area under the curve of theacrine without altering theacrine half-life. Theacrine had no impact on caffeine or paraxanthine pharmacokinetics. There was no difference between treatment groups with regard to heart rate or systolic/diastolic blood pressure. Conclusions: Coadministration of theacrine and caffeine results in a clinically significant pharmacokinetic interaction, viz., increased theacrine exposure. Enhanced oral bioavailability is the most likely mechanism by which caffeine alters theacrine exposure. However, further studies examining the contribution of presystemic elimination mechanisms, for example, efflux transport and/or gut metabolism, to theacrine bioavailability are needed to confirm the exact mechanism(s). Hemodynamic parameters were unaltered despite the pharmacokinetic interaction, suggesting

  12. Evidence of a drug-drug interaction linked to inhibition of ester hydrolysis by orlistat.

    PubMed

    Bentley, Darren; Young, Anne-Marie; Rowell, Lucy; Gross, Günter; Tardio, Joseph; Carlile, David

    2012-10-01

    : Orlistat, a lipase inhibitor taken with meals at doses of 60 mg (available over-the-counter) or 120 mg (prescription only) for treatment of obesity, is known to impair the absorption of fat-soluble molecules. Dalcetrapib, a modulator of cholesteryl ester transfer protein activity, is a lipophilic thioester prodrug. Lipase-induced and pancreatin-induced hydrolysis of dalcetrapib in biorelevant media in vitro was very efficiently inhibited by orlistat. Thus, the potential for orlistat to affect the bioavailability of concomitantly administered dalcetrapib was studied in an open-label 2-cohort study in 24 healthy volunteers as follows: single 600-mg doses of dalcetrapib were administered with increasing doses of orlistat (cohort A: 10, 40, 120 mg; cohort B: 20, 60, 120 mg). Exposure to the active form of dalcetrapib was more than 50% lower when taken with orlistat 60 mg or 120 mg than when taken alone. Similar trends were observed with lower orlistat doses (20 mg and 40 mg). Concomitant administration of orlistat also reduced the pharmacodynamic effects of dalcetrapib treatment on cholesteryl ester transfer protein activity. The interaction exceeds that predicted on the basis of dalcetrapib lipophilicity. These findings demonstrate the potential for large interactions between orlistat and esters that undergo de-esterification in the gastrointestinal tract, independent of lipophilicity.

  13. ABC multidrug transporters: target for modulation of drug pharmacokinetics and drug-drug interactions.

    PubMed

    Marquez, Béatrice; Van Bambeke, Françoise

    2011-05-01

    Nine proteins of the ABC superfamily (P-glycoprotein, 7 MRPs and BCRP) are involved in multidrug transport. Being localised at the surface of endothelial or epithelial cells, they expel drugs back to the external medium (if located at the apical side [P-glycoprotein, BCRP, MRP2, MRP4 in the kidney]) or to the blood (if located at the basolateral side [MRP1, MRP3, MRP4, MRP5]), modulating thereby their absorption, distribution, and elimination. In the CNS, most transporters are oriented to expel drugs to the blood. Transporters also cooperate with Phase I/Phase II metabolism enzymes by eliminating drug metabolites. Their major features are (i) their capacity to recognize drugs belonging to unrelated pharmacological classes, and (ii) their redundancy, a single molecule being possibly substrate for different transporters. This ensures an efficient protection of the body against invasion by xenobiotics. Competition for transport is now characterized as a mechanism of interaction between co-administered drugs, one molecule limiting the transport of the other, potentially affecting bioavailability, distribution, and/or elimination. Again, this mechanism reinforces drug interactions mediated by cytochrome P450 inhibition, as many substrates of P-glycoprotein and CYP3A4 are common. Induction of the expression of genes coding for MDR transporters is another mechanism of drug interaction, which could affect all drug substrates of the up-regulated transporter. Overexpression of MDR transporters confers resistance to anticancer agents and other therapies. All together, these data justify why studying drug active transport should be part of the evaluation of new drugs, as recently recommended by the FDA.

  14. A novel algorithm for analyzing drug-drug interactions from MEDLINE literature

    PubMed Central

    Lu, Yin; Shen, Dan; Pietsch, Maxwell; Nagar, Chetan; Fadli, Zayd; Huang, Hong; Tu, Yi-Cheng; Cheng, Feng

    2015-01-01

    Drug–drug interaction (DDI) is becoming a serious clinical safety issue as the use of multiple medications becomes more common. Searching the MEDLINE database for journal articles related to DDI produces over 330,000 results. It is impossible to read and summarize these references manually. As the volume of biomedical reference in the MEDLINE database continues to expand at a rapid pace, automatic identification of DDIs from literature is becoming increasingly important. In this article, we present a random-sampling-based statistical algorithm to identify possible DDIs and the underlying mechanism from the substances field of MEDLINE records. The substances terms are essentially carriers of compound (including protein) information in a MEDLINE record. Four case studies on warfarin, ibuprofen, furosemide and sertraline implied that our method was able to rank possible DDIs with high accuracy (90.0% for warfarin, 83.3% for ibuprofen, 70.0% for furosemide and 100% for sertraline in the top 10% of a list of compounds ranked by p-value). A social network analysis of substance terms was also performed to construct networks between proteins and drug pairs to elucidate how the two drugs could interact. PMID:26612138

  15. Use of physiologically based pharmacokinetic modeling for assessment of drug-drug interactions.

    PubMed

    Baneyx, Guillaume; Fukushima, Yumi; Parrott, Neil

    2012-04-01

    Interactions between co-administered medicines can reduce efficacy or lead to adverse effects. Understanding and managing such interactions is essential in bringing safe and effective medicines to the market. Ideally, interaction potential should be recognized early and minimized in compounds that reach late stages of drug development. Physiologically based pharmacokinetic models combine knowledge of physiological factors with compound-specific properties to simulate how a drug behaves in the human body. These software tools are increasingly used during drug discovery and development and, when integrating relevant in vitro data, can simulate drug interaction potential. This article provides some background and presents illustrative examples. Physiologically based models are an integral tool in the discovery and development of drugs, and can significantly aid our understanding and prediction of drug interactions.

  16. Transgender Women Living with HIV Frequently Take Antiretroviral Therapy and/or Feminizing Hormone Therapy Differently Than Prescribed Due to Drug-Drug Interaction Concerns.

    PubMed

    Braun, Hannan M; Candelario, Jury; Hanlon, Courtney L; Segura, Eddy R; Clark, Jesse L; Currier, Judith S; Lake, Jordan E

    2017-09-06

    Both hormone therapy (HT) and antiretroviral therapy (ART) can be lifesaving for transgender women (TW) living with HIV, but each has side effects and potential drug-drug interactions (DDI). We assessed how concerns about HT-ART interactions affect treatment adherence. This study used a cross-sectional survey of TW (n = 87) in Los Angeles, CA. Fifty-four percent were living with HIV; 64% used HT. Only 49% of TW living with HIV discussed ART-HT DDI with their provider; 40% reported not taking ART (12%), HT (12%), or both (16%) as directed due to DDI concerns. Imperfect HT/ART use and limited provider communication suggests a need for improved HT-ART integration.

  17. An apparent clinical pharmacokinetic drug-drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism.

    PubMed

    Wang, Ka; Stark, Franziska Schaedeli; Schlothauer, Tilman; Lahr, Angelika; Cosson, Valerie; Zhi, Jianguo; Habben, Kai; Tessier, Jean; Schick, Eginhard; Staack, Roland F; Krieter, Oliver

    2017-04-01

    RO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an apparent drug-drug interaction observed when RO5323441 was administered in combination with bevacizumab. The four Phase I studies were a multiple-ascending dose study in 23 patients with solid tumors (Study 1), an open-label study in seven patients with colorectal/ovarian cancer (Study 2), a sorafenib combination study in nine patients with hepatocellular carcinoma (Study 3), and a bevacizumab combination study in 22 patients with recurrent glioblastoma (Study 4). A two-compartment linear population PK model was developed from these four studies to characterize the PK of RO5323441 in patients with cancer. The PK properties of RO5323441 were similar in the first three studies. However, substantially higher RO5323441 exposures were observed in Study 4 when RO5323441 was administered in combination with bevacizumab. A linear two-compartmental population PK model indicated that the co-administration of bevacizumab would decrease the clearance of RO5323441 by 53%. Clinical data suggested that the decrease in RO5323441 clearance was inversely associated with bevacizumab exposure. The exact reason for the increase in RO5323441 exposure following bevacizumab co-administration is not currently known. One possibility is a drug-drug interaction via a target-trapping mechanism that is mediated by the vascular endothelial growth factor receptor-1 (VEGFR-1).

  18. In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1

    PubMed Central

    Long, Amanda J.; Annes, William F.; Witcher, Jennifer W.; Knadler, Mary Pat; Ayan-Oshodi, Mosun A.; Mitchell, Malcolm I.; Leese, Phillip; Hillgren, Kathleen M.

    2017-01-01

    Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter. PMID:27895114

  19. Drug-drug interactions between antiretroviral and immunosuppressive agents in HIV-infected patients after solid organ transplantation: a review.

    PubMed

    van Maarseveen, Erik M; Rogers, Christin C; Trofe-Clark, Jennifer; van Zuilen, Arjan D; Mudrikova, Tania

    2012-10-01

    Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive therapy proved to be extremely challenging, as witnessed by high rates of allograft rejection and drug toxicity, but the profound drug-drug interactions between immunosuppressants and cART, especially protease inhibitors (PIs) also play an important role. Caution and frequent drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients. Furthermore, the pharmacokinetics of glucocorticoids and mTOR inhibitors are seriously affected by PIs. With the introduction of integrase inhibitors, CCR5-antagonists and fusion inhibitors which cause significantly less pharmacokinetic interactions, have minor overlapping toxicity, and offer the advantage of pharmacodynamic synergy, it is time to revaluate what may be considered the optimal antiretroviral regimen in SOT recipients. In this review we provide a brief overview of the recent success of SOT in the HIV population, and an update on the pharmacokinetic and pharmacodynamic interactions between currently available cART and immunosuppressants in HIV-infected patients, who underwent SOT.

  20. DDI-CPI, a server that predicts drug-drug interactions through implementing the chemical-protein interactome.

    PubMed

    Luo, Heng; Zhang, Ping; Huang, Hui; Huang, Jialiang; Kao, Emily; Shi, Leming; He, Lin; Yang, Lun

    2014-07-01

    Drug-drug interactions (DDIs) may cause serious side-effects that draw great attention from both academia and industry. Since some DDIs are mediated by unexpected drug-human protein interactions, it is reasonable to analyze the chemical-protein interactome (CPI) profiles of the drugs to predict their DDIs. Here we introduce the DDI-CPI server, which can make real-time DDI predictions based only on molecular structure. When the user submits a molecule, the server will dock user's molecule across 611 human proteins, generating a CPI profile that can be used as a feature vector for the pre-constructed prediction model. It can suggest potential DDIs between the user's molecule and our library of 2515 drug molecules. In cross-validation and independent validation, the server achieved an AUC greater than 0.85. Additionally, by investigating the CPI profiles of predicted DDI, users can explore the PK/PD proteins that might be involved in a particular DDI. A 3D visualization of the drug-protein interaction will be provided as well. The DDI-CPI is freely accessible at http://cpi.bio-x.cn/ddi/.

  1. Analysis and prediction of drug-drug interaction by minimum redundancy maximum relevance and incremental feature selection.

    PubMed

    Liu, Lili; Chen, Lei; Zhang, Yu-Hang; Wei, Lai; Cheng, Shiwen; Kong, Xiangyin; Zheng, Mingyue; Huang, Tao; Cai, Yu-Dong

    2017-02-01

    Drug-drug interaction (DDI) defines a situation in which one drug affects the activity of another when both are administered together. DDI is a common cause of adverse drug reactions and sometimes also leads to improved therapeutic effects. Therefore, it is of great interest to discover novel DDIs according to their molecular properties and mechanisms in a robust and rigorous way. This paper attempts to predict effective DDIs using the following properties: (1) chemical interaction between drugs; (2) protein interactions between the targets of drugs; and (3) target enrichment of KEGG pathways. The data consisted of 7323 pairs of DDIs collected from the DrugBank and 36,615 pairs of drugs constructed by randomly combining two drugs. Each drug pair was represented by 465 features derived from the aforementioned three categories of properties. The random forest algorithm was adopted to train the prediction model. Some feature selection techniques, including minimum redundancy maximum relevance and incremental feature selection, were used to extract key features as the optimal input for the prediction model. The extracted key features may help to gain insights into the mechanisms of DDIs and provide some guidelines for the relevant clinical medication developments, and the prediction model can give new clues for identification of novel DDIs.

  2. Nonclinical Pharmacokinetics, Disposition, and Drug-Drug Interaction Potential of a Novel d-Amino Acid Peptide Agonist of the Calcium-Sensing Receptor AMG 416 (Etelcalcetide).

    PubMed

    Subramanian, Raju; Zhu, Xiaochun; Kerr, Savannah J; Esmay, Joel D; Louie, Steven W; Edson, Katheryne Z; Walter, Sarah; Fitzsimmons, Michael; Wagner, Mylo; Soto, Marcus; Pham, Roger; Wilson, Sarah F; Skiles, Gary L

    2016-08-01

    AMG 416 (etelcalcetide) is a novel synthetic peptide agonist of the calcium-sensing receptor composed of a linear chain of seven d-amino acids (referred to as the d-amino acid backbone) with a d-cysteine linked to an l-cysteine via a disulfide bond. AMG 416 contains four basic d-arginine residues and is a +4 charged peptide at physiologic pH with a mol. wt. of 1048.3 Da. The pharmacokinetics (PK), disposition, and potential of AMG 416 to cause drug-drug interaction were investigated in nonclinical studies with two single (14)C-labels placed either at a potentially metabolically labile acetyl position or on the d-alanine next to d-cysteine in the interior of the d-amino acid backbone. After i.v. dosing, the PK and disposition of AMG 416 were similar in male and female rats. Radioactivity rapidly distributed to most tissues in rats with intact kidneys, and renal elimination was the predominant clearance pathway. No strain-dependent differences were observed. In bilaterally nephrectomized rats, minimal radioactivity (1.2%) was excreted via nonrenal pathways. Biotransformation occurred primarily via disulfide exchange with endogenous thiol-containing molecules in whole blood rather than metabolism by enzymes, such as proteases or cytochrome P450s; the d-amino acid backbone remained unaltered. A substantial proportion of the plasma radioactivity was covalently conjugated to albumin. AMG 416 presents a low risk for P450 or transporter-mediated drug-drug interactions because it showed no interactions in vitro. These studies demonstrated a (14)C label on either the acetyl or the d-alanine in the d-amino acid backbone would be appropriate for clinical studies. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Potential drug-drug and drug-disease interactions in prescriptions for ambulatory patients over 50 years of age in family medicine clinics in Mexico City

    PubMed Central

    Doubova (Dubova), Svetlana Vladislavovna; Reyes-Morales, Hortensia; Torres-Arreola, Laura del Pilar; Suárez-Ortega, Magdalena

    2007-01-01

    Background In Mexico, inappropriate prescription of drugs with potential interactions causing serious risks to patient health has been little studied. Work in this area has focused mainly on hospitalized patients, with only specific drug combinations analyzed; moreover, the studies have not produced conclusive results. In the present study, we determined the frequency of potential drug-drug and drug-disease interactions in prescriptions for ambulatory patients over 50 years of age, who used Mexican Institute of Social Security (IMSS) family medicine clinics. In addition, we aimed to identify the associated factors for these interactions. Methods We collected information on general patient characteristics, medical histories, and medication (complete data). The study included 624 ambulatory patients over 50 years of age, with non-malignant pain syndrome, who made ambulatory visits to two IMSS family medicine clinics in Mexico City. The patients received 7-day prescriptions for non-opioid analgesics. The potential interactions were identified by using the Thompson Micromedex program. Data were analyzed using descriptive, bivariate and multiple logistic regression analyses. Results The average number of prescribed drugs was 5.9 ± 2.5. About 80.0% of patients had prescriptions implying one or more potential drug-drug interactions and 3.8% of patients were prescribed drug combinations with interactions that should be avoided. Also, 64.0% of patients had prescriptions implying one or more potential drug disease interactions. The factors significantly associated with having one or more potential interactions included: taking 5 or more medicines (adjusted Odds Ratio (OR): 4.34, 95%CI: 2.76–6.83), patient age 60 years or older (adjusted OR: 1.66, 95% CI: 1.01–2.74) and suffering from cardiovascular diseases (adjusted OR: 7.26, 95% CI: 4.61–11.44). Conclusion The high frequency of prescription of drugs with potential drug interactions showed in this study suggests that

  4. Evaluation of Mutual Drug-Drug Interaction within Geneva Cocktail for Cytochrome P450 Phenotyping using Innovative Dried Blood Sampling Method.

    PubMed

    Bosilkovska, Marija; Samer, Caroline; Déglon, Julien; Thomas, Aurélien; Walder, Bernhard; Desmeules, Jules; Daali, Youssef

    2016-09-01

    Cytochrome P450 (CYP) activity can be assessed using a 'cocktail' phenotyping approach. Recently, we have developed a cocktail (Geneva cocktail) which combines the use of low-dose probes with a low-invasiveness dried blood spots (DBS) sampling technique and a single analytical method for the phenotyping of six major CYP isoforms. We have previously demonstrated that modulation of CYP activity after pre-treatment with CYP inhibitors/inducer could be reliably predicted using Geneva cocktail. To further validate this cocktail, in this study, we have verified whether probe drugs contained in the latter cause mutual drug-drug interactions. In a randomized, four-way, Latin-square crossover study, 30 healthy volunteers received low-dose caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam (a previously validated combination with no mutual drug-drug interactions); fexofenadine alone; bupropion alone; or all seven drugs simultaneously (Geneva cocktail). Pharmacokinetic profiles of the probe drugs and their metabolites were determined in DBS samples using both conventional micropipette sampling and new microfluidic device allowing for self-sampling. The 90% confidence intervals for the geometric mean ratios of AUC metabolite/AUC probe for CYP probes administered alone or within Geneva cocktail fell within the 0.8-1.25 bioequivalence range indicating the absence of pharmacokinetic interaction. The same result was observed for the chosen phenotyping indices, that is metabolic ratios at 2 hr (CYP1A2, CYP3A) or 3 hr (CYP2B6, CYP2C9, CYP2C19, CYP2D6) post-cocktail administration. DBS sampling could successfully be performed using a new microfluidic device. In conclusion, Geneva cocktail combined with an innovative DBS sampling device can be used routinely as a test for simultaneous CYP phenotyping. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  5. UHPLC-MS/MS bioanalysis of urinary DHEA, cortisone and their hydroxylated metabolites as potential biomarkers for CYP3A-mediated drug-drug interactions.

    PubMed

    Zheng, Naiyu; Christopher, Lisa J; Ma, Xuewen; Ji, Qin C; Buzescu, Adela; Kandoussi, Hamza; Garonzik, Samira M; LaCreta, Frank; Aubry, Anne-Francoise; Arnold, Mark E; Zeng, Jianing

    2016-12-01

    A UHPLC-MS/MS assay was developed to quantify urinary dehydroepiandrosterone (DHEA), 7β-hydroxy-DHEA, cortisone and 6β-hydroxycortisone as potential biomarkers to predict CYP3A activity. A sensitive assay at LLOQ of 0.500 ng/ml with good accuracy and precision was developed for the four analytes in human urine. This UHPLC-MS/MS assay was optimized by eliminating nonspecific loss of the analytes in urine, ensuring complete hydrolysis of the conjugates to unconjugated forms and use of the product ions of [M+H-H2O](+) for multiple reaction monitoring detection of DHEA and 7β-hydroxy-DHEA. This assay was successfully applied to a pilot clinical study. It is also suitable for future drug-drug interaction studies to continue evaluating the potential of these steroids as biomarkers for CYP3A inhibition and induction.

  6. Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.

    PubMed

    Karlgren, Maria; Vildhede, Anna; Norinder, Ulf; Wisniewski, Jacek R; Kimoto, Emi; Lai, Yurong; Haglund, Ulf; Artursson, Per

    2012-05-24

    The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.

  7. Low Potential of Basimglurant to Be Involved in Drug-Drug Interactions: Influence of Non-Michaelis-Menten P450 Kinetics on Fraction Metabolized.

    PubMed

    Fowler, Stephen; Guerini, Elena; Qiu, NaHong; Cleary, Yumi; Parrott, Neil; Greig, Gerard; Mallalieu, Navita L

    2017-01-01

    Basimglurant, a novel mGlu5-negative allosteric modulator under development for the treatment of major depressive disorder, is cleared via cytochrome P450 (P450)-mediated oxidative metabolism. Initial enzyme phenotyping studies indicated that CYP3A4/5 dominates basimglurant metabolism and highlights a risk for drug-drug interactions when it is comedicated with strong CYP3A4/5 inhibitors or inactivators; however, a clinical drug-drug interaction (DDI) study using the potent and selective CYP3A4/5 inhibitor ketoconazole resulted in an area under the curve (AUC) AUCi/AUC ratio of only 1.24. A further study using the CYP3A4 inducer carbamazepine resulted in an AUCi/AUC ratio of 0.69. More detailed in vitro enzyme phenotyping and kinetics studies showed that, at the low concentrations attained clinically, basimglurant metabolic clearance is catalyzed mainly by CYP1A2. The relative contributions of the enzymes were estimated as 70:30 CYP1A2:CYP3A4/5. Using this information, a clinical study using the CYP1A2 inhibitor fluvoxamine was performed, resulting in an AUCi/AUC ratio of 1.60, confirming the role of CYP1A2 and indicating a balanced DDI risk profile. Basimglurant metabolism kinetics show enzyme dependency: CYP1A2-mediated metabolism follows Michaelis-Menten kinetics, whereas CYP3A4 and CYP3A5 follow sigmoidal kinetics [with similar constant (KM) and S50 values]. The interplay of the different enzyme kinetics leads to changing fractional enzyme contributions to metabolism with substrate concentration, even though none of the metabolic enzymes is saturated. This example demonstrates the relevance of non-Michaelis-Menten P450 enzyme kinetics and highlights the need for a thorough understanding of metabolism enzymology to make accurate predictions for human metabolism in vivo.

  8. Mining clinical text for signals of adverse drug-drug interactions

    PubMed Central

    Iyer, Srinivasan V; Harpaz, Rave; LePendu, Paea; Bauer-Mehren, Anna; Shah, Nigam H

    2014-01-01

    Background and objective Electronic health records (EHRs) are increasingly being used to complement the FDA Adverse Event Reporting System (FAERS) and to enable active pharmacovigilance. Over 30% of all adverse drug reactions are caused by drug–drug interactions (DDIs) and result in significant morbidity every year, making their early identification vital. We present an approach for identifying DDI signals directly from the textual portion of EHRs. Methods We recognize mentions of drug and event concepts from over 50 million clinical notes from two sites to create a timeline of concept mentions for each patient. We then use adjusted disproportionality ratios to identify significant drug–drug–event associations among 1165 drugs and 14 adverse events. To validate our results, we evaluate our performance on a gold standard of 1698 DDIs curated from existing knowledge bases, as well as with signaling DDI associations directly from FAERS using established methods. Results Our method achieves good performance, as measured by our gold standard (area under the receiver operator characteristic (ROC) curve >80%), on two independent EHR datasets and the performance is comparable to that of signaling DDIs from FAERS. We demonstrate the utility of our method for early detection of DDIs and for identifying alternatives for risky drug combinations. Finally, we publish a first of its kind database of population event rates among patients on drug combinations based on an EHR corpus. Conclusions It is feasible to identify DDI signals and estimate the rate of adverse events among patients on drug combinations, directly from clinical text; this could have utility in prioritizing drug interaction surveillance as well as in clinical decision support. PMID:24158091

  9. Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone

    PubMed Central

    Wang, R.; Luo, W.-L.; Wastall, P.; Kandoussi, H.; DeMicco, M.; Bruce, R. D.; Hwang, C.; Bertz, R.; Bifano, M.

    2015-01-01

    Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (Cmax) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized Cmax for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. PMID:26124175

  10. Assessment of drug-drug interactions between daclatasvir and methadone or buprenorphine-naloxone.

    PubMed

    Garimella, T; Wang, R; Luo, W-L; Wastall, P; Kandoussi, H; DeMicco, M; Bruce, R D; Hwang, C; Bertz, R; Bifano, M

    2015-09-01

    Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (C max) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. Copyright © 2015, American Society for

  11. Decreased tacrolimus plasma concentrations during HCV therapy: a drug-drug interaction or is there an alternative explanation?

    PubMed

    Smolders, E J; Pape, S; de Kanter, C T M M; van den Berg, A P; Drenth, J P H; Burger, D M

    2017-03-01

    Chronic hepatitis C virus (HCV) infection can cause severe liver cirrhosis, for which liver transplantation is the only therapy. To prevent organ rejection, transplanted patients are treated with immunosuppressive agents. We describe two transplanted patients treated with tacrolimus who were simultaneously treated with direct-acting antivirals (DAAs) for their chronic HCV infection. No pharmacokinetic drug-drug interactions (DDIs) were expected between tacrolimus and the selected DAAs. However, in both patients, tacrolimus plasma concentrations decreased during HCV treatment. We hypothesise that decreased plasma concentrations were not caused by a DDI but were an indirect result of the clearance of the HCV infection. During chronic HCV infection, pro-inflammatory cytokines may inhibit cytochrome P450 (CYP) enzymes, which are primarily responsible for tacrolimus metabolism. If this is true, then with clearance of the virus the activity of these enzymes will normalise and tacrolimus metabolism will increase. These changes were clinically relevant because the tacrolimus dosage needed to be adjusted. Therefore, physicians should be aware that CYP substrates with narrow therapeutic ranges might require dose adaption during HCV therapy with DAAs.

  12. Text mining for pharmacovigilance: Using machine learning for drug name recognition and drug-drug interaction extraction and classification.

    PubMed

    Ben Abacha, Asma; Chowdhury, Md Faisal Mahbub; Karanasiou, Aikaterini; Mrabet, Yassine; Lavelli, Alberto; Zweigenbaum, Pierre

    2015-12-01

    Pharmacovigilance (PV) is defined by the World Health Organization as the science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. An essential aspect in PV is to acquire knowledge about Drug-Drug Interactions (DDIs). The shared tasks on DDI-Extraction organized in 2011 and 2013 have pointed out the importance of this issue and provided benchmarks for: Drug Name Recognition, DDI extraction and DDI classification. In this paper, we present our text mining systems for these tasks and evaluate their results on the DDI-Extraction benchmarks. Our systems rely on machine learning techniques using both feature-based and kernel-based methods. The obtained results for drug name recognition are encouraging. For DDI-Extraction, our hybrid system combining a feature-based method and a kernel-based method was ranked second in the DDI-Extraction-2011 challenge, and our two-step system for DDI detection and classification was ranked first in the DDI-Extraction-2013 task at SemEval. We discuss our methods and results and give pointers to future work.

  13. An Appraisal of Drug-Drug Interactions with Green Tea (Camellia sinensis).

    PubMed

    Albassam, Ahmed A; Markowitz, John S

    2017-04-01

    This review summarizes published in vitro, animal, and clinical studies investigating the effects of green tea (Camellia sinensis) extract and associated catechins on drug-metabolizing enzymes and drug transporters. In vitro studies suggest that green tea extract and its main catechin, (-)-epigallocatechin-3-gallate, to varying degrees, inhibit the activity of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. UGT1A1 and UGT1A4 isoforms were also inhibited by (-)-epigallocatechin-3-gallate. Animal studies suggest green tea extract and/or (-)-epigallocatechin-3-gallate significantly increase the bioavailability of diltazem, verapamil, tamoxifen simvastatin, 5-fluorouracil, and nicardipine. Conversely, green tea extract and/or (-)-epigallocatechin-3-gallate reduce the bioavailability of quetiapine, sunitinib, clozapine, and nadolol. Of the few clinical studies available for review, it appears neither green tea extract nor (-)-epigallocatechin-3-gallate inhibit any major cytochrome P450 enzyme. Regarding drug transporters, in vitro studies indicate P-glycoprotein, organic anion transporting polypeptide 1A1, organic anion transporting polypeptide 1B1, organic anion transporting polypeptide 1B3, organic anion transporting polypeptide 2B1, organic cation transporter 1, organic cation transporter 2, multidrug and toxin extrusion 1, and multidrug and toxin extrusion 2-K are potentially inhibited by green tea extract. A clinical study indicates the organic anion transporting polypeptide 1A1 transporter is inhibited by (-)-epigallocatechin-3-gallate while P-glycoprotein is unaffected. In conclusion, the ingestion of green tea extract or its associated catechins is not expected to result in clinically significant influences on major cytochrome P450 or uridine 5'-diphospho-glucuronosyltransferase enzyme substrates or drugs serving as substrates of P-glycoprotein. However, some caution is advised in the consumption of significant amounts of green tea beverages or green

  14. A survey of attitudes, practices, and knowledge regarding drug-drug interactions among medical residents in Iran.

    PubMed

    Nabovati, Ehsan; Vakili-Arki, Hasan; Taherzadeh, Zhila; Saberi, Mohammad Reza; Abu-Hanna, Ameen; Eslami, Saeid

    2017-04-05

    Background When prescribing medications, physicians should recognize clinically relevant potential drug-drug interactions (DDIs). To improve medication safety, it is important to understand prescribers' knowledge and opinions pertaining to DDIs. Objective To determine the current DDI information sources used by medical residents, their knowledge of DDIs, their opinions about performance feedback on co-prescription of interacting drugs. Setting Academic hospitals of Mashhad University of Medical Sciences (MUMS) in Iran. Methods A questionnaire containing questions regarding demographic and practice characteristics, DDI information sources, ability to recognize DDIs, and opinions about performance feedback was distributed to medical residents of 22 specialties in eight academic hospitals in Iran. We analyzed their perception pertaining to DDIs, their performance on classifying drug pairs, and we used a linear regression model to assess the association of potential determinants on their DDI knowledge. Main Outcome Measure prescribers' knowledge and opinions pertaining to DDIs. Results The overall response rate and completion rate for 315 distributed questionnaires were 90% (n = 295) and 86% (n = 281), respectively. Among DDI information sources, books, software on mobile phone or tablet, and Internet were the most commonly-used references. Residents could correctly classify only 41% (5.7/14) of the drug pairs. The regression model showed no significant association between residents' characteristics and their DDI knowledge. An overwhelming majority of the respondents (n = 268, 95.4%) wished to receive performance feedback on co-prescription of interacting drugs in their prescriptions. They mostly selected information technology-based tools (i.e. short text message and email) as their preferred method of receiving feedback. Conclusion Our findings indicate that prescribers may have poor ability to prevent clinically relevant potential DDI occurrence, and they

  15. Evaluation of Potential Pharmacokinetic Drug-Drug Interaction between Armodafinil and Aripiprazole in Healthy Adults.

    PubMed

    Darwish, M; Bond, M; Yang, R; Hellriegel, E T; Robertson, P

    2015-07-01

    Armodafinil, a moderate inducer of cytochrome P450 (CYP) 3A4, has been studied as adjunctive therapy to maintenance medications for major depressive episodes associated with bipolar I disorder. We evaluated the effect of daily dosing with armodafinil on the pharmacokinetics and safety of the CYP3A4 substrate aripiprazole, an atypical antipsychotic used to treat bipolar I disorder. Healthy adults received 15 mg aripiprazole alone and after armodafinil (250 mg/day) pretreatment. Pharmacokinetic parameters were derived from plasma concentrations of aripiprazole and its active metabolite, dehydro-aripiprazole, obtained over 16 days after each aripiprazole administration. Steady-state pharmacokinetics of armodafinil and its 2 circulating metabolites was assessed. Of 36 subjects enrolled, 24 were evaluable for pharmacokinetic analysis. Armodafinil reduced systemic exposure to aripiprazole (Cmax, - 8%; AUC0-∞, -34%) and dehydro-aripiprazole, which is both formed and eliminated in part via CYP3A4 (Cmax, - 10%; AUC0-∞, - 32%). Adverse events were generally consistent with known safety profiles of each agent. Systemic exposure to aripiprazole and dehydro-aripiprazole was moderately reduced following armodafinil pretreatment. The combination was generally well tolerated under the conditions studied. © Georg Thieme Verlag KG Stuttgart · New York.

  16. From bench to bedside: utilization of an in vitro model to predict potential drug-drug interactions in the kidney: the digoxin-mifepristone example.

    PubMed

    Woodland, Cindy; Koren, Gideon; Ito, Shinya

    2003-07-01

    Drug interactions are a common source of drug-induced toxicity. For drugs with narrow therapeutic windows, such as digoxin, an understanding of the potential mechanisms by which drugs might interact is essential to clinical practice. This article describes the utility of a renal tubular cell culture model in the prediction of drug interactions involving P-glycoprotein. Digoxin is a cardiac glycoside that undergoes active secretion in the renal tubules by the MDR1 (P-glycoprotein) drug efflux pump. Mifepristone (RU486) is a recently introduced abortifacient that is largely unstudied in terms of drug-drug interactions. The authors used an in vitro model to study the effects of mifepristone on the renal tubular secretion and cellular uptake of digoxin by Madin-Darby canine kidney (MDCK) cells. Mifepristone significantly inhibited the renal tubular secretion of digoxin (p = 0.0005), without interfering with its ability to enter the renal tubular cell. Similar results were found with the P-glycoprotein substrate vinblastine. The findings suggest that drug interactions may result if mifepristone is administered with P-glycoprotein substrates, highlighting the usefulness of this model in the study of not only common but also rare combinations of drugs.

  17. Evaluation of potential pharmacokinetic drug-drug interaction between armodafinil and risperidone in healthy adults.

    PubMed

    Darwish, Mona; Bond, Mary; Yang, Ronghua; Hellriegel, Edward T; Robertson, Philmore

    2015-11-01

    Patients with bipolar I disorder and schizophrenia have an increased risk of obstructive sleep apnea. The effects of armodafinil, a weak cytochrome P450 (CYP) 3A4 inducer, on pharmacokinetics and safety of risperidone, an atypical antipsychotic used to treat major psychiatric illness, were investigated. Healthy subjects received 2 mg risperidone alone and after armodafinil pretreatment (titrated to 250 mg/day). Pharmacokinetic parameters were derived from plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (formed via CYP2D6 and CYP3A4), collected before and over 4 days after risperidone administration, and from steady-state plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone. Safety and tolerability were assessed. Thirty-six subjects receiving study drug were evaluable for safety; 34 were evaluable for pharmacokinetics. Risperidone maximum plasma concentration (C max) decreased from mean 16.5 ng/mL when given alone to 9.2 ng/mL after armodafinil pretreatment (geometric mean ratio [90 % CI] 0.55 [0.50-0.61]); area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) decreased from 92.3 to 44.5 ng·h/mL (geometric mean ratio [90 % CI] 0.51 [0.46-0.55]). C max and AUC0-∞ for 9-hydroxyrisperidone were also reduced (geometric mean ratios [90 % CI] 0.81 [0.77-0.85] and 0.73 [0.69-0.77], respectively). Adverse events were consistent with known safety profiles. Consistent with CYP3A4 induction, risperidone and 9-hydroxyrisperidone systemic exposure was reduced in the presence of armodafinil. Concomitant armodafinil and risperidone use may necessitate risperidone dosage adjustment, particularly when starting or stopping coadministration of the two drugs. However, any such decision should be based on patient disease state and clinical status.

  18. Use of a physiologically based pharmacokinetic model to simulate drug-drug interactions between antineoplastic and antiretroviral drugs.

    PubMed

    Moltó, José; Rajoli, Rajith; Back, David; Valle, Marta; Miranda, Cristina; Owen, Andrew; Clotet, Bonaventura; Siccardi, Marco

    2017-03-01

    Co-administration of antineoplastics with ART is challenging due to potential drug-drug interactions (DDIs). However, trials specifically assessing such DDIs are lacking. Our objective was to simulate DDIs between the antineoplastics erlotinib and gefitinib with key antiretroviral drugs and to predict dose adjustments using a physiologically based pharmacokinetic (PBPK) model. In vitro data describing chemical properties and pharmacokinetic processes of each drug and their effect on cytochrome P450 isoforms were obtained from the literature. Plasma drug-concentration profiles were simulated in a virtual population of 50 individuals receiving erlotinib or gefitinib alone or with darunavir/ritonavir, efavirenz or etravirine. Simulated pharmacokinetic parameters and the magnitude of DDIs with probe drugs (midazolam, maraviroc) were compared with literature values. Erlotinib and gefitinib pharmacokinetics with and without antiretrovirals were compared and dose-adjustment strategies were evaluated. Simulated parameters of each drug and the magnitude of DDIs with probe drugs were in agreement with reference values. Darunavir/ritonavir increased erlotinib and gefitinib exposure, while efavirenz and etravirine decreased erlotinib and gefitinib concentrations. Based on our predictions, dose-adjustment strategies may consist of once-daily dosing erlotinib at 25 mg and gefitinib at 125 mg with darunavir/ritonavir; or erlotinib at 200 mg and gefitinib at 375 mg with etravirine. The interaction with efavirenz was not overcome even after doubling erlotinib or gefitinib doses. PBPK models predicted the in vivo pharmacokinetics of erlotinib, gefitinib and the antiretrovirals darunavir/ritonavir, efavirenz and etravirine, and the DDIs between them. The simulated dose-adjustments may represent valuable strategies to optimize antineoplastic therapy in HIV-infected patients.

  19. Impact of Multiple Pharmacy Use on Medication Adherence and Drug-drug Interactions in Older Adults with Medicare Part D

    PubMed Central

    Marcum, Zachary A.; Driessen, Julia; Thorpe, Carolyn T.; Gellad, Walid F.; Donohue, Julie M.

    2014-01-01

    Objective To assess the association between multiple pharmacy use and medication adherence and potential drug-drug interactions (DDIs) among older adults. Design, Setting, and Participants Cross-sectional propensity score-weighted analysis of 2009 claims data from a nationally representative sample of 926,956 Medicare Part D beneficiaries aged >65 continuously enrolled in fee-for-service Medicare and Part D that year, and filled >1 prescription at a community/retail or mail order pharmacy. Multiple pharmacy use was defined as concurrent (overlapping time periods) or sequential use (non-overlapping time periods) of >2 pharmacies in the year. Measurements Medication adherence was calculated using a proportion of days covered ≥0.80 for eight therapeutic categories (β-blockers, renin angiotensin system antagonists, calcium channel blockers, statins, sulfonylureas, biguanides [i.e., metformin], thiazolidinediones, and dipeptidyl peptidase-IV inhibitors). Potential DDIs arising from use of certain drugs across a broad set of classes were defined as the concurrent filling of two interacting drugs. Results Overall, 38.1% of the sample used multiple pharmacies. Those using multiple pharmacies (both concurrently and sequentially) consistently had higher adjusted odds of non-adherence (ranging from 1.10 to 1.31, p<0.001) across all chronic medication classes assessed after controlling for socio-demographic, health status and access to care factors, compared to single pharmacy users. The adjusted predicted probability of exposure to a DDI was also slightly higher for those using multiple pharmacies concurrently (3.6%) compared to single pharmacy users (3.2%, AOR 1.11, 95% CI 1.08–1.15) but lower in individuals using multiple pharmacies sequentially (2.8%, AOR 0.85, 95% CI 0.81–0.91). Conclusions Filling prescriptions at multiple pharmacies was associated with lower medication adherence across multiple chronic medications, and a small but statistically significant

  20. Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites.

    PubMed

    Ellens, Harma; Johnson, Marta; Lawrence, Sarah K; Watson, Cory A; Chen, Liangfu; Richards-Peterson, Lauren E

    2017-03-20

    The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the MEK inhibitor trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction risk assessment, which is currently an important part of drug development, regulatory submission and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy- and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters Pgp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1 and OAT3. The DDI guidance risk assessment decision criteria for inhibition of BCRP, OATP1B1 and OAT3 were slightly exceeded and therefore a minor DDI effect resulting from inhibition of these transporters remained possible. Biliary secretion is the major excretion pathway of dabrafenib related material (71% of orally administered radiolabeled dose recovered in feces), while urinary excretion was observed as well (22.7% of the dose). In vitro uptake into human hepatocytes of the dabrafenib metabolites, but not of dabrafenib parent compound, was mediated, at least in part, by hepatic uptake transporters. The transporters responsible for uptake of the pharmacologically active hydroxy- and desmethyl dabrafenib could not be identified, whereas carboxy-dabrafenib was a substrate of several OATPs. Dabrafenib, hydroxy- and desmethyl dabrafenib were substrates of P-gp and BCRP, while carboxy-dabrafenib was not. While a small increase in exposure to carboxy-dabrafenib upon inhibition of OATPs and an increase in exposure to desmethyl-dabrafenib upon inhibition of P-gp or BCRP cannot be excluded, the clinical significance of such increases is likely low.

  1. Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.

    PubMed

    Ishiguro, Naoki; Shimizu, Hidetada; Kishimoto, Wataru; Ebner, Thomas; Schaefer, Olaf

    2013-01-01

    Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.

  2. Therapeutic protein drug-drug interactions: navigating the knowledge gaps-highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA workshop.

    PubMed

    Kenny, Jane R; Liu, Maggie M; Chow, Andrew T; Earp, Justin C; Evers, Raymond; Slatter, J Greg; Wang, Diane D; Zhang, Lei; Zhou, Honghui

    2013-10-01

    The investigation of therapeutic protein drug-drug interactions has proven to be challenging. In May 2012, a roundtable was held at the American Association of Pharmaceutical Scientists National Biotechnology Conference to discuss the challenges of preclinical assessment and in vitro to in vivo extrapolation of these interactions. Several weeks later, a 2-day workshop co-sponsored by the U.S. Food and Drug Administration and the International Consortium for Innovation and Quality in Pharmaceutical Development was held to facilitate better understanding of the current science, investigative approaches and knowledge gaps in this field. Both meetings focused primarily on drug interactions involving therapeutic proteins that are pro-inflammatory cytokines or cytokine modulators. In this meeting synopsis, we provide highlights from both meetings and summarize observations and recommendations that were developed to reflect the current state of the art thinking, including a four-step risk assessment that could be used to determine the need (or not) for a dedicated clinical pharmacokinetic interaction study.

  3. Absence of Drug-Drug Interactions Between Luseogliflozin, a Sodium-Glucose Co-transporter-2 Inhibitor, and Various Oral Antidiabetic Drugs in Healthy Japanese Males.

    PubMed

    Sasaki, Takashi; Seino, Yutaka; Fukatsu, Atsushi; Ubukata, Michito; Sakai, Soichi; Samukawa, Yoshishige

    2015-05-01

    We investigated the possibilities of drug-drug interactions between luseogliflozin, a sodium-glucose co-transporter-2 inhibitor, and oral antidiabetic drugs (OADs) in healthy Japanese males. We conducted six independent studies to investigate potential drug-drug interactions between 5 mg luseogliflozin and the following OADs usually used in Japan: 1 mg glimepiride, 250 mg metformin, 30 mg pioglitazone, 50 mg sitagliptin, 50 mg miglitol, or 0.6 mg voglibose (0.2 mg before each meal). Twelve subjects were enrolled in each study. The glimepiride, metformin, sitagliptin, and miglitol studies were randomized, open-label, single-dose, three-way crossover studies. The pioglitazone and voglibose studies were open-label studies, where a single dose of luseogliflozin was added to multiple doses of pioglitazone or voglibose. The endpoints were the area under the curve from 0 to 24 h (AUC0-24 h) or to infinity (AUCinf) and the maximum concentration (Cmax) of each drug administered alone or in combination. The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) for Cmax of luseogliflozin in the pioglitazone and miglitol studies were beyond the reference range for bioequivalence (0.80-1.25) (miglitol: 0.851 [0.761, 0.952]; pioglitazone: 1.16 [1.04, 1.30]). However, the 90% CIs for AUC0-24 h were within the reference range. The 90% CIs of the GMRs for Cmax and AUC0-24 h of pioglitazone were beyond the reference range (Cmax 0.884 [0.746, 1.05]; AUC0-24 h 0.896 [0.774, 1.04]), but the 90% CIs for the active metabolites of pioglitazone were within the reference range. For the other combinations tested, the 90% CIs and GMRs for luseogliflozin and the individual OADs were within the reference range. No clinically meaningful interactions were observed between luseogliflozin and six commonly used OADs in Japan, although there were some changes in the pharmacokinetics of pioglitazone co-administered with luseogliflozin and for luseogliflozin co-administered with miglitol or

  4. Integrated in vitro analysis for the in vivo prediction of cytochrome P450-mediated drug-drug interactions.

    PubMed

    McGinnity, Dermot F; Waters, Nigel J; Tucker, James; Riley, Robert J

    2008-06-01

    Unbound IC(50) (IC(50,u)) values of 15 drugs were determined in eight recombinantly expressed human cytochromes P450 (P450s) and human hepatocytes, and the data were used to simulate clinical area under the plasma concentration-time curve changes (deltaAUC) on coadministration with prototypic CYP2D6 substrates. Significant differences in IC(50,u) values between enzyme sources were observed for quinidine (0.02 microM in recombinant CYP2D6 versus 0.5 microM in hepatocytes) and propafenone (0.02 versus 4.1 microM). The relative contribution of individual P450s toward the oxidative metabolism of clinical probes desipramine, imipramine, tolterodine, propranolol, and metoprolol was estimated via determinations of intrinsic clearance using recombinant P450s (rP450s). Simulated deltaAUC were compared with those observed in vivo via the ratios of unbound inhibitor concentration at the entrance to the liver to inhibition constants determined against rP450s ([I](in,u)/K(i)) and incorporating parallel substrate elimination pathways. For this dataset, there were 20% false negatives (observed deltaAUC >or= 2, predicted deltaAUC < 2), 77% correct predictions, and 3% false positives. Thus, the [I](in,u)/K(i) approach appears relatively successful at estimating the degree of clinical interactions and can be incorporated into drug discovery strategies. Using a Simcyp ADME (absorption, metabolism, distribution, elimination) simulator (Simcyp Ltd., Sheffield, UK), there were 3% false negatives, 94% correct simulations, and 3% false positives. False-negative predictions were rationalized as a result of mechanism-based inhibition, production of inhibitory metabolites, and/or hepatic uptake. Integrating inhibition and reaction phenotyping data from automated rP450 screens have shown applicability to predict the occurrence and degree of in vivo drug-drug interactions, and such data may identify the clinical consequences for candidate drugs as both "perpetrators" and "victims" of P450

  5. Cost comparison of drug-drug and drug-condition interactions in patients with painful diabetic peripheral neuropathy treated with pregabalin versus duloxetine.

    PubMed

    Johnston, Stephen S; Udall, Margarita; Cappelleri, Joseph C; Johnson, Barbara H; Shrady, George; Chu, Bong-Chul; Silverman, Stuart L

    2013-12-15

    The frequency and financial impact of potential drug-drug interactions (DDIs) and drug-condition interactions (DCIs) in patients with painful diabetic peripheral neuropathy (DPN) treated with either pregabalin or duloxetine were compared. This retrospective cohort study was conducted using a large U.S. administrative claims database. Patients selected for study inclusion had a diagnosis of DPN and were newly initiated on either pregabalin or duloxetine between July 1, 2008, and October 1, 2010. Data on potential DDIs and DCIs were collected. Health care costs were measured as the sum of gross covered payments for all medical and prescription claims incurred during the six months after the index date. The study sample comprised 2499 pregabalin users and 1354 duloxetine users. Among pregabalin users, 48 (1.8%) had at least one potential pregabalin DCI; none had potential pregabalin DDIs. Among duloxetine users, 966 (71%) had at least one potential duloxetine DDI or DCI. The frequencies of potential DDIs and DCIs differed significantly between pregabalin and duloxetine users (p < 0.001). Potential duloxetine DDIs and DCIs were associated with a significant increase in mean health care costs in duloxetine users (p = 0.002). Potential pregabalin DDIs and DCIs were not associated with additional health care costs in pregabalin users. Among patients with painful DPN treated with either pregabalin or duloxetine, the frequency of potential duloxetine DDIs and DCIs was substantially higher than that of pregabalin. Potential DDIs and DCIs were associated with significantly increased health care costs in duloxetine users.

  6. Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males.

    PubMed

    Wang, Liupeng; Wu, Chunyong; Shen, Lu; Liu, Haiyan; Chen, Ying; Liu, Fang; Wang, Youqun; Yang, Jin

    2016-08-01

    1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin-independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two-period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co-administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0-24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0-24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin Cmax (GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co-administered with metformin without dose adjustment of either drug.

  7. Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage.

    PubMed

    Sugimoto, Hiroshi; Matsumoto, Shin-ichi; Tachibana, Miho; Niwa, Shin-ichi; Hirabayashi, Hideki; Amano, Nobuyuki; Moriwaki, Toshiya

    2011-09-01

    The decision tree to determine whether the P-glycoprotein (P-gp)/multidrug resistance protein 1 (MDR1)-mediated drug-drug interaction (DDI) study is recommended has been proposed by the International Transporter Consortium. We, therefore, designed an in vitro P-gp inhibition assay and determined the appropriate risk criteria for P-gp-mediated DDI at the drug discovery stage. Effects of P-gp inhibitors on digoxin transport across a monolayer of MDR1-expressing cells were examined. The IC(50) (half-maximal inhibitory concentration) values generated from the efflux ratio (ER) were smaller than those generated from basolateral-to-apical directional apparent permeability. The difference in IC(50) values was kinetically described in a compartment model analysis. This analysis indicated that ER is a highly sensitive parameter that can be used for the degree of P-gp inhibition. Considering IC(50) values and the increase in digoxin exposure in clinical DDI studies, the risk criteria of [I(2)]/IC(50) = 30 ([I(2)], theoretically maximal gastrointestinal concentration) was the optimal cutoff value to predict a clinically relevant DDI. We also investigated whether the IC(50) value itself is applicable to assess the DDI risk. In conclusion, compounds with IC(50) values less than 2 μM exhibit high risk for P-gp-mediated DDIs. However, compounds with IC(50) values greater than or equal to 2 μM are inconclusive because clinical doses should be considered for the precise DDI risk assessment.

  8. Prediction of drug-drug interactions with carbamazepine-10,11-epoxide using a new in vitro assay for epoxide hydrolase inhibition.

    PubMed

    Rosa, Maria; Bonnaillie, Pierre; Chanteux, Hugues

    2016-12-01

    1. Carbamazepine is an antiepileptic drug which is metabolized by CYP3A4 into carbamazepine-10,11-epoxide. This metabolite is then detoxified by epoxide hydrolase. As carbamazepine-10,11-epoxide has been associated with neurotoxicity, it is critical to identify whether a new antiepileptic drug has the potential to inhibit epoxide hydrolase and therefore increase carbamazepine-10,11-epoxide plasma levels. 2. In this study, an in vitro assay was developed to evaluate epoxide hydrolase activity by using carbamazepine-10,11-epoxide as probe substrate. The ability of this assay to predict drug-drug interactions (DDI) at the epoxide hydrolase level was also investigated. 3. To this aim, known inhibitors of epoxide hydrolase for which in vivo data are available were used. Firstly, carbamazepine-10,11-epoxide hydrolase activity was determined in liver microsomes, cytosol and hepatocytes. Thereafter, the IC50 of epoxide hydrolase inhibitors (progabide, valproic acid, valpromide and valnoctamide) was determined in liver microsomes and hepatocytes. Finally, prediction of AUC increase was performed using the in vitro data generated. 4. Interestingly, epoxide hydrolase activity was found to be much higher in human hepatocytes compared to liver microsomes/cytosol. Even though assessed on a limited number of compounds, this study demonstrated that the use of hepatocytes seems to be a more relevant model to assess and predict DDI at the epoxide hydrolase level.

  9. Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8.

    PubMed

    Takagi, Motoi; Sakamoto, Masaya; Itoh, Tomoo; Fujiwara, Ryoichi

    2015-08-01

    While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 μM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo.

  10. Identification of Endogenous Biomarkers to Predict the Propensity of Drug Candidates to Cause Hepatic or Renal Transporter-Mediated Drug-Drug Interactions.

    PubMed

    Chu, Xiaoyan; Chan, Grace Hoyee; Evers, Raymond

    2017-09-01

    Drug transporters expressed in liver and kidney play a critical role in the elimination of a wide range of drugs and xenobiotics and inhibition of these transporters may therefore cause clinically significant drug-drug interactions (DDIs). Currently, in vitro transporter inhibition data are used to assess the risk that a drug candidate may act as an inhibitor of a transporter in patients at clinically relevant exposures. However, this approach is hampered by low confidence in in vitro to in vivo extrapolations, and large inter-system and inter-laboratory variability in in vitro data. Several endogenous compounds have been identified as substrates of drug transporters. Determining the impact of perpetrator drugs on the plasma or urinary exposure of these potential endogenous biomarkers in humans is being explored as an alternative approach to assess the DDI liability of drug candidates, especially in early drug development. In this review, we provide an overview of recently identified biomarkers used to study the inhibition of hepatic and renal transporters; summarize the methods and strategies employed to identify biomarkers; and discuss the utility, limitation, and future direction of biomarker approaches to predict transporter-mediated DDIs. Copyright © 2017. Published by Elsevier Inc.

  11. Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions.

    PubMed

    Grandvuinet, Anne Sophie; Vestergaard, Henrik Tang; Rapin, Nicolas; Steffansen, Bente

    2012-11-01

    This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in-vitro methods presently employed in drug-drug interaction (DDI) investigations. Current knowledge on the intestinal expression of the apical sodium-dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3-5, the multidrug resistance associated proteins (MRP) 1-6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in-vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in-vitro parameters for transporters (K(m) /K(i) /IC50, efflux ratio). The applicability of using a cut-off value (estimated based on the intestinal drug concentration divided by the K(i) or IC50) has also been considered. A re-evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P-glycoprotein. Moreover, the interplay between various processes that a drug is subject to in-vivo such as translocation by several transporters and dissolution should be considered. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

  12. Clinical-pharmacist intervention reduces clinically relevant drug-drug interactions in patients with heart failure: A randomized, double-blind, controlled trial.

    PubMed

    Roblek, Tina; Deticek, Andreja; Leskovar, Bostjan; Suskovic, Stanislav; Horvat, Matej; Belic, Ales; Mrhar, Ales; Lainscak, Mitja

    2016-01-15

    Incidence of drug-drug interactions (DDIs) increases with complexity of treatment and comorbidities, as in heart failure (HF). This randomized, double-blind study evaluated the intervention of the pharmacist on prevalence of clinically relevant DDIs (NCT01855165). Patients admitted with HF were screened for clinically relevant DDIs, and randomized to control or intervention. All attending physicians received standard advice about pharmacological therapy; those in the intervention group also received alerts about clinically relevant DDIs. Primary endpoint was DDI at discharge and secondary were re-hospitalization or death during follow-up. Of 213 patients, 51 (mean age, 79 ± 6 years; male, 47%) showed 66 clinically relevant DDIs and were randomized. For intervention (n=26) versus control (n=25), the number of patients with and the number of DDIs were significantly lower at discharge: 8 vs. 18 and 10 vs. 31; p=0.003 and 0.0049, respectively. Over a 6 month follow-up period, 11 control and 9 intervention patients were re-hospitalized or died (p>0.2 for all). No significant differences were seen between control and intervention for patients with eGFR <60 mL/min/1.73 m(2) (78%) for re-hospitalization or death (10 vs. 7; p=0.74). Pharmacist intervention significantly reduces the number of patients with clinically relevant DDIs, but not clinical endpoints 6 months from discharge. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Quantitative Prediction of Human Renal Clearance and Drug-Drug Interactions of Organic Anion Transporter Substrates Using In Vitro Transport Data: A Relative Activity Factor Approach.

    PubMed

    Mathialagan, Sumathy; Piotrowski, Mary A; Tess, David A; Feng, Bo; Litchfield, John; Varma, Manthena V

    2017-04-01

    Organic anion transporters (OATs) are important in the renal secretion, and thus, the clearance, of many drugs; and their functional change can result in pharmacokinetic variability. In this study, we applied transport rates measured in vitro using OAT-transfected human embryonic kidney cells to predict human renal secretory and total renal clearance of 31 diverse drugs. Selective substrates to OAT1 (tenofovir), OAT2 (acyclovir and ganciclovir), and OAT3 (benzylpenicillin, oseltamivir acid) were used to obtain relative activity factors (RAFs) for these individual transporters by relating in vitro transport clearance (after physiologic scaling) to in vivo secretory clearance. Using the estimated RAFs (0.64, 7.3, and 4.1, respectively, for OAT1, OAT2, and OAT3, respectively) and the in vitro active clearances, renal secretory clearance and total renal clearance were predicted with average fold errors (AFEs) of 1.89 and 1.40, respectively. The results show that OAT3-mediated transport play a predominant role in renal secretion for 22 of the 31 drugs evaluated. This mechanistic static approach was further applied to quantitatively predict renal drug-drug interactions (AFE ∼1.6) of the substrate drugs with probenecid, a clinical probe OAT inhibitor. In conclusion, the proposed in vitro-in vivo extrapolation approach is the first comprehensive attempt toward mechanistic modeling of renal secretory clearance based on routinely employed in vitro cell models.

  14. Application of Physiologically Based Pharmacokinetic Modeling to the Understanding of Bosutinib Pharmacokinetics: Prediction of Drug-Drug and Drug-Disease Interactions.

    PubMed

    Ono, Chiho; Hsyu, Poe-Hirr; Abbas, Richat; Loi, Cho-Ming; Yamazaki, Shinji

    2017-04-01

    Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Bosutinib is predominantly metabolized by CYP3A4 as the primary clearance mechanism. The main objectives of this study were to 1) develop physiologically based pharmacokinetic (PBPK) models of bosutinib; 2) verify and refine the PBPK models based on clinical study results of bosutinib single-dose drug-drug interaction (DDI) with ketoconazole and rifampin, as well as single-dose drug-disease interaction (DDZI) in patients with renal and hepatic impairment; 3) apply the PBPK models to predict DDI outcomes in patients with weak and moderate CYP3A inhibitors; and 4) apply the PBPK models to predict DDZI outcomes in renally and hepatically impaired patients after multiple-dose administration. Results showed that the PBPK models adequately predicted bosutinib oral exposures in patients after single- and multiple-dose administrations. The PBPK models also reasonably predicted changes in bosutinib exposures in the single-dose DDI and DDZI results, suggesting that the PBPK models were sufficiently developed and verified based on the currently available data. Finally, the PBPK models predicted 2- to 4-fold increases in bosutinib exposures by moderate CYP3A inhibitors, as well as comparable increases in bosutinib exposures in renally and hepatically impaired patients between single- and multiple-dose administrations. Given the challenges in conducting numerous DDI and DDZI studies of anticancer drugs in patients, we believe that the PBPK models verified in our study would be valuable to reasonably predict bosutinib exposures under various scenarios that have not been tested clinically. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  15. An evaluation of the potential for drug-drug interactions between bendamustine and rituximab in indolent non-Hodgkin lymphoma and mantle cell lymphoma.

    PubMed

    Darwish, Mona; Burke, John M; Hellriegel, Edward; Robertson, Philmore; Phillips, Luann; Ludwig, Elizabeth; Munteanu, Mihaela C; Bond, Mary

    2014-06-01

    Bendamustine plus rituximab has been reported to be effective in treating lymphoid malignancies. This analysis investigated the potential for drug-drug interactions between the drugs in patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma. Data were derived from a bendamustine-rituximab combination therapy study, a bendamustine monotherapy study, and published literature on rituximab monotherapy and combination therapy. Analysis of the potential for rituximab to affect bendamustine systemic exposure included comparing bendamustine concentration-time profile following monotherapy to that following combination therapy and comparing model-predicted Bayesian bendamustine clearance in the presence and absence of rituximab. Analysis of the potential for bendamustine to affect rituximab systemic exposure included plotting observed minimum, median, and maximum serum rituximab concentrations at the end of rituximab infusion (EOI) and 24 h and 7 days post-infusion in patients receiving combination therapy versus concentrations reported in literature following rituximab monotherapy. The established population pharmacokinetic model following bendamustine monotherapy was evaluated to determine its applicability to combination therapy for the purpose of confirming lack of pharmacokinetic interaction. The model adequately described the bendamustine concentration-time profile following monotherapy and combination therapy in adults. There was no statistically significant difference in estimated bendamustine clearance either alone or in combination. Also, rituximab concentrations from EOI to 24 h and 7 days demonstrated a pattern of decline similar to that seen in rituximab studies without bendamustine, suggesting that bendamustine does not affect the rituximab clearance rate. Neither bendamustine nor rituximab appears to affect systemic exposure of the other drug when coadministered.

  16. Differential drug-drug interactions of the synthetic Cannabinoids JWH-018 and JWH-073: implications for drug abuse liability and pain therapy.

    PubMed

    Brents, Lisa K; Zimmerman, Sarah M; Saffell, Amanda R; Prather, Paul L; Fantegrossi, William E

    2013-09-01

    Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for Δ(9)-tetrahydrocannabinol (Δ(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018:JWH-073) of these drugs were administered to mice in assays of Δ(9)-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the Δ(9)-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail-immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, whereas a 1:3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type cells. Interestingly, synergy occurred in the competition receptor-binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug-drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective Δ(9)-THC-like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia but not hypothermia or task disruption was potentiated. Importantly, synergy in the competition receptor-binding assay

  17. Application of permeability-limited physiologically-based pharmacokinetic models: part II - prediction of P-glycoprotein mediated drug-drug interactions with digoxin.

    PubMed

    Neuhoff, Sibylle; Yeo, Karen Rowland; Barter, Zoe; Jamei, Masoud; Turner, David B; Rostami-Hodjegan, Amin

    2013-09-01

    Digoxin is the recommended substrate for assessment of P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) in vivo. The overall aim of our study was to investigate the inhibitory potential of both verapamil and norverapamil on the P-gp-mediated efflux of digoxin in both gut and liver. Therefore, a physiologically-based pharmacokinetic (PBPK) model for verapamil and its primary metabolite was developed and validated through the recovery of observed clinical plasma concentration data for both moieties and the reported interaction with midazolam, albeit a cytochrome P450 3A4-mediated DDI. The validated inhibitor model was then used in conjunction with the model developed previously for digoxin. The range of values obtained for the 10 trials indicated that increases in area under the plasma concentration-time curve (AUC) profiles and maximum plasma concentration observed (Cmax ) values of digoxin following administration of verapamil were more comparable with in vivo observations, when P-gp inhibition by the metabolite, norverapamil, was considered as well. The predicted decrease in AUC and Cmax values of digoxin following administration of rifampicin because of P-gp induction was 1.57- (range: 1.42-1.77) and 1.62-fold (range: 1.53-1.70), which were reasonably consistent with observed values of 1.4- and 2.2-fold, respectively. This study demonstrates the application of permeability-limited models of absorption and distribution within a PBPK framework together with relevant in vitro data on transporters to assess the clinical impact of modulated P-gp-mediated efflux by drugs in development.

  18. Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.

    PubMed

    Yu, Hongbin; Balani, Suresh K; Chen, Weichao; Cui, Donghui; He, Ling; Humphreys, W Griffith; Mao, Jialin; Lai, W George; Lee, Anthony J; Lim, Heng-Keang; MacLauchlin, Christopher; Prakash, Chandra; Surapaneni, Sekhar; Tse, Susanna; Upthagrove, Alana; Walsky, Robert L; Wen, Bo; Zeng, Zhaopie

    2015-04-01

    Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R(met) strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Predictions of cytochrome P450-mediated drug-drug interactions using cryopreserved human hepatocytes: comparison of plasma and protein-free media incubation conditions.

    PubMed

    Mao, Jialin; Mohutsky, Michael A; Harrelson, John P; Wrighton, Steven A; Hall, Stephen D

    2012-04-01

    Cryopreserved human hepatocytes suspended in human plasma (HHSHP) have previously provided accurate CYP3A drug-drug interaction (DDI) predictions from a single IC(50) that captures both reversible and time-dependent inhibition. The goal of this study was to compare the accuracy of DDI predictions by a protein-free human hepatocyte system combined with the fraction unbound in plasma for inhibitor(s) with those obtained with protein-containing incubations. Seventeen CYP3A, CYP2C9, or CYP2D6 inhibitors were incubated with hepatocytes in human plasma or hepatocyte maintenance medium (HMM) for 20 min over a range of concentrations after which midazolam 1'-hydroxylation, diclofenac 4'-hydroxylation or (R)-bufuralol 1'-hydroxylation were used to quantify the corresponding cytochrome P450 (P450) catalytic activities. Two methods were used to predict the human exposure ratio of the victim drug in the presence and absence of inhibitor. The HMM K(i, app) values were combined with the free average systemic plasma concentration ("free [I] with HMM K(i, app)") and the plasma K(i, app) values were combined with the total average systemic plasma concentration ("total [I] with plasma K(i, app)"). Of 63 clinical DDI studies, the total [I] with plasma K(i, app) method predicted 89% of cases within 2-fold of the reported interaction whereas the free [I] with HMM K(i, app) method predicted only 59%. There was a general underprediction by the free [I] with HMM K(i, app) method, which is consistent with an underestimation of in vitro inhibition potency in this system. In conclusion, the HHSHP system proved to be a simple, accurate predictor of DDIs for three major P450s and superior to the protein-free approach.

  20. In Vitro Dissolution of Fluconazole and Dipyridamole in Gastrointestinal Simulator (GIS), Predicting in Vivo Dissolution and Drug-Drug Interaction Caused by Acid-Reducing Agents.

    PubMed

    Matsui, Kazuki; Tsume, Yasuhiro; Amidon, Gregory E; Amidon, Gordon L

    2015-07-06

    Weakly basic drugs typically exhibit pH-dependent solubility in the physiological pH range, displaying supersaturation or precipitation along the gastrointestinal tract. Additionally, their oral bioavailabilities may be affected by coadministration of acid-reducing agents that elevate gastric pH. The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, Gastrointestinal Simulator (GIS), in predicting in vivo dissolution of certain oral medications. In vitro dissolution studies of fluconazole, a BCS class I, and dipyridamole, a BCS class II weak bases (class IIb), were performed in the GIS as well as United States Pharmacopeia (USP) apparatus II and compared with the results of clinical drug-drug interaction (DDI) studies. In both USP apparatus II and GIS, fluconazole completely dissolved within 60 min regardless of pH, reflecting no DDI between fluconazole and acid-reducing agents in a clinical study. On the other hand, seven-fold and 15-fold higher concentrations of dipyridamole than saturation solubility were observed in the intestinal compartments in GIS with gastric pH 2.0. Precipitation of dipyridamole was also observed in the GIS, and the percentage of dipyridamole in solution was 45.2 ± 7.0%. In GIS with gastric pH 6.0, mimicking the coadministration of acid-reducing agents, the concentration of dipyridamole was equal to its saturation solubility, and the percentage of drug in solution was 9.3 ± 2.7%. These results are consistent with the clinical DDI study of dipyridamole with famotidine, which significantly reduced the Cmax and area under the curve. An In situ mouse infusion study combined with GIS revealed that high concentration of dipyridamole in the GIS enhanced oral drug absorption, which confirmed the supersaturation of dipyridamole. In conclusion, GIS was shown to be a useful apparatus to predict in vivo dissolution for BCS class IIb drugs.

  1. An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects.

    PubMed

    Patroneva, Albena; Connolly, Sandra M; Fatato, Penny; Pedersen, Ron; Jiang, Qin; Paul, Jeffrey; Guico-Pabia, Christine; Isler, Jennifer A; Burczynski, Michael E; Nichols, Alice I

    2008-12-01

    A number of antidepressants inhibit the activity of the cytochrome P450 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least-square mean ratios (coadministration versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (C(max)) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C(max) of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C(max) that was significant compared with the small increase seen with desvenlafaxine and desipramine (-24 versus 9%; P < 0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P = 0.054). Overall, desvenlafaxine had a minimal impact on the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions.

  2. How the Probability and Potential Clinical Significance of Pharmacokinetically Mediated Drug-Drug Interactions Are Assessed in Drug Development: Desvenlafaxine as an Example

    PubMed Central

    Nichols, Alice I.; Preskorn, Sheldon H.

    2015-01-01

    Objective: The avoidance of adverse drug-drug interactions (DDIs) is a high priority in terms of both the US Food and Drug Administration (FDA) and the individual prescriber. With this perspective in mind, this article illustrates the process for assessing the risk of a drug (example here being desvenlafaxine) causing or being the victim of DDIs, in accordance with FDA guidance. Data Sources/Study Selection: DDI studies for the serotonin-norepinephrine reuptake inhibitor desvenlafaxine conducted by the sponsor and published since 2009 are used as examples of the systematic way that the FDA requires drug developers to assess whether their new drug is either capable of causing clinically meaningful DDIs or being the victim of such DDIs. In total, 8 open-label studies tested the effects of steady-state treatment with desvenlafaxine (50–400 mg/d) on the pharmacokinetics of cytochrome (CYP) 2D6 and/or CYP 3A4 substrate drugs, or the effect of CYP 3A4 inhibition on desvenlafaxine pharmacokinetics. The potential for DDIs mediated by the P-glycoprotein (P-gp) transporter was assessed in in vitro studies using Caco-2 monolayers. Data Extraction: Changes in area under the plasma concentration-time curve (AUC; CYP studies) and efflux (P-gp studies) were reviewed for potential DDIs in accordance with FDA criteria. Results: Desvenlafaxine coadministration had minimal effect on CYP 2D6 and/or 3A4 substrates per FDA criteria. Changes in AUC indicated either no interaction (90% confidence intervals for the ratio of AUC geometric least-squares means [GM] within 80%–125%) or weak inhibition (AUC GM ratio 125% to < 200%). Coadministration with ketoconazole resulted in a weak interaction with desvenlafaxine (AUC GM ratio of 143%). Desvenlafaxine was not a substrate (efflux ratio < 2) or inhibitor (50% inhibitory drug concentration values > 250 μM) of P-gp. Conclusions: A 2-step process based on FDA guidance can be used first to determine whether a pharmacokinetically mediated

  3. Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction.

    PubMed

    Ripp, Sharon L; Mills, Jessica B; Fahmi, Odette A; Trevena, Kristen A; Liras, Jennifer L; Maurer, Tristan S; de Morais, Sonia M

    2006-10-01

    Cytochrome P4503A4 (CYP3A4) is the principal drug-metabolizing enzyme in human liver. Drug-drug interactions (DDIs) caused by induction of CYP3A4 can result in decreased exposure to coadministered drugs, with potential loss of efficacy. Immortalized hepatocytes (Fa2N-4 cells) have been proposed as a tool to identify CYP3A4 inducers. The purpose of the current studies was to characterize the effect of known inducers on CYP3A4 in Fa2N-4 cells, and to determine whether these in vitro data could reliably project the magnitude of DDIs caused by induction. Twenty-four compounds were chosen for these studies, based on previously published data using primary human hepatocytes. Eighteen compounds had been shown to be positive for induction, and six compounds had been shown to be negative for induction. In Fa2N-4 cells, all 18 positive controls produced greater than 2-fold maximal CYP3A4 induction, and all 6 negative controls produced less than 1.5-fold maximal CYP3A4 induction. Subsequent studies were conducted to determine the relationship between in vitro induction data and in vivo induction response. The approach was to relate in vitro induction data (E(max) and EC(50) values) with efficacious free plasma concentrations to calculate a relative induction score. This score was then correlated with decreases in area under the plasma concentration versus time curve values for coadministered CYP3A4 object drugs (midazolam or ethinylestradiol) from previously published clinical DDI studies. Excellent correlations (r(2) values >0.92) were obtained, suggesting that Fa2N-4 cells can be used for identification of inducers as well as prediction of the magnitude of clinical DDIs.

  4. VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions.

    PubMed

    Zetterberg, Craig; Maltais, Francois; Laitinen, Leena; Liao, Shengkai; Tsao, Hong; Chakilam, Ananthsrinivas; Hariparsad, Niresh

    2016-08-01

    (R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (VX-509, decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxyl-metabolite of VX-509, which is involved in clinically significant TDI-based DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident.

  5. Performance of a clinical decision support system and of clinical pharmacists in preventing drug-drug interactions on a geriatric ward.

    PubMed

    Cornu, Pieter; Steurbaut, Stephane; Soštarić, Sabina; Mrhar, Aleš; Dupont, Alain G

    2014-06-01

    Drug-drug interactions (DDIs) can lead to adverse drug events and compromise patient safety. Two common approaches to reduce these interactions in hospital practice are the use of clinical decision support systems and interventions by clinical pharmacists. To compare the performance of both approaches with the main objective of learning from one approach to improve the other. Acute geriatric ward in a university hospital. Prospective single-centre, cohort study of patients admitted to the geriatric ward. An independent pharmacist compared the clinical decision support alerts with the DDIs identified by clinical pharmacists and evaluated their interventions. Contextual factors used by the clinical pharmacists for evaluation of the clinical relevance were analysed. Adverse drug events related to DDIs were investigated and the causality was evaluated by a clinical pharmacologist based on validated criteria. Number of alerts, interventions and the acceptance rates. Fifty patients followed by the clinical pharmacists, were included. The clinical pharmacists identified 240 DDIs (median of 3.5 per patient) and advised a therapy change for 16 of which 13 (81.2 %) were accepted and three (18.8 %) were not. The decision support system generated only six alerts of which none were accepted by the physicians. Thirty-seven adverse drug events were identified for 29 patients that could be related to 55 DDIs. For two interactions the causality was evaluated as certain, for 31 as likely, for ten as possible and for 12 as unlikely. Mainly intermediate level interactions were related to adverse drug events. Contextual factors taken into account by the clinical pharmacists for evaluation of the interactions were blood pressure, international normalised ratio, heart rate, potassium level and glycemia. Additionally, the clinical pharmacists looked at individual administration intervals and drug sequence to determine the clinical relevance of the interactions. Clinical pharmacists

  6. Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers.

    PubMed

    Macha, Sreeraj; Sennewald, Regina; Rose, Peter; Schoene, Katja; Pinnetti, Sabine; Woerle, Hans J; Broedl, Uli C

    2013-03-01

    Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. The goal of this study was to investigate potential drug-drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. The potential drug-drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5. Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0-∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87-107.20; Cmax: GMR, 92.39%; 90% CI, 85.38-99.97) or ramipril (AUC over a uniform dosing interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05-100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65-111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% CI 100.51-116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73-119.64) or its active metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00-101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67-104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0-∞ (GMR, 106.11%; 90% CI, 96.71-116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33-130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation

  7. Prediction of time-dependent CYP3A4 drug-drug interactions by physiologically based pharmacokinetic modelling: impact of inactivation parameters and enzyme turnover.

    PubMed

    Rowland Yeo, K; Walsky, R L; Jamei, M; Rostami-Hodjegan, A; Tucker, G T

    2011-06-14

    Predicting the magnitude of time-dependent metabolic drug-drug (mDDIs) interactions involving cytochrome P-450 3A4 (CYP3A4) from in vitro data requires accurate knowledge of the inactivation parameters of the inhibitor (K(I), k(inact)) and of the turnover of the enzyme (k(deg)) in both the gut and the liver. We have predicted the magnitude of mDDIs observed in 29 in vivo studies involving six CYP3A4 probe substrates and five mechanism based inhibitors of CYP3A4 of variable potency (azithromycin, clarithromycin, diltiazem, erythromycin and verapamil). Inactivation parameters determined anew in a single laboratory under standardised conditions together with data from substrate and inhibitor files within the Simcyp Simulator (Version 9.3) were used to determine a value of the hepatic k(deg) (0.0193 or 0.0077h(-1)) most appropriate for the prediction of mDDIs involving time-dependent inhibition of CYP3A4. The higher value resulted in decreased bias (geometric mean fold error - 1.05 versus 1.30) and increased precision (root mean squared error - 1.29 versus 2.30) of predictions of mean ratios of AUC in the absence and presence of inhibitor. Depending on the k(deg) value used (0.0193 versus 0.0077h(-1)), predicted mean ratios of AUC were within 2-fold of the observed values for all (100%) and 27 (93%) of the 29 studies, respectively and within 1.5-fold for 24 (83%) and 17 (59%) of the 29 studies, respectively. Comprehensive PBPK models were applied for accurate assessment of the potential for mDDIs involving time-dependent inhibition of CYP3A4 using a hepatic k(deg) value of 0.0193h(-1) in conjunction with inactivation parameters determined by the conventional experimental approach.

  8. Time-dependent inhibition and estimation of CYP3A clinical pharmacokinetic drug-drug interactions using plated human cell systems.

    PubMed

    Albaugh, Daniel R; Fullenwider, Cody L; Fisher, Michael B; Hutzler, J Matthew

    2012-07-01

    The current studies assessed the utility of freshly plated hepatocytes, cryopreserved plated hepatocytes, and cryopreserved plated HepaRG cells for the estimation of inactivation parameters k(inact) and K(I) for CYP3A. This was achieved using a subset of CYP3A time-dependent inhibitors (fluoxetine, verapamil, clarithromycin, troleandomycin, and mibefradil) representing a range of potencies. The estimated k(inact) and K(I) values for each time-dependent inhibitor were compared with those obtained using human liver microsomes and used to estimate the magnitude of clinical pharmacokinetic drug-drug interaction (DDI). The inactivation kinetic parameter, k(inact), was most consistent across systems tested for clarithromycin, verapamil, and troleandomycin, with a high k(inact) of 0.91 min(-1) observed for mibefradil in HepaRG cells. The apparent K(I) estimates derived from the various systems displayed a range of variability from 3-fold for clarithromycin (5.4-17.7 μM) to 6-fold for verapamil (1.9-12.6 μM). In general, the inactivation kinetic parameters derived from the cell systems tested fairly replicated what was observed in time-dependent inhibition studies using human liver microsomes. Despite some of the observed differences in inactivation kinetic parameters, the estimated DDIs derived from each of the tested systems generally agreed with the clinically reported DDI within approximately 2-fold. In addition, a plated cell approach offered the ability to conduct longer primary incubations (greater than 30 min), which afforded improved ability to identify the weak time-dependent inhibitor fluoxetine. Overall, results from these studies suggest that in vitro inactivation parameters generated from plated cell systems may be a practical approach for identifying time-dependent inhibitors and for estimating the magnitude of clinical DDIs.

  9. Severe hypokalemia due to a possible drug-drug interaction between vinblastine and antiretrovirals in a HIV-infected patient with Hodgkin's lymphoma.

    PubMed

    Cordova, Ezequiel; Morganti, Laura; Odzak, Andrea; Arcondo, Florencia; Silva, Mariana; Zylberman, Marcelo; Rodriguez, Claudia

    2017-01-01

    A 60-year-old HIV-1 infected woman on antiretroviral therapy (emtricitabine/tenofovir, and ritonavir-boosted atazanavir) developed Hodgkin's lymphoma. The patient initiated ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy and presented with neutropenia and severe hypokalemia. Hypokalemia was considered as part of a proximal tubular renal dysfunction, and other causes of hypokalemia were excluded. Due to suspicion of drug--drug interactions between antiretrovirals and vinblastine, ritonavir-boosted atazanavir was switched to dolutegravir and the patient continued emtricitabine/tenofovir. In the subsequent ABVD cycles, no neutropenia or hypokalemia were observed. Vinblastine is metabolized by the hepatic P450 cytochrome isoenzyme CYP3A4, therefore, concomitant administration with protease inhibitors may increase plasma levels of vinblastine. Vinblastine is also a substrate and inhibitor of multidrug resistance-associated protein 2 (MRP2) transporter in the proximal renal tubule. Inhibition of this renal transporter could increase tenofovir renal toxicity. Our hypothesis is that the hypokalemia could be a result of a tenofovir-mediated tubular damage triggered by the increased vinblastine serum levels secondary to a CYP3A4 inhibition by ritonavir. To the best of our knowledge, this is the first report of severe hypokalemia and proximal tubular renal dysfunction as a result of a possible drug-drug interaction between vinblastine, tenofovir and ritonavir-boosted atazanavir.

  10. Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection

    PubMed Central

    Seden, Kay; Gibbons, Sara; Marzolini, Catia; Schapiro, Jonathan M.; Burger, David M.; Back, David J.; Khoo, Saye H.

    2017-01-01

    Background In all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria. Methods and findings This was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs. Conclusions There is significant potential for DDIs between antiretrovirals and antimalarials. The application of

  11. Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection.

    PubMed

    Seden, Kay; Gibbons, Sara; Marzolini, Catia; Schapiro, Jonathan M; Burger, David M; Back, David J; Khoo, Saye H

    2017-01-01

    In all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria. This was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs. There is significant potential for DDIs between antiretrovirals and antimalarials. The application of quality of evidence and strength of

  12. Evaluation of CYP2B6 Induction and Prediction of Clinical Drug-Drug Interactions: Considerations from the IQ Consortium Induction Working Group-An Industry Perspective.

    PubMed

    Fahmi, Odette A; Shebley, Mohamad; Palamanda, Jairam; Sinz, Michael W; Ramsden, Diane; Einolf, Heidi J; Chen, Liangfu; Wang, Hongbing

    2016-10-01

    Drug-drug interactions (DDIs) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by regulatory agencies. This work aimed to evaluate the potency of CYP2B6 versus CYP3A4 induction in vitro and from clinical studies and to assess the predictability of efavirenz versus bupropion as clinical probe substrates of CYP2B6 induction. The analysis indicates that the magnitude of CYP3A4 induction was higher than CYP2B6 both in vitro and in vivo. The magnitude of DDIs caused by induction could not be predicted for bupropion with static or dynamic models. On the other hand, the relative induction score, net effect, and physiologically based pharmacokinetics SimCYP models using efavirenz resulted in improved DDI predictions. Although bupropion and efavirenz have been used and are recommended by regulatory agencies as clinical CYP2B6 probe substrates for DDI studies, CYP3A4 contributes to the metabolism of both probes and is induced by all reference CYP2B6 inducers. Therefore, caution must be taken when interpreting clinical induction results because of the lack of selectivity of these probes. Although in vitro-in vivo extrapolation for efavirenz performed better than bupropion, interpretation of the clinical change in exposure is confounded by the coinduction of CYP2B6 and CYP3A4, as well as the increased contribution of CYP3A4 to efavirenz metabolism under induced conditions. Current methods and probe substrates preclude accurate prediction of CYP2B6 induction. Identification of a sensitive and selective clinical substrate for CYP2B6 (fraction metabolized > 0.9) is needed to improve in vitro-in vivo extrapolation for characterizing the potential for CYP2B6-mediated DDIs. Alternative strategies and a framework for evaluating the CYP2B6 induction risk are proposed.

  13. In vitro selective inhibition of human UDP-glucuronosyltransferase (UGT) 1A4 by finasteride, and prediction of in vivo drug-drug interactions.

    PubMed

    Lee, Seung Jun; Park, Jung Bae; Kim, Doyun; Bae, Soo Hyeon; Chin, Young-Won; Oh, Euichaul; Bae, Soo Kyung

    2015-01-22

    In the present study, we evaluated the inhibitory potentials of finasteride for the major human hepatic UDP-glucuronosyltransferases (UGTs) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15) in vitro using LC-MS/MS by specific marker reactions in human liver microsomes (except for UGT2B15) or recombinant supersomes (UGT2B15). Of the seven tested UGTs, finasteride potently, selectively, and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation in human liver microsomes with an IC₅₀ value of 11.5 ± 1.78 μM and Ki value of 6.03 ± 0.291 μM. This inhibitory potency was similar to that of hecogenin, a well-known inhibitor of UGT1A4. However, finasteride did not seem to inhibit any of the other six UGTs: UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, or UGT2B15. Similarly, finasteride markedly inhibited UGT1A4 activity in recombinant human UGT1A4 supersomes, with a Ki value of 6.05 ± 0.410 μM. In addition, finasteride strongly inhibited UGT1A4-catalyzed imipramine-N-β-D-glucuronidation. However, on the basis of an in vitro-in vivo extrapolation, our data strongly suggested that finasteride is unlikely to cause clinically significant drug-drug interactions mediated via inhibition of the hepatic UGT enzymes involved in drug metabolism in vivo.

  14. Metabolite Identification, Reaction Phenotyping and Retrospective Drug-Drug Interaction Predictions of 17-deacetylnorgestimate, the Active Component of the Oral Contraceptive Norgestimate.

    PubMed

    Ahire, Deepak; Sinha, Sarmistha; Brock, Barry; Iyer, Ramaswamy; Mandlekar, Sandhya; Subramanian, Murali

    2017-03-10

    Ortho-Tri-Cyclen® (OTC), a two drug cocktail comprising of ethinylestradiol (EE) and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17α-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported. Hence, detailed biotransformation and reaction phenotyping studies of NGMN with recombinant cytochrome P450s (rCYPs), recombinant uridine 5'-diphospho-glucuronosyltransferases (rUGTs) and human liver microsomes (HLM) in the presence and absence of selective cytochrome P450 (CYP) inhibitors were conducted. It was found that cytochrome P450 3A4 (CYP3A4) plays a key role in NGNM metabolism with a fraction metabolized (fm) of 0.57. CYP2B6 and to an even lesser extent CYP2C9 were also observed to catalyze NGMN metabolism. Using this CYP3A4 fm, the predicted area under the plasma concentration vs. time curve (AUC) change in NGMN using a basic/mechanistic static model was found to be within 1.3-fold of reported NGMN AUC changes for four modulators of CYP3A4. In addition to NGMN, we have also elucidated the biotransformation of norgestrel (NG), a downstream norgestimate and NGMN metabolite, and found that CYP3A4 and UGT1A1 have a major contribution to the elimination of NG with a combined fm of 1. The data presented in this manuscript will lead to a better understanding and management of NGMN based drug-drug interactions (DDIs) when norgestimate is co-administered with CYP3A4 modulators.

  15. Drug-drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus.

    PubMed

    Scheen, André J

    2014-04-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. They are proposed as a novel approach for the management of type 2 diabetes mellitus. They have proven their efficacy in reducing glycated haemoglobin, without inducing hypoglycaemia, as monotherapy or in combination with various other glucose-lowering agents, with the add-on value of promoting some weight loss and lowering arterial blood pressure. As they may be used concomitantly with many other drugs, we review the potential drug-drug interactions (DDIs) regarding the three leaders in the class (dapagliglozin, canagliflozin and empagliflozin). Most of the available studies were performed in healthy volunteers and have assessed the pharmacokinetic interferences with a single administration of the SGLT2 inhibitor. The exposure [assessed by peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC)] to each SGLT2 inhibitor tested was not significantly influenced by the concomitant administration of other glucose-lowering agents or cardiovascular agents commonly used in patients with type 2 diabetes. Reciprocally, these medications did not influence the pharmacokinetic parameters of dapagliflozin, canagliflozin or empagliflozin. Some modest changes were not considered as clinically relevant. However, drugs that could specifically interfere with the metabolic pathways of SGLT2 inhibitors [rifampicin, inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)] may result in significant changes in the exposure of SGLT2 inhibitors, as shown for dapagliflozin and canagliflozin. Potential DDIs in patients with type 2 diabetes receiving chronic treatment with an SGLT2 inhibitor deserve further attention, especially in individuals treated with several medications or in more fragile patients with hepatic and/or renal impairment.

  16. A Physiologically-Based Pharmacokinetic Modeling Approach To Predict Drug-Drug Interactions of Sonidegib (LDE225) with Perpetrators of CYP3A in Cancer Patients.

    PubMed

    Einolf, Heidi J; Zhou, Jocelyn; Won, Christina; Wang, Lai; Rebello, Sam

    2017-04-01

    Sonidegib (Odomzo) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro. The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. These data were used to verify a physiologically-based pharmacokinetic (PBPK) model developed to 1) bridge the clinical drug-drug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady state and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients. Treatment of healthy subjects with KTZ resulted in an increased sonidegib exposure of 2.25- and 1.49-fold (area under the curve0-240h and maximal concentration respectively), and RIF decreased exposure by 72% and 54%, respectively. The model simulated the single- and/or multiple-dose PK of sonidegib (healthy subjects and patients) within ∼50% of observed values. The effect of KTZ and RIF on sonidegib in healthy subjects was also simulated well, and the predicted DDI in patients was slightly less and independent of sonidegib dose. At steady state, sonidegib was predicted to have a higher DDI magnitude with strong or moderate CYP3A perpetrators compared with a single dose. Different dosing regimens of sondigeb with the perpetrators were also simulated and provided guidance to the current dosing recommendations incorporated in the product label.

  17. Potential pharmacodynamic drug-drug interaction between concomitantly administered lisinopril and diclofenac sodium: a call for appropriate management in hypertensive osteoarthritic patients.

    PubMed

    Goswami, Sailendra Kumar; Jain, Sunita; Chudasama, Hiren; Santani, Devdas

    2011-01-01

    The present study was designed as an open label, multiple-dose, randomized, parallel trial to evaluate the pharmacodynamic drug-drug interaction of lisinopril and concomitantly administered diclofenac sodium in non-diabetic and diabetic, mild to moderate hypertensive, osteoarthritic patients. Post-screening and on inclusion, patients were put on a 2-week washout period and then randomly assigned to either only lisinopril 10 mg or combination of lisinopril 10 mg and diclofenac sodium 100 mg treatments for 8-12 weeks in diseased states of hypertension and osteoarthritis with or without type 2 diabetes mellitus. The blood pressure (BP) control with lisinopril was reduced by concomitantly administered diclofenac sodium in non-diabetic (SBP: p=0.00002; DBP: p=0.000008) and diabetic (SBP: p=0.002; DBP: p=0.001) patients when compared with the patients receiving lisinopril alone. Insulin sensitivity was improved (p=0.00002) and urinary albumin excretion rate was better controlled (p=0.0096) in lisinopril-treated patients when compared with the combination treatment in diabetic pool. Serum creatinine levels increased significantly in non-diabetic patients (p=0.00004) receiving combination treatment. In addition, creatinine clearance (CLCR) and blood urea nitrogen (BUN) were significantly higher in diabetic (CLCR: p<0.00001; BUN: p=0.0098) as well as in non-diabetic (CLCR: p<0.00001; BUN: p=0.03) patients treated with combination treatment. The alterations in serum electrolytes, reduction in % platelet aggregation activity and improvement in lipid profile was more profound with combination treatment in comparison to lisinopril alone. The antihypertensive efficacy and insulin sensitivity improving property of lisinopril along with the renal function might get worse in hypertensive osteoarthritic patients receiving concomitant treatment of oral diclofenac sodium with lisinopril. In addition to this, close monitoring of serum electrolytes is also suggested to rule out any long

  18. Screening approach for identifying candidate drugs and drug-drug interactions related to hip fracture risk in persons with Alzheimer disease.

    PubMed

    Tolppanen, Anna-Maija; Taipale, Heidi; Koponen, Marjaana; Tanskanen, Antti; Lavikainen, Piia; Paananen, Jussi; Tiihonen, Jari; Hartikainen, Sirpa

    2017-08-01

    To assess whether a "drugome-wide" screen with case-crossover design is a feasible approach for identifying candidate drugs and drug-drug interactions. All community-dwelling residents of Finland who received a clinically verified Alzheimer disease diagnosis in 2005 to 2011 and experienced incident hip fracture (HF) afterwards (N = 4851). Three scenarios were used to test the sensitivity of this approach (1) hazard period 0 to 30 and control period 31 to 61 days before HF, (2) hazard period 0 to 30 and control period 336 to 366 days before HF, and (3) hazard period 0 to 14 and control period 16 to 30 days before HF. Nine, 44, and 5 drugs were associated with increased HF risk and 8, 23, and 4 with decreased risk in scenarios 1, 2, and 3, respectively. Six drugs were identified with scenario 1 only and 54 and 1 with scenarios 2 and 3, respectively. Only six drugs (metoprolol, simvastatin, trimethoprim, codeine combinations, fentanyl, and paracetamol) were associated with HF in all scenarios, four with 1 and 2 (cefalexin, buprenorphine, olanzapine, and memantine), and one with 1 and 3 (enalapril) or 2 and 3 (ciprofloxacin). The direction of associations was the same in all/both scenarios. The interaction results were equally versatile, with hydroxocobalamin*oxazepam being the only interaction observed in all scenarios. Case-crossover analysis is a potential approach for identifying candidate drugs and drug-drug interactions associated with adverse events as it implicitly controls for fixed confounders. The results are highly dependent on applied hazard and control periods, but the choice of periods can help in targeting the analyses to different phases of drug use. Copyright © 2017 John Wiley & Sons, Ltd.

  19. A Prediction Method for P-glycoprotein-Mediated Drug-Drug Interactions at the Human Blood-Brain Barrier From Blood Concentration-Time Profiles, Validated With PET Data.

    PubMed

    Matsuda, Akihiro; Karch, Rudolf; Bauer, Martin; Traxl, Alexander; Zeitlinger, Markus; Langer, Oliver

    2017-09-01

    The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration-time profiles and P-glycoprotein (Pgp)-mediated brain drug-drug interactions between the model Pgp substrate (R)-[(11)C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [(11)C]tariquidar (TQD), and the Pgp inhibitor tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration-time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration-time profiles and rank the magnitude of the Pgp-mediated brain drug-drug interaction potential for both Pgp and Pgp/BCRP substrates in humans. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  20. A combined model for predicting CYP3A4 clinical net drug-drug interaction based on CYP3A4 inhibition, inactivation, and induction determined in vitro.

    PubMed

    Fahmi, Odette A; Maurer, Tristan S; Kish, Mary; Cardenas, Edwin; Boldt, Sherri; Nettleton, David

    2008-08-01

    Although approaches to the prediction of drug-drug interactions (DDIs) arising via time-dependent inactivation have recently been developed, such approaches do not account for simple competitive inhibition or induction. Accordingly, these approaches do not provide accurate predictions of DDIs arising from simple competitive inhibition (e.g., ketoconazole) or induction of cytochromes P450 (e.g., phenytoin). In addition, methods that focus upon a single interaction mechanism are likely to yield misleading predictions in the face of mixed mechanisms (e.g., ritonavir). As such, we have developed a more comprehensive mathematical model that accounts for the simultaneous influences of competitive inhibition, time-dependent inactivation, and induction of CYP3A in both the liver and intestine to provide a net drug-drug interaction prediction in terms of area under the concentration-time curve ratio. This model provides a framework by which readily obtained in vitro values for competitive inhibition, time-dependent inactivation and induction for the precipitant compound as well as literature values for f(m) and F(G) for the object drug can be used to provide quantitative predictions of DDIs. Using this model, DDIs arising via inactivation (e.g., erythromycin) continue to be well predicted, whereas those arising via competitive inhibition (e.g., ketoconazole), induction (e.g., phenytoin), and mixed mechanisms (e.g., ritonavir) are also predicted within the ranges reported in the clinic. This comprehensive model quantitatively predicts clinical observations with reasonable accuracy and can be a valuable tool to evaluate candidate drugs and rationalize clinical DDIs.

  1. Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition.

    PubMed

    Lai, Yurong; Mandlekar, Sandhya; Shen, Hong; Holenarsipur, Vinay K; Langish, Robert; Rajanna, Prabhakar; Murugesan, Senthilkumar; Gaud, Nilesh; Selvam, Sabariya; Date, Onkar; Cheng, Yaofeng; Shipkova, Petia; Dai, Jun; Humphreys, William G; Marathe, Punit

    2016-09-01

    In the present study, an open-label, three-treatment, three-period clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 ± 0.21 and 0.15 ± 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (Cmax) of CP-I and CP-III by 5.7- and 5.4-fold (RIF) or 5.7- and 6.5-fold (RIF+RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC0-24h) of CP-I and CP-III with RIF and RSV increased by 4.0- and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, Cmax and AUC0-24h of RSV increased by 13.2- and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies.

  2. Optimization of drug-drug interaction alert rules in a pediatric hospital's electronic health record system using a visual analytics dashboard.

    PubMed

    Simpao, Allan F; Ahumada, Luis M; Desai, Bimal R; Bonafide, Christopher P; Gálvez, Jorge A; Rehman, Mohamed A; Jawad, Abbas F; Palma, Krisha L; Shelov, Eric D

    2015-03-01

    To develop and evaluate an electronic dashboard of hospital-wide electronic health record medication alerts for an alert fatigue reduction quality improvement project. We used visual analytics software to develop the dashboard. We collaborated with the hospital-wide Clinical Decision Support committee to perform three interventions successively deactivating clinically irrelevant drug-drug interaction (DDI) alert rules. We analyzed the impact of the interventions on care providers' and pharmacists' alert and override rates using an interrupted time series framework with piecewise regression. We evaluated 2 391 880 medication alerts between January 31, 2011 and January 26, 2014. For pharmacists, the median alert rate prior to the first DDI deactivation was 58.74 alerts/100 orders (IQR 54.98-60.48) and 25.11 alerts/100 orders (IQR 23.45-26.57) following the three interventions (p<0.001). For providers, baseline median alert rate prior to the first round of DDI deactivation was 19.73 alerts/100 orders (IQR 18.66-20.24) and 15.11 alerts/100 orders (IQR 14.44-15.49) following the three interventions (p<0.001). In a subgroup analysis, we observed a decrease in pharmacists' override rates for DDI alerts that were not modified in the system from a median of 93.06 overrides/100 alerts (IQR 91.96-94.33) to 85.68 overrides/100 alerts (IQR 84.29-87.15, p<0.001). The medication serious safety event rate decreased during the study period, and there were no serious safety events reported in association with the deactivated alert rules. An alert dashboard facilitated safe rapid-cycle reductions in alert burden that were temporally associated with lower pharmacist override rates in a subgroup of DDIs not directly affected by the interventions; meanwhile, the pharmacists' frequency of selecting the 'cancel' option increased. We hypothesize that reducing the alert burden enabled pharmacists to devote more attention to clinically relevant alerts. © The Author 2014. Published by

  3. An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome.

    PubMed

    Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Mathy, Francois-Xavier; Braun, Marina

    2015-04-01

    This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D₃/D₂/D₁ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile

  4. In vitro metabolism and drug-drug interaction potential of UTL-5g, a novel chemo- and radioprotective agent.

    PubMed

    Wu, Jianmei; Shaw, Jiajiu; Dubaisi, Sarah; Valeriote, Frederick; Li, Jing

    2014-12-01

    N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g), a potential chemo- and radioprotective agent, acts as a prodrug requiring bioactivation to the active metabolite 5-methylisoxazole-3-carboxylic acid (ISOX). UTL-5g hydrolysis to ISOX and 2,4-dichloroaniline (DCA) has been identified in porcine and rabbit liver esterases. The purpose of this study was to provide insights on the metabolism and drug interaction potential of UTL-5g in humans. The kinetics of UTL-5g hydrolysis was determined in human liver microsomes (HLM) and recombinant human carboxylesterases (hCE1b and hCE2). The potential of UTL-5g and its metabolites for competitive inhibition and time-dependent inhibition of microsomal cytochrome P450 (P450) was examined in HLM. UTL-5g hydrolysis to ISOX and DCA in HLM were NADPH-independent, with a maximum rate of reaction (Vmax) of 11.1 nmol/min per mg and substrate affinity (Km) of 41.6 µM. Both hCE1b and hCE2 effectively catalyzed UTL-5g hydrolysis, but hCE2 exhibited ∼30-fold higher catalytic efficiency (Vmax/Km) than hCE1b. UTL-5g and DCA competitively inhibited microsomal CYP1A2, CYP2B6, and CYP2C19 (IC50 values <50 µM), and exhibited time-dependent inhibition of microsomal CYP1A2 with the inactivation efficiency (kinact/KI) of 0.68 and 0.51 minute(-1)·mM(-1), respectively. ISOX did not inhibit or inactivate any tested microsomal P450. In conclusion, hCE1b and hCE2 play a key role in the bioactivation of UTL-5g. Factors influencing carboxylesterase activities may have a significant impact on the pharmacological and therapeutic effects of UTL-5g. UTL-5g has the potential to inhibit P450-mediated metabolism through competitive inhibition or time-dependent inhibition. Caution is particularly needed for potential drug interactions involving competitive inhibition or time-dependent inhibition of CYP1A2 in the future clinical development of UTL-5g. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  5. In Vitro Metabolism and Drug-Drug Interaction Potential of UTL-5g, a Novel Chemo- and Radioprotective Agent

    PubMed Central

    Wu, Jianmei; Shaw, Jiajiu; Dubaisi, Sarah; Valeriote, Frederick

    2014-01-01

    N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g), a potential chemo- and radioprotective agent, acts as a prodrug requiring bioactivation to the active metabolite 5-methylisoxazole-3-carboxylic acid (ISOX). UTL-5g hydrolysis to ISOX and 2,4-dichloroaniline (DCA) has been identified in porcine and rabbit liver esterases. The purpose of this study was to provide insights on the metabolism and drug interaction potential of UTL-5g in humans. The kinetics of UTL-5g hydrolysis was determined in human liver microsomes (HLM) and recombinant human carboxylesterases (hCE1b and hCE2). The potential of UTL-5g and its metabolites for competitive inhibition and time-dependent inhibition of microsomal cytochrome P450 (P450) was examined in HLM. UTL-5g hydrolysis to ISOX and DCA in HLM were NADPH-independent, with a maximum rate of reaction (Vmax) of 11.1 nmol/min per mg and substrate affinity (Km) of 41.6 µM. Both hCE1b and hCE2 effectively catalyzed UTL-5g hydrolysis, but hCE2 exhibited ∼30-fold higher catalytic efficiency (Vmax/Km) than hCE1b. UTL-5g and DCA competitively inhibited microsomal CYP1A2, CYP2B6, and CYP2C19 (IC50 values <50 µM), and exhibited time-dependent inhibition of microsomal CYP1A2 with the inactivation efficiency (kinact/KI) of 0.68 and 0.51 minute−1·mM−1, respectively. ISOX did not inhibit or inactivate any tested microsomal P450. In conclusion, hCE1b and hCE2 play a key role in the bioactivation of UTL-5g. Factors influencing carboxylesterase activities may have a significant impact on the pharmacological and therapeutic effects of UTL-5g. UTL-5g has the potential to inhibit P450-mediated metabolism through competitive inhibition or time-dependent inhibition. Caution is particularly needed for potential drug interactions involving competitive inhibition or time-dependent inhibition of CYP1A2 in the future clinical development of UTL-5g. PMID:25249693

  6. Drug-drug Interaction between Losartan and Paclitaxel in Human Liver Microsomes with Different CYP2C8 Genotypes.

    PubMed

    Mukai, Yuji; Senda, Asuna; Toda, Takaki; Hayakawa, Toru; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

    2015-06-01

    The cytochrome P450 (CYP) 2C8*3 allele is associated with reduced metabolic activity of paclitaxel. This study was aimed to investigate the inhibitory effect of losartan on paclitaxel metabolism in human liver microsomes (HLMs) and to determine the impact of the CYP2C8*3 polymorphism. HLMs that contained the CYP2C8*1 homozygote (HL60) or CYP2C8*3 heterozygote (HL54) genotype were used for the inhibition study. Losartan, at a concentration of 50 μmol/L, significantly inhibited paclitaxel metabolism by 29% and 57% in the HL60 (p < 0.001) and HL54 (p < 0.01), respectively. When using HL60, losartan and the CYP3A4-selective inhibitors, erythromycin and ketoconazole, caused a greater inhibition of the paclitaxel metabolism than quercetin, a CYP2C8-selective inhibitor. This demonstrated that the paclitaxel metabolism was mainly catalysed by CYP3A4 in HL60. There were no significant differences found for the inhibitory effects caused by the four inhibitors of the paclitaxel metabolism in HL54, indicating that both CYP2C8 and CYP3A4 play important roles in paclitaxel metabolism in HL54. These findings suggest that 50 μmol/L of losartan inhibits both CYP2C8 and CYP3A4 in HLMs. In summary, losartan inhibited paclitaxel metabolism, with concentrations over 50 μmol/L in HLMs. The CYP2C8*3 allele carriers are likely susceptible to the interactions of losartan and CYP3A4 inhibitors to paclitaxel metabolism.

  7. An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug-drug and drug-herb interaction by LC-ESI/MS/MS.

    PubMed

    Borkar, Roshan M; Bhandi, Murali Mohan; Dubey, Ajay P; Ganga Reddy, V; Komirishetty, Prashanth; Nandekar, Prajwal P; Sangamwar, Abhay T; Kamal, Ahmed; Banerjee, Sanjay K; Srinivas, R

    2016-10-01

    The aim of the present study was to evaluate the contribution of metabolites to drug-drug interaction and drug-herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α-hydroxy metoprolol (HM), O-desmethyl metoprolol (ODM) and N-desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration-time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4-catalyzed midazolam metabolism and CYP2D6-catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd.

  8. Metabolic drug-drug interaction potential of macrolactin A and 7-O-succinyl macrolactin A assessed by evaluating cytochrome P450 inhibition and induction and UDP-glucuronosyltransferase inhibition in vitro.

    PubMed

    Bae, Soo Hyeon; Kwon, Min Jo; Park, Jung Bae; Kim, Doyun; Kim, Dong-Hee; Kang, Jae-Seon; Kim, Chun-Gyu; Oh, Euichaul; Bae, Soo Kyung

    2014-09-01

    Macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. MA and SMA are currently being evaluated as antitumor agents in preclinical studies in Korea. We evaluated the potential of MA and SMA for the inhibition or induction of human liver cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs) in vitro to assess their safety as new molecular entities. We demonstrated that MA and SMA are potent competitive inhibitors of CYP2C9, with Ki values of 4.06 μM and 10.6 μM, respectively. MA and SMA also weakly inhibited UGT1A1 activity, with Ki values of 40.1 μM and 65.3 μM, respectively. However, these macrolactins showed no time-dependent inactivation of the nine CYPs studied. In addition, MA and SMA did not induce CYP1A2, CYP2B6, or CYP3A4/5. On the basis of an in vitro-in vivo extrapolation, our data strongly suggested that MA and SMA are unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most of the CYPs involved in drug metabolism in vivo, except for the inhibition of CYP2C9 by MA. Similarly, MA and SMA are unlikely to inhibit the activity of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzymes in vivo. Although further investigations will be required to clarify the in vivo interactions of MA with CYP2C9-targeted drugs, our findings offer a clearer understanding and prediction of drug-drug interactions for the safe use of MA and SMA in clinical practice.

  9. Metabolic Drug-Drug Interaction Potential of Macrolactin A and 7-O-Succinyl Macrolactin A Assessed by Evaluating Cytochrome P450 Inhibition and Induction and UDP-Glucuronosyltransferase Inhibition In Vitro

    PubMed Central

    Bae, Soo Hyeon; Kwon, Min Jo; Park, Jung Bae; Kim, Doyun; Kim, Dong-Hee; Kang, Jae-Seon; Kim, Chun-Gyu; Oh, Euichaul

    2014-01-01

    Macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. MA and SMA are currently being evaluated as antitumor agents in preclinical studies in Korea. We evaluated the potential of MA and SMA for the inhibition or induction of human liver cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs) in vitro to assess their safety as new molecular entities. We demonstrated that MA and SMA are potent competitive inhibitors of CYP2C9, with Ki values of 4.06 μM and 10.6 μM, respectively. MA and SMA also weakly inhibited UGT1A1 activity, with Ki values of 40.1 μM and 65.3 μM, respectively. However, these macrolactins showed no time-dependent inactivation of the nine CYPs studied. In addition, MA and SMA did not induce CYP1A2, CYP2B6, or CYP3A4/5. On the basis of an in vitro-in vivo extrapolation, our data strongly suggested that MA and SMA are unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most of the CYPs involved in drug metabolism in vivo, except for the inhibition of CYP2C9 by MA. Similarly, MA and SMA are unlikely to inhibit the activity of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzymes in vivo. Although further investigations will be required to clarify the in vivo interactions of MA with CYP2C9-targeted drugs, our findings offer a clearer understanding and prediction of drug-drug interactions for the safe use of MA and SMA in clinical practice. PMID:24890600

  10. [Predictive factors of clinically significant drug-drug interactions among regimens based on protease inhibitors, non-nucleoside reverse transcriptase inhibitors and raltegravir].

    PubMed

    Cervero, Miguel; Torres, Rafael; Jusdado, Juan José; Pastor, Susana; Agud, Jose Luis

    2016-04-15

    To determine the prevalence and types of clinically significant drug-drug interactions (CSDI) in the drug regimens of HIV-infected patients receiving antiretroviral treatment. retrospective review of database. Centre: Hospital Universitario Severo Ochoa, Infectious Unit. one hundred and forty-two participants followed by one of the authors were selected from January 1985 to December 2014. from their outpatient medical records we reviewed information from the last available visit of the participants, in relation to HIV infection, comorbidities, demographics and the drugs that they were receiving; both antiretroviral drugs and drugs not related to HIV infection. We defined CSDI from the information sheet and/or database on antiretroviral drug interactions of the University of Liverpool (http://www.hiv-druginteractions.org) and we developed a diagnostic tool to predict the possibility of CSDI. By multivariate logistic regression analysis and by estimating the diagnostic performance curve obtained, we identified a quick tool to predict the existence of drug interactions. Of 142 patients, 39 (29.11%) had some type of CSDI and in 11.2% 2 or more interactions were detected. In only one patient the combination of drugs was contraindicated (this patient was receiving darunavir/r and quetiapine). In multivariate analyses, predictors of CSDI were regimen type (PI or NNRTI) and the use of 3 or more non-antiretroviral drugs (AUC 0.886, 95% CI 0.828 to 0.944; P=.0001). The risk was 18.55 times in those receiving NNRTI and 27,95 times in those receiving IP compared to those taking raltegravir. Drug interactions, including those defined as clinically significant, are common in HIV-infected patients treated with antiretroviral drugs, and the risk is greater in IP-based regimens. Raltegravir-based prescribing, especially in patients who receive at least 3 non-HIV drugs could avoid interactions. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  11. Drug disposition and drug-drug interaction data in 2013 FDA new drug applications: a systematic review.

    PubMed

    Yu, Jingjing; Ritchie, Tasha K; Mulgaonkar, Aditi; Ragueneau-Majlessi, Isabelle

    2014-12-01

    The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in 2013, using the University of Washington Drug Interaction Database, and to highlight significant findings. Among 27 NMEs approved, 22 (81%) were well characterized with regard to drug metabolism, transport, or organ impairment, in accordance with the FDA drug interaction guidance (2012) and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. However, in vivo, only half (n = 11) showed clinically relevant drug interactions, with most related to the NMEs as victim drugs and CYP3A being the most affected enzyme. As perpetrators, the overall effects for NMEs were much less pronounced, compared with when they served as victims. In addition, the pharmacokinetic evaluation in patients with hepatic or renal impairment provided useful information for further understanding of the drugs' disposition.

  12. Strategy for the Prediction of Steady-State Exposure of Digoxin to Determine Drug-Drug Interaction Potential of Digoxin With Other Drugs in Digitalization Therapy.

    PubMed

    Srinivas, Nuggehally R

    2016-01-20

    Digoxin, a narrow therapeutic index drug, is widely used in congestive heart failure. However, the digitalization therapy involves dose titration and can exhibit drug-drug interaction. Ctrough versus area under the plasma concentration versus time curve in a dosing interval of 24 hours (AUC0-24h) and Cmax versus AUC0-24h for digoxin were established by linear regression. The predictions of digoxin AUC0-24h values were performed using published Ctrough or Cmax with appropriate regression lines. The fold difference, defined as the quotient of the observed/predicted AUC0-24h values, was evaluated. The mean square error and root mean square error, correlation coefficient (r), and goodness of the fold prediction were used to evaluate the models. Both Ctrough versus AUC0-24h (r = 0.9215) and Cmax versus AUC0-24h models for digoxin (r = 0.7781) showed strong correlations. Approximately 93.8% of the predicted digoxin AUC0-24h values were within 0.76-fold to 1.25-fold difference for Ctrough model. In sharp contrast, the Cmax model showed larger variability with only 51.6% of AUC0-24h predictions within 0.76-1.25-fold difference. The r value for observed versus predicted AUC0-24h for Ctrough (r = 0.9551; n = 177; P < 0.001) was superior to the Cmax (r = 0.6134; n = 275; P < 0.001) model. The mean square error and root mean square error (%) for the Ctrough model were 11.95% and 16.2% as compared to 67.17% and 42.3% obtained for the Cmax model. Simple linear regression models for Ctrough/Cmax versus AUC0-24h were derived for digoxin. On the basis of statistical evaluation, Ctrough was superior to Cmax model for the prediction of digoxin AUC0-24h and can be potentially used in a prospective setting for predicting drug-drug interaction or lack of it.

  13. Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions.

    PubMed

    Rietjens, Saskia J; Hondebrink, Laura; Westerink, Remco H S; Meulenbelt, Jan

    2012-11-01

    Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA-induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user's genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT(2A) or α-β adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients.

  14. In vitro assessment of the roles of drug transporters in the disposition and drug-drug interaction potential of olaparib.

    PubMed

    McCormick, Alex; Swaisland, Helen

    2017-10-01

    1. In vitro assessments were conducted to examine interactions between olaparib (a potent oral inhibitor of poly[ADP-ribose] polymerase) and drug transporters. 2. Olaparib showed inhibition of the hepatic drug uptake transporters OATP1B1 (IC50 values of 20.3 μM and 27.1 μM) and OCT1 (IC50 37.9 μM), but limited inhibition of OATP1B3 (25% at 100 μM); inhibition of the renal uptake transporters OCT2 (IC50 19.9 μM) and OAT3 (IC50 18.4 μM), but limited inhibition of OAT1 (13.5% at 100 μM); inhibition of the renal efflux transporters MATE1 and MATE2K (IC50s 5.50 μM and 47.1 μM, respectively); inhibition of the efflux transporter MDR1 (IC50 76.0 μM), but limited inhibition of BCRP (47% at 100 μM) and no inhibition of MRP2. At clinically relevant exposures, olaparib has the potential to cause pharmacokinetic interactions via inhibition of OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K in the liver and kidney, as well as MDR1 in the liver and GI tract. Olaparib was found to be a substrate of MDR1 but not of several other transporters. 3. Our assessments indicate that olaparib is a substrate of MDR1 and may cause clinically meaningful inhibition of MDR1, OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K.

  15. Downregulation of Organic Anion Transporting Polypeptide (OATP) 1B1 Transport Function by Lysosomotropic Drug Chloroquine: Implication in OATP-Mediated Drug-Drug Interactions.

    PubMed

    Alam, Khondoker; Pahwa, Sonia; Wang, Xueying; Zhang, Pengyue; Ding, Kai; Abuznait, Alaa H; Li, Lang; Yue, Wei

    2016-03-07

    and Drug Administration Adverse Event Reporting System indicated that CQ plus pitavastatin, rosuvastatin, and pravastatin, which are minimally metabolized by the cytochrome P450 enzymes, led to higher myopathy risk than these statins alone. In summary, the present studies report novel findings that lysosome is involved in degradation of OATP1B1 protein and that pre-incubation with lysosomotropic drug CQ downregulates OATP1B1 transport activity. Our in vitro data in combination with pharmacoepidemiologic studies support that CQ has potential to cause OATP-mediated drug-drug interactions.

  16. Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications.

    PubMed

    Marzolini, Catia; Gibbons, Sara; Khoo, Saye; Back, David

    2016-07-01

    Nearly all HIV PIs and the integrase inhibitor elvitegravir require a pharmacokinetic enhancer in order to achieve therapeutic plasma concentrations at the desired dose and frequency. Whereas ritonavir has been the only available pharmacokinetic enhancer for more than a decade, cobicistat has recently emerged as an alternative boosting agent. Cobicistat and ritonavir are equally strong inhibitors of cytochrome P450 (CYP) 3A4 and consequently were shown to be equivalent pharmacokinetic enhancers for elvitegravir and for the PIs atazanavir and darunavir. Since cobicistat is a more selective CYP inhibitor than ritonavir and is devoid of enzyme-inducing properties, differences are expected in their interaction profiles with some co-medications. Drugs whose exposure might be altered by ritonavir but unaltered by cobicistat are drugs primarily metabolized by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 or drugs undergoing mainly glucuronidation. Thus, co-medications should be systematically reviewed when switching the pharmacokinetic enhancer to anticipate potential dosage adjustments.

  17. Addressing Antiretroviral Therapy-Associated Drug-Drug Interactions in Patients Requiring Treatment for Opportunistic Infections in Low-Income and Resource-Limited Settings.

    PubMed

    Chastain, Daniel B; Franco-Paredes, Carlos; Stover, Kayla R

    2017-09-08

    An increasing number of human immunodeficiency virus (HIV)-infected patients are achieving virologic suppression on antiretroviral therapy (ART) limiting the use of primary and secondary antimicrobial prophylaxis. However, in low-income and resource-limited settings, half of those infected with HIV are unaware of their diagnosis, and fewer than 50% of patients on ART achieve virologic suppression. Management of comorbidities and opportunistic infections among patients on ART may lead to inevitable drug-drug interactions (DDIs) and even toxicities. Elderly patients, individuals with multiple comorbidities, those receiving complex ART, and patients living in low-income settings experience higher rates of DDIs. Management of these cytochrome P450-mediated, nonmediated, and drug transport system DDIs is critical in HIV-infected patients, particularly those in resource-limited settings with few options for ART. This article critically analyzes and provides recommendations to manage significant DDIs and drug toxicities in HIV-infected patients receiving ART. © 2017, The American College of Clinical Pharmacology.

  18. Clinical Pharmacokinetic, Pharmacodynamic, and Drug-Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor.

    PubMed

    Devineni, Damayanthi; Polidori, David

    2015-10-01

    The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1-2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50-1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose

  19. The use of HepaRG and human hepatocyte data in predicting CYP induction drug-drug interactions via static equation and dynamic mechanistic modelling approaches.

    PubMed

    Grime, Ken; Ferguson, Douglas D; Riley, Robert J

    2010-12-01

    The method of predicting CYP induction drug-drug interactions (DDIs) from a relative induction score (RIS) calibration has been developed to provide a novel model facilitating predictions for any CYP-inducer substrate combination by inclusion of parameters such as the fraction of hepatic clearance mediated by a specific CYP and fraction of the dose escaping intestinal extraction. In vitro HepaRG CYP3A4 induction data were used as a basis for the approach and a large number of DDIs were well predicted. Primary human hepatocyte data were also used to make predictions, using the HepaRG calibration as a foundation. Similar predictive accuracy suggests that HepaRG and primary hepatocyte data can be used inter-changeably within the same laboratory. A comparison of this 'indirect' calibration method with a direct in vitro-in vivo scaling approach was made and investigations undertaken to define the most appropriate in vivo inducer concentration to use. Additionally, a reasonably effective prediction model based on F(2) (the concentration of inducer taken to increase the CYP mRNA 2-fold above background) was established. An accurate prediction for the CYP1A2-dependent omeprazole-caffeine interaction was also made, demonstrating that the methods are useful for the evaluation of DDIs from induction involving mechanisms other than PXR activation. Finally, a dynamic mechanistic model accounting for the simultaneous influence of CYP induction and reversible and irreversible CYP inhibition in both the liver and intestine was written to provide a prediction of the overall DDI when several interactions occur concurrently. The rationale for using the various models described, alongside commercially available prediction tools, at various stages of the drug discovery process is described.

  20. Evaluation of the potential for a pharmacokinetic drug-drug interaction between armodafinil and ziprasidone in healthy adults.

    PubMed

    Darwish, Mona; Bond, Mary; Yang, Ronghua; Hellriegel, Edward T; Robertson, Philmore

    2014-10-01

    Armodafinil has been studied as adjunctive therapy for major depressive episodes associated with bipolar I disorder. This open-label, single-centre, 2-period study evaluated the effect of armodafinil, a moderate inducer of cytochrome-P450 (CYP) isoenzyme CYP3A4, on the pharmacokinetics and safety of ziprasidone, an atypical antipsychotic used to treat bipolar I disorder and metabolized in part by CYP3A4. Thirty-five healthy subjects received ziprasidone (20 mg) alone and after armodafinil pretreatment (titrated to 250 mg/day); of those, 25 were evaluable for pharmacokinetics. Pharmacokinetic parameters were derived from plasma concentrations of ziprasidone collected prior to and over the 48 h after each ziprasidone administration. Plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone, were also obtained after repeated daily dosing of armodafinil alone. Safety and tolerability were assessed. Systemic exposure to ziprasidone was similar following administration alone or after pretreatment with armodafinil, as assessed by mean peak plasma concentration (C max, 52.1 vs 50.4 ng/mL) and area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞, 544.6 vs 469.1 ng·h/mL). Geometric mean ratios of systemic exposure (ziprasidone alone: ziprasidone after pretreatment with armodafinil) were close to unity, with associated 90 % confidence intervals (CIs) within the range of 0.80-1.25 (C max, 0.97; 90 % CI, 0.87-1.08; AUC0-∞, 0.86; 90 % CI, 0.82-0.91). Adverse events were consistent with the known safety profiles of each agent. Systemic exposure to ziprasidone was not affected by pretreatment with armodafinil. Both drugs were generally safe and well tolerated under the conditions studied.

  1. Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug-drug interactions.

    PubMed

    Arimany-Nardi, C; Koepsell, H; Pastor-Anglada, M

    2015-12-01

    The SCL22A1 gene encodes the broad selectivity transporter hOCT1. hOCT1 is expressed in most epithelial barriers thereby contributing to drug pharmacokinetics. It is also expressed in different drug target cells, including immune system cells and others. Thus, this membrane protein might also contribute to drug pharmacodynamics. Up to 1000 hOCT1 polymorphisms have been identified so far, although only a small fraction of those have been mechanistically studied. A paradigm in the field of drug transporter pharmacogenetics is the impact of hOCT1 gene variability on metformin clinical parameters, affecting area under the concentration-time curve, Cmax and responsiveness. However, hOCT1 also mediates the translocation of a variety of drugs used as anticancer, antiviral, anti-inflammatory, antiemetic agents as well as drugs used in the treatment of neurological diseases among. This review focuses exclusively on those drugs for which some pharmacogenetic data are available, and aims at highlighting the need for further clinical research in this area.

  2. Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria

    PubMed Central

    Bentz, Joe; O’Connor, Michael P.; Bednarczyk, Dallas; Coleman, JoAnn; Lee, Caroline; Palm, Johan; Pak, Y. Anne; Perloff, Elke S.; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K.; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E.; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M.; Xia, Cindy Q.; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei

    2013-01-01

    A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells—Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations

  3. The efficacy and safety of direct acting antiviral treatment and clinical significance of drug-drug interactions in elderly patients with chronic hepatitis C virus infection.

    PubMed

    Vermehren, J; Peiffer, K-H; Welsch, C; Grammatikos, G; Welker, M-W; Weiler, N; Zeuzem, S; Welzel, T M; Sarrazin, C

    2016-10-01

    Direct antiviral therapies for chronic hepatitis C virus (HCV) infection have expanded treatment options for neglected patient populations, including elderly patients who are ineligible/intolerant to receive interferon (IFN)-based therapy. To investigate the efficacy, tolerability and potential for drug-drug interactions (DDIs) of IFN-free treatment in patients aged ≥65 years in a large real-world cohort. A total of 541 patients were treated with different combinations of direct antiviral agents (DAAs: ledipasvir/sofosbuvir ±ribavirin; daclatasvir/sofosbuvir ±ribavirin; paritaprevir/ombitasvir ±dasabuvir ±ribavirin or simeprevir/sofosbuvir ±ribavirin in genotype 1/4, and daclatasvir/sofosbuvir ±ribavirin or sofosbuvir/ribavirin in genotype 2/3). Efficacy, safety and potential DDIs were analysed and compared between patients aged <65 years (n = 404) and patients aged ≥65 years (n = 137) of whom 41 patients were ≥75 years. Sustained virological response rates were 98% and 91% in patients aged ≥65 years and <65 years, respectively. Elderly patients took significantly more concomitant medications (79% vs. 51%; P < 0.0001). The number of concomitant drugs per patient was highest in patients ≥65 years with cirrhosis (median, three per patient; range, 0-10). Based on the hep-druginteractions database, the proportion of predicted clinically significant DDIs was significantly higher in elderly patients (54% vs. 28%; P < 0.0001). The number of patients who experienced treatment-associated adverse events was similar between the two age groups (63% vs. 65%; P = n.s.). Elderly patients are at increased risk for significant DDIs when treated with DAAs for chronic HCV infection. However, with careful pre-treatment assessment of concomitant medications, on-treatment monitoring or dose-modifications, significant DDIs and associated adverse events can be avoided. © 2016 John Wiley & Sons Ltd.

  4. Characterization of simvastatin acid uptake by organic anion transporting polypeptide 3A1 (OATP3A1) and influence of drug-drug interaction.

    PubMed

    Atilano-Roque, Amandla; Joy, Melanie S

    2017-09-06

    Human organic anion transporting polypeptide 3A1 (OATP3A1) is predominately expressed in the heart. The ability of OATP3A1 to transport statins into cardiomyocytes is unknown, although other OATPs are known to mediate the uptake of statin drugs in liver. The pleiotropic effects and uptake of simvastatin acid were analyzed in primary human cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. Treatment with simvastatin acid reduced indoxyl sulfate-mediated reactive oxygen species and modulated OATP3A1 expression in cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. We observed a pH-dependent effect on OATP3A1 uptake, with more efficient simvastatin acid uptake at pH5.5 in HEK293 cells transfected with the OATP3A1 gene. The Michaelis-Menten constant (Km) for simvastatin acid uptake by OATP3A1 was 0.017±0.002μM and the Vmax was 0.995±0.027fmol/min/10(5) cells. Uptake of simvastatin acid was significantly increased by known (benzylpenicillin and estrone-3-sulfate) and potential (indoxyl sulfate and cyclosporine) substrates of OATP3A1. In conclusion, the presence of OATP3A1 in cardiomyocytes suggests that this transporter may modulate the exposure of cardiac tissue to simvastatin acid due to its enrichment in cardiomyocytes. Increases in uptake of simvastatin acid by OATP3A1 when combined with OATP substrates suggest the potential for drug-drug interactions that could influence clinical outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Comparison of different algorithms for predicting clinical drug-drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction.

    PubMed

    Fahmi, Odette A; Hurst, Susan; Plowchalk, David; Cook, Jack; Guo, Feng; Youdim, Kuresh; Dickins, Maurice; Phipps, Alex; Darekar, Amanda; Hyland, Ruth; Obach, R Scott

    2009-08-01

    Cytochrome P450 3A4 (CYP3A4) is the most important enzyme in drug metabolism and because it is the most frequent target for pharmacokinetic drug-drug interactions (DDIs) it is highly desirable to be able to predict CYP3A4-based DDIs from in vitro data. In this study, the prediction of clinical DDIs for 30 drugs on the pharmacokinetics of midazolam, a probe substrate for CYP3A4, was done using in vitro inhibition, inactivation, and induction data. Two DDI prediction approaches were used, which account for effects at both the liver and intestine. The first was a model that simultaneously combines reversible inhibition, time-dependent inactivation, and induction data with static estimates of relevant in vivo concentrations of the precipitant drug to provide point estimates of the average magnitude of change in midazolam exposure. This model yielded a success rate of 88% in discerning DDIs with a mean -fold error of 1.74. The second model was a computational physiologically based pharmacokinetic model that uses dynamic estimates of in vivo concentrations of the precipitant drug and accounts for interindividual variability among the population (Simcyp). This model yielded success rates of 88 and 90% (for "steady-state" and "time-based" approaches, respectively) and mean -fold errors of 1.59 and 1.47. From these findings it can be concluded that in vivo DDIs for CYP3A4 can be predicted from in vitro data, even when more than one biochemical phenomenon occurs simultaneously.

  6. Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.

    PubMed

    Bentz, Joe; O'Connor, Michael P; Bednarczyk, Dallas; Coleman, Joann; Lee, Caroline; Palm, Johan; Pak, Y Anne; Perloff, Elke S; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M; Xia, Cindy Q; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei; Ellens, Harma

    2013-07-01

    A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC₅₀ values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC₅₀ values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC₅₀ values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC₅₀ values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC₅₀ values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC₅₀ determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens

  7. Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4.

    PubMed

    Sager, J E; Lutz, J D; Foti, R S; Davis, C; Kunze, K L; Isoherranen, N

    2014-06-01

    Fluoxetine and its circulating metabolite norfluoxetine comprise a complex multiple-inhibitor system that causes reversible or time-dependent inhibition of the cytochrome P450 (CYP) family members CYP2D6, CYP3A4, and CYP2C19 in vitro. Although significant inhibition of all three enzymes in vivo was predicted, the areas under the concentration-time curve (AUCs) for midazolam and lovastatin were unaffected by 2-week dosing of fluoxetine, whereas the AUCs of dextromethorphan and omeprazole were increased by 27- and 7.1-fold, respectively. This observed discrepancy between in vitro risk assessment and in vivo drug-drug interaction (DDI) profile was rationalized by time-varying dynamic pharmacokinetic models that incorporated circulating concentrations of fluoxetine and norfluoxetine enantiomers, mutual inhibitor-inhibitor interactions, and CYP3A4 induction. The dynamic models predicted all DDIs with less than twofold error. This study demonstrates that complex DDIs that involve multiple mechanisms, pathways, and inhibitors with their metabolites can be predicted and rationalized via characterization of all the inhibitory species in vitro.

  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. In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP.

    PubMed

    Yamane, Mizuki; Kawashima, Kosuke; Yamaguchi, Koji; Nagao, Shunsuke; Sato, Mika; Suzuki, Masayuki; Honda, Kiyofumi; Hagita, Hitoshi; Kuhlmann, Olaf; Poirier, Agnes; Fowler, Stephen; Funk, Christoph; Simon, Sandrine; Aso, Yoshinori; Ikeda, Sachiya; Ishigai, Masaki

    2015-03-01

    Abstract 1. The metabolism and drug-drug interaction (DDI) risk of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, were evaluated by in vitro studies using human liver microsomes, human hepatocytes, and recombinant human CYPs. 2. The main metabolite of tofogliflozin was the carboxylated derivative (M1) in human hepatocytes, which was the same as in vivo. The metabolic pathway of tofogliflozin to M1 was considered to be as follows: first, tofogliflozin was catalyzed to the primary hydroxylated derivative (M4) by CYP2C18, CYP4A11 and CYP4F3B, then M4 was oxidized to M1. 3. Tofogliflozin had no induction potential on CYP1A2 and CYP3A4. Neither tofogliflozin nor M1 had inhibition potential on CYPs, with the exception of a weak CYP2C19 inhibition by M1. 4. Not only are multiple metabolic enzymes involved in the tofogliflozin metabolism, but the drug is also excreted into urine after oral administration, indicating that tofogliflozin is eliminated through multiple pathways. Thus, the exposure of tofogliflozin would not be significantly altered by DDI caused by any co-administered drugs. Also, tofogliflozin seems not to cause significant DDI of co-administered drugs because tofogliflozin has no CYP induction or inhibition potency, and the main metabolite M1 has no clinically relevant CYP inhibition potency.

  10. Quantitative Analyses of the Influence of Parameters Governing Rate-Determining Process of Hepatic Elimination of Drugs on the Magnitudes of Drug-Drug Interactions via Hepatic OATPs and CYP3A Using Physiologically Based Pharmacokinetic Models.

    PubMed

    Yoshikado, Takashi; Maeda, Kazuya; Kusuhara, Hiroyuki; Furihata, Ken-Ichi; Sugiyama, Yuichi

    2017-09-01

    Physiologically based pharmacokinetic models were constructed for hepatic organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) substrates (bosentan, repaglinide, clarithromycin, and simeprevir), a CYP3A probe substrate (midazolam), and selective inhibitors for OATPs (rifampicin) and CYP3A (itraconazole), although the role of OATPs in the hepatic uptake of clarithromycin is unclear. The pharmacokinetic data were obtained from our previous clinical drug-drug interaction (DDI) study. Parameters optimized from clinical PK data were confirmed to reproduce their blood concentrations in control phase. DDIs with rifampicin and itraconazole were simulated using in vivo Rdif (ratio of diffusional uptake to active uptake) and β (the fraction of the sum of intrinsic clearances for metabolism and biliary excretion in all possible itineraries of intracellular drugs including basolateral efflux) estimated by static analyses based on the extended clearance concept, in vivo inhibition constant (Ki) for hepatic OATPs reported previously, and in vivo Ki for CYP3A determined from DDI data with midazolam and itraconazole. Sensitivity analyses showed the magnitudes of DDIs largely depended on Rdif and β. In conclusion, our approach using physiologically based pharmacokinetic modeling showed that the rational estimation of parameters governing rate-determining process of hepatic elimination is critical to accurately predict DDI magnitudes involving OATPs/CYP3A inhibition. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  11. Quantitative Analysis of Complex Drug-Drug Interactions Between Repaglinide and Cyclosporin A/Gemfibrozil Using Physiologically Based Pharmacokinetic Models With In Vitro Transporter/Enzyme Inhibition Data.

    PubMed

    Kim, Soo-Jin; Toshimoto, Kota; Yao, Yoshiaki; Yoshikado, Takashi; Sugiyama, Yuichi

    2017-09-01

    Quantitative analysis of transporter- and enzyme-mediated complex drug-drug interactions (DDIs) is challenging. Repaglinide (RPG) is transported into the liver by OATP1B1 and then is metabolized by CYP2C8 and CYP3A4. The purpose of this study was to describe the complex DDIs of RPG quantitatively based on unified physiologically based pharmacokinetic (PBPK) models using in vitro Ki values for OATP1B1, CYP3A4, and CYP2C8. Cyclosporin A (CsA) or gemfibrozil (GEM) increased the blood concentrations of RPG. The time profiles of RPG and the inhibitors were analyzed by PBPK models, considering the inhibition of OATP1B1 and CYP3A4 by CsA or OATP1B1 inhibition by GEM and its glucuronide and the mechanism-based inhibition of CYP2C8 by GEM glucuronide. RPG-CsA interaction was closely predicted using a reported in vitro Ki,OATP1B1 value in the presence of CsA preincubation. RPG-GEM interaction was underestimated compared with observed data, but the simulation was improved with the increase of fm,CYP2C8. These results based on in vitro Ki values for transport and metabolism suggest the possibility of a bottom-up approach with in vitro inhibition data for the prediction of complex DDIs using unified PBPK models and in vitro fm value of a substrate for multiple enzymes should be considered carefully for the prediction. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  12. Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments.

    PubMed

    Watanabe, Takao; Kusuhara, Hiroyuki; Watanabe, Tomoko; Debori, Yasuyuki; Maeda, Kazuya; Kondo, Tsunenori; Nakayama, Hideki; Horita, Shigeru; Ogilvie, Brian W; Parkinson, Andrew; Hu, Zhuohan; Sugiyama, Yuichi

    2011-06-01

    The present study investigated prediction of the overall renal tubular secretion and hepatic clearances of anionic drugs based on in vitro transport studies. The saturable uptake of eight drugs, most of which were OAT3 substrates (rosuvastatin, pravastatin, pitavastatin, valsartan, olmesartan, trichlormethiazide, p-aminohippurate, and benzylpenicillin) by freshly prepared human kidney slices underestimated the overall intrinsic clearance of the tubular secretion; therefore, a scaling factor of 10 was required for in vitro-in vivo extrapolation. We examined the effect of gemfibrozil and its metabolites, gemfibrozil glucuronide and the carboxylic metabolite, gemfibrozil M3, on pravastatin uptake by human kidney slices. The inhibition study using human kidney slices suggests that OAT3 plays a predominant role in the renal uptake of pravastatin. Comparison of unbound concentrations and K(i) values (1.5, 9.1, and 4.0 μM, for gemfibrozil, gemfibrozil glucuronide, and gemfibrozil M3, respectively) suggests that the mechanism of the interaction is due mainly to inhibition by gemfibrozil and gemfibrozil glucuronide. Furthermore, extrapolation of saturable uptake by cryopreserved human hepatocytes predicts clearance comparable with the observed hepatic clearance although fluvastatin and rosuvastatin required a scaling factor of 11 and 6.9, respectively. This study suggests that in vitro uptake assays using human kidney slices and hepatocytes provide a good prediction of the overall tubular secretion and hepatic clearances of anionic drugs and renal drug-drug interactions. It is also recommended that in vitro-in vivo extrapolation be performed in animals to obtain more reliable prediction.

  13. Investigation of bioequivalence of a new fixed-dose combination of nifedipine and candesartan with the corresponding loose combination as well as the drug-drug interaction potential between both drugs under fasting conditions.

    PubMed

    Brendel, Erich; Weimann, Boris; Dietrich, Hartmut; Froede, Christoph; Thomas, Dirk

    2013-09-01

    To determine the bioequivalence of a nifedipine and candesartan fixed-dose combination (FDC) with the corresponding loose combination, and to investigate the pharmacokinetic drug-drug interaction potential between both drugs. 49 healthy, white, male subjects received: 60 mg nifedipine and 32 mg candesartan FDC, the loose combination of 60 mg nifedipine GITS and 32 mg candesartan, 60 mg nifedipine GITS alone, or 32 mg candesartan alone in a randomized, non-blinded, 4-period, 4-way crossover design with each dosing following overnight fasting. Treatment periods were separated by washout periods of ≥ 5 days. Plasma samples were collected for 48 hours after dosing and assayed using a validated LC-MS/MS method. Bioequivalence between the FDC and the loose combination as well as the impact of combined treatment with both drugs on candesartan pharmacokinetics was evaluated in 47 subjects, while the corresponding impact of treatment with both drugs on nifedipine pharmacokinetics was assessed in 46 patients. For AUC(0-tlast) and Cmax the 90% confidence intervals (CIs) for the ratios of the FDC vs. the corresponding loose combination were within the acceptance range for bioequivalence of 80 - 125%. When comparing AUC(0-tlast) and Cmax of nifedipine and candesartan after dosing with the loose combination vs. each drug alone, the 90% CIs remained within the range of 80 - 125% indicating the absence of a clinically relevant pharmacokinetic drug-drug interaction. Nifedipine and candesartan as well as the combinations were well tolerated. The FDC containing 60 mg nifedipine and 32 mg candesartan was bioequivalent to the corresponding loose combination following single oral doses under fasting conditions. No clinically relevant pharmacokinetic drug-drug interaction between nifedipine and candesartan was observed.

  14. Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks.

    PubMed

    Prado-Prado, Francisco J; Martinez de la Vega, Octavio; Uriarte, Eugenio; Ubeira, Florencio M; Chou, Kuo-Chen; González-Díaz, Humberto

    2009-01-15

    One limitation of almost all antiviral Quantitative Structure-Activity Relationships (QSAR) models is that they predict the biological activity of drugs against only one species of virus. Consequently, the development of multi-tasking QSAR models (mt-QSAR) to predict drugs activity against different species of virus is of the major vitally important. These mt-QSARs offer also a good opportunity to construct drug-drug Complex Networks (CNs) that can be used to explore large and complex drug-viral species databases. It is known that in very large CNs we can use the Giant Component (GC) as a representative sub-set of nodes (drugs) and but the drug-drug similarity function selected may strongly determines the final network obtained. In the three previous works of the present series we reported mt-QSAR models to predict the antimicrobial activity against different fungi [Gonzalez-Diaz, H.; Prado-Prado, F. J.; Santana, L.; Uriarte, E. Bioorg.Med.Chem.2006, 14, 5973], bacteria [Prado-Prado, F. J.; Gonzalez-Diaz, H.; Santana, L.; Uriarte E. Bioorg.Med.Chem.2007, 15, 897] or parasite species [Prado-Prado, F.J.; González-Díaz, H.; Martinez de la Vega, O.; Ubeira, F.M.; Chou K.C. Bioorg.Med.Chem.2008, 16, 5871]. However, including these works, we do not found any report of mt-QSAR models for antivirals drug, or a comparative study of the different GC extracted from drug-drug CNs based on different similarity functions. In this work, we used Linear Discriminant Analysis (LDA) to fit a mt-QSAR model that classify 600 drugs as active or non-active against the 41 different tested species of virus. The model correctly classifies 143 of 169 active compounds (specificity=84.62%) and 119 of 139 non-active compounds (sensitivity=85.61%) and presents overall training accuracy of 85.1% (262 of 308 cases). Validation of the model was carried out by means of external predicting series, classifying the model 466 of 514, 90.7% of compounds. In order to illustrate the performance of the

  15. In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation.

    PubMed

    Sager, Jennifer E; Tripathy, Sasmita; Price, Lauren S L; Nath, Abhinav; Chang, Justine; Stephenson-Famy, Alyssa; Isoherranen, Nina

    2017-01-01

    Bupropion is a widely used antidepressant and smoking cessation aid and a strong inhibitor of CYP2D6 in vivo. Bupropion is administered as a racemic mixture of R- and S-bupropion and has stereoselective pharmacokinetics. Four primary metabolites of bupropion, threo- and erythro-hydrobupropion and R,R- and S,S-OH-bupropion, circulate at higher concentrations than the parent drug and are believed to contribute to the efficacy and side effects of bupropion as well as to the CYP2D6 inhibition. However, bupropion and its metabolites are only weak inhibitors of CYP2D6 in vitro, and the magnitude of the in vivo drug-drug interactions (DDI) caused by bupropion cannot be explained by the in vitro data even when CYP2D6 inhibition by the metabolites is accounted for. The aim of this study was to quantitatively explain the in vivo CYP2D6 DDI magnitude by in vitro DDI data. Bupropion and its metabolites were found to inhibit CYP2D6 stereoselectively with up to 10-fold difference in inhibition potency between enantiomers. However, the reversible inhibition or active uptake into hepatocytes did not explain the in vivo DDIs. In HepG2 cells and in plated human hepatocytes bupropion and its metabolites were found to significantly downregulate CYP2D6 mRNA in a concentration dependent manner. The in vivo DDI was quantitatively predicted by significant down-regulation of CYP2D6 mRNA and reversible inhibition of CYP2D6 by bupropion and its metabolites. This study is the first example of a clinical DDI resulting from CYP down-regulation and first demonstration of a CYP2D6 interaction resulting from transcriptional regulation. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure.

    PubMed

    Elsby, Robert; Martin, Paul; Surry, Dominic; Sharma, Pradeep; Fenner, Katherine

    2016-03-01

    The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC50 > 10 μM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration-time curve (AUC) and Cmax, respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC50) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293-OATP1B1 cells versus estradiol 17β-glucuronide. Calculated parameters of maximum enterocyte concentration [Igut max], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant

  17. Development of an enantioselective assay for simultaneous separation of venlafaxine and O-desmethylvenlafaxine by micellar electrokinetic chromatography-tandem mass spectrometry: Application to the analysis of drug-drug interaction.

    PubMed

    Liu, Yijin; Jann, Michael; Vandenberg, Chad; Eap, Chin B; Shamsi, Shahab A

    2015-11-13

    To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L,L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150-5000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy.

  18. Validation of membrane vesicle-based breast cancer resistance protein and multidrug resistance protein 2 assays to assess drug transport and the potential for drug-drug interaction to support regulatory submissions.

    PubMed

    Elsby, Robert; Smith, Veronica; Fox, Lisa; Stresser, David; Butters, Caroline; Sharma, Pradeep; Surry, Dominic D

    2011-09-01

    Breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2) can play a role in the absorption, distribution, metabolism, and excretion of drugs, impacting on the potential for drug-drug interactions. This study has characterized insect cell- and mammalian cell-derived ABC-transporter-expressing membrane vesicle test systems and validated methodologies for evaluation of candidate drugs as substrates or inhibitors of BCRP or MRP2. Concentration-dependent uptake of BCRP ([³H]oestrone 3-sulfate, [³H]methotrexate, [³H]rosuvastatin) and MRP2 ([³H]oestradiol 17β-glucuronide, [³H]pravastatin, carboxydichlorofluorescein) substrates, and inhibitory potencies (IC₅₀) of BCRP (sulfasalazine, novobiocin, fumitremorgin C) and MRP2 (benzbromarone, MK-571, terfenadine) inhibitors were determined. The apparent K(m) for probes [³H]oestrone 3-sulfate and [³H]oestradiol 17β-glucuronide was determined in insect cell vesicles to be 7.4 ± 1.7 and 105 ± 8.3 µM, respectively. All other substrates exhibited significant uptake ratios. Positive control inhibitors sulfasalazine and benzbromarone gave IC₅₀ values of 0.74 ± 0.18 and 36 ± 6.1 µM, respectively. All other inhibitors exhibited concentration-dependent inhibition. There was no significant difference in parameters generated between test systems. On the basis of the validation results, acceptance criteria to identify substrates/inhibitors of BCRP and MRP2 were determined for insect cell vesicles. The approach builds on earlier validations to support drug registration and extends from those cell-based systems to encompass assay formats using membrane vesicles.

  19. Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control.

    PubMed

    Hariparsad, Niresh; Ramsden, Diane; Palamanda, Jairam; Dekeyser, Joshua G; Fahmi, Odette A; Kenny, Jane R; Einolf, Heidi; Mohutsky, Michael; Pardon, Magalie; Siu, Y Amy; Chen, Liangfu; Sinz, Michael; Jones, Barry; Walsky, Robert; Dallas, Shannon; Balani, Suresh K; Zhang, George; Buckley, David; Tweedie, Donald

    2017-10-01

    The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (PMDA), and the Food and Drug Administration (FDA) have issued guidelines for the conduct of drug-drug interaction studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (IWG). A team of 19 scientists, from 16 of the 39 pharmaceutical companies that are members of the IQ Consortium and two Contract Research Organizations reviewed the recommendations, focusing initially on the current EMA guidelines. Questions were collated from IQ member companies as to which aspects of the guidelines require further evaluation. The EMA was then approached to provide insights into their recommendations on the following: 1) evaluation of downregulation, 2) in vitro assessment of CYP2C induction, 3) the use of CITCO as the positive control for CYP2B6 induction by CAR, 4) data interpretation (a 2-fold increase in mRNA as evidence of induction), and 5) the duration of incubation of hepatocytes with test article. The IWG conducted an anonymous survey among IQ member companies to query current practices, focusing specifically on the aforementioned key points. Responses were received from 19 companies. All data and information were blinded before being shared with the IWG. The results of the survey are presented, together with consensus recommendations on downregulation, CYP2C induction, and CYP2B6 positive control. Results and recommendations related to data interpretation and induction time course will be reported in subsequent articles. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  20. Development of an enantioselective assay for simultaneous separation of venlafaxine and O-desmethylvenlafaxine by micellar electrokinetic chromatography-tandem mass spectrometry: Application to the analysis of drug-drug interaction

    PubMed Central

    Liu, Yijin; Jann, Michael; Vandenberg, Chad; Eap, Chin B.; A.Shamsi, Shahab

    2016-01-01

    To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150–5,000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy. PMID:26460073

  1. Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System

    PubMed Central

    Neto, Zoraima; Machado, Marta; Lindeza, Ana; do Rosário, Virgílio; Gazarini, Marcos L.; Lopes, Dinora

    2013-01-01

    Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT) is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS) were analyzed. In vivo efficacy of curcumin was studied in BALB/c mice infected with Plasmodium chabaudi clones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs). Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group's 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest. PMID:23691276

  2. Drug-drug interactions between antiretrovirals and drugs used in the management of neglected tropical diseases: important considerations in the WHO 2020 Roadmap and London Declaration on Neglected Tropical Diseases.

    PubMed

    Seden, Kay; Khoo, Saye; Back, David; Prevatt, Natalie; Lamorde, Mohammed; Byakika-Kibwika, Pauline; Mayito, Jonathan; Ryan, Mairin; Merry, Concepta

    2013-03-13

    The group of infections known as the neglected tropical diseases (NTDs) collectively affect one billion people worldwide, equivalent to one-sixth of the world's population. The NTDs cause severe physical and emotional morbidity, and have a profound effect on cycles of poverty; it is estimated that NTDs account for 534 000 deaths per year. NTDs such as soil-transmitted helminth infections and the vector-borne protozoal infections leishmaniasis and trypanosomiasis occur predominantly in the most economically disadvantaged and marginalized communities. It is estimated that all low-income countries harbour at least five of the NTDs simultaneously. NTDs are neglected because they do not individually rank highly in terms of mortality data, and because they affect populations with little political voice. There is considerable geographic overlap between areas with high prevalence of NTDs and HIV, raising the possibility of complex polypharmacy and drug-drug interactions. Antiretrovirals pose a particularly high risk for potential drug-drug interactions, which may be pharmacokinetic or pharmacodynamic in nature and can result in raising or lowering plasma or tissue concentrations of co-prescribed drugs. Elevated drug concentrations may be associated with drug toxicity and lower drug concentrations may be associated with therapeutic failure. The aim of this paper is to review the currently available data on interactions between antiretrovirals and drugs used in the management of NTDs. It is intended to serve as a resource for policy makers and clinicians caring for these patients, and to support the recent WHO 2020 Roadmap and the 2012 London Declaration on NTDs.

  3. Molecular docking to understand the metabolic behavior of GNF-351 by CYP3A4 and its potential drug-drug interaction with ketoconazole.

    PubMed

    Liu, Tao; Qian, Ge; Wang, WenTing; Zhang, YanGuo

    2015-06-01

    GNF-351 is a candidate drug used to treat some diseases through antagonizing aryl hydrocarbon receptor. In the present study, molecular docking method was employed to understand the interaction between ketoconazole and GNF-351. The structure of cytochrome P450 (CYP) 3A4 was obtained from protein data bank, and 2-dimensional structure of GNF-351 with standard bond lengths and angles was drawn using chemdraw software. 30 possible binding orientations was generated and docked into the X-ray crystallographic structure of human CYP3A4. The predicted binding mode of GNF-351 into CYP3A4 appeared to adopt an orientation with interactions between their flat aromatic rings and Phe 302 and Phe 304. The comparison for the binding of GNF-351 and ketoconazole into the activity cavity indicated that they exhibited similar distance towards heme, indicating the potential interaction between GNF-351 and ketoconazole. These data remind us the necessary monitoring when future utilization between GNF-351 and ketoconazole.

  4. The Impact of the Hepatocyte-to-Plasma pH Gradient on the Prediction of Hepatic Clearance and Drug-Drug Interactions for CYP2D6 Substrates.

    PubMed

    Rougée, Luc R A; Mohutsky, Michael A; Bedwell, David W; Ruterbories, Kenneth J; Hall, Stephen D

    2016-11-01

    The proton gradient from the intracellular space to plasma creates an unbound drug gradient for weak acids and bases that could modulate apparent drug clearance and drug-drug interactions. Cytochrome P450 intrinsic clearance and inhibitor potency are routinely determined in vitro at the plasma pH of 7.4 rather than the intrahepatocyte pH of 7.0. We determined the impact of pH on in vitro enzyme kinetic parameters and inhibition potency for substrates (bufuralol, dextromethorphan), reversible inhibitors (quinidine, amiodarone, desethylamiodarone, clozapine), and mechanism-based inhibitors (paroxetine, desethylamiodarone) of the major drug metabolizing-enzyme CYP2D6. The lower intracellular pH 7.0 compared with pH 7.4 resulted in a 60 and 50% decrease in intrinsic clearance for the substrates bufuralol and dextromethorphan, respectively. Reversible inhibition constants for three of the four inhibitors tested were unaffected by pH, whereas for the inhibitor quinidine, a 2-fold increase in the inhibition constant was observed at pH 7.0. For time-dependent inhibitors desethylamiodarone and paroxetine, changes in time-dependent inhibition parameters were different for each inhibitor. These results were incorporated into physiologically based pharmacokinetic models indicating that the changes in in vitro parameters determined at pH 7.0 offset the effect of increased unbound intracellular concentrations on apparent clearance and extent of drug-drug interactions. However, this offset between concentration and enzyme activity cannot be generalized for all substrates, inhibitors, and enzymes, as the effect of a lower pH in vitro varied significantly; therefore, it would be prudent to determine in vitro enzyme parameters at the hepatocyte-appropriate pH 7.0. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  5. CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.

    PubMed

    Boulenc, Xavier; Nicolas, Olivier; Hermabessière, Stéphanie; Zobouyan, Isabelle; Martin, Valérie; Donazzolo, Yves; Ollier, Céline

    2016-02-01

    The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect.

  6. Evaluation of pharmacokinetic and pharmacodynamic drug-drug interaction of sacubitril/valsartan (LCZ696) and sildenafil in patients with mild-to-moderate hypertension.

    PubMed

    Hsiao, Hsiu-Ling; Langenickel, Thomas H; Petruck, Jesika; Kode, Kiran; Ayalasomayajula, Surya; Schuehly, Uwe; Greeley, Michael; Pal, Parasar; Zhou, Wei; Prescott, Margaret F; Sunkara, Gangadhar; Rajman, Iris

    2017-06-09

    Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cGMP, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, 3-period, single sequence study, patients with mild-to-moderate hypertension (153.8±8.2 mm Hg mean SBP) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil co-administration. When co-administered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Co-administration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mm Hg mean ambulatory SBP/DBP/MAP) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. This article is protected by copyright. All rights reserved. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  7. Metoprolol-pridopidine drug-drug interaction and food effect assessments of pridopidine, a new drug for treatment of Huntington's disease.

    PubMed

    Rabinovich-Guilatt, Laura; Steiner, Lilach; Hallak, Hussein; Pastino, Gina; Muglia, Pierandrea; Spiegelstein, Ofer

    2017-10-01

    Pridopidine is an oral drug in clinical development for treatment of patients with Huntington's disease. This study examined the interactions of pridopidine with in vitro cytochrome P450 activity and characterized the effects of pridopidine on CYP2D6 activity in healthy volunteers using metoprolol as a probe substrate. The effect of food on pridopidine exposure was assessed. The ability of pridopidine to inhibit and/or induce in vitro activity of drug metabolizing enzymes was examined in human liver microsomes and fresh hepatocytes. CYP2D6 inhibition potency and reversibility was assessed using dextromethorphan. For the clinical assessment, 22 healthy subjects were given metoprolol 100 mg alone and concomitantly with steady-state pridopidine 45 mg twice daily. Food effect on a single 90 mg dose of pridopidine was evaluated in a crossover manner. Safety assessments and pharmacokinetic sampling occurred throughout the study. Pridopidine was found to be a metabolism dependent inhibitor of CYP2D6, the main enzyme catalysing its own metabolism. Flavin-containing monooxygenase heat inactivation of liver microsomes did not affect pridopidine metabolism-dependent inhibition of CYP2D6 and its inhibition of CYP2D6 was not reversible with addition of FeCN3 . Exposure to metoprolol was markedly increased when coadministered with pridopidine; the ratio of the geometric means (90% confidence interval) for maximum observed plasma concentration, and area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration and extrapolated to infinity were 3.5 (2.9, 4.22), 6.64 (5.27, 8.38) and 6.55 (5.18, 8.28), respectively. Systemic exposure to pridopidine was unaffected by food conditions. As pridopidine is a metabolism-dependent inhibitor of CYP2D6, systemic levels of drugs metabolized by CYP2D6 may increase with chronic coadministration of pridopidine. Pridopidine can be administered without regard to food. © 2017 Teva Pharmaceutical

  8. Drug-drug interactions in older patients with cancer: a report from the 15th Conference of the International Society of Geriatric Oncology, Prague, Czech Republic, November 2015

    PubMed Central

    Stepney, Rob; Lichtman, Stuart M; Danesi, Romano

    2016-01-01

    Drugs taken for cancer can interact with each other, with agents taken as part of supportive care, with drugs taken for comorbid conditions (which are particularly common in the elderly patients), and with herbal supplements and complementary medicines. We tend to focus on the narrow therapeutic window of cytotoxics, but the metabolism of tyrosine kinase inhibitors by the cytochrome P450 3A4 enzyme (CYP3A4) makes some TKIs particularly prone to interference with or from other agents sharing this pathway. There is also potential for adverse pharmacokinetic interactions with new hormonal agents used in advanced prostate cancer. PMID:26823680

  9. [Rhabdomyolysis and severe hepatotoxicity due to a drug-drug interaction between ritonavir and simvastatin. Could we use the most cost-effective statin in all human immunodeficiency virus-infected patients?].

    PubMed

    Bastida, Carla; Also, Maria Antonia; Pericas, Juan Manuel; Letang, Emili; Tuset, Montse; Miró, Josep Maria

    2014-11-01

    Drugs like statins may induce rhabdomyolysis. Simvastatin and lovastatin have a high hepatic metabolism and their potential toxicity could be increased by interactions with other drugs that reduce their metabolism. A case-report is presented of an HIV-infected patient treated with antiretroviral drugs who developed a rhabdomyolysis-induced renal failure and liver toxicity when simvastatin was substituted for atorvastatin. A literature review is also presented. The patient required hospital admission and showed a favorable response after hydration and urine alkalinization. There were 4 additional cases published of which there was one death. Drug-drug interactions can increase the risk of statin induced rhabdomyolysis. In order to evaluate them properly, physicians at all levels of clinical care should be aware of all drugs prescribed to their patients and the contraindicated combinations. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  10. San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review

    PubMed Central

    Wu, Jiasi; Hu, Yingfan; Xiang, Li; Li, Sheng; Yuan, Yi; Chen, Xiaomei; Zhang, Yan; Huang, Wenge; Meng, Xianli; Wang, Ping

    2016-01-01

    Inflammatory disorders underlie varieties of human diseases. San-Huang-Xie-xin-Tang (SHXXT), composed with Rhizoma Rhei (Rheum palmatum L.), Rhizoma Coptidis (Coptis chinensis Franch), and Radix Scutellaria (Scutellaria baicalensis Georgi), is a famous formula which has been widely used in the fight against inflammatory abnormalities. Mutual reinforcement is one of the basic theories of traditional Chinese medicine. Here this article reviewed and analyzed the recent research on (1) How the main constituents of SHXXT impact on inflammation-associated signaling pathway molecules. (2) The interaction between the main constituents and efflux pumps or intestinal transporters. The goal of this work was to, (1) Provide evidence to support the theory of mutual reinforcement. (2) Clarify the key targets of SHXXT and suggest which targets need further investigation. (3) Give advice for the clinical use of SHXXT to elevated the absorption of main constituents and eventually promote oral bioavailability. We search literatures in scientific databases with key words of “each main SHXXT constituent,” in combination with “each main inflammatory pathway target molecule” or each main intestinal transporter, respectively. We report the effect of five main constituents on target molecules which lies in three main inflammatory signaling pathways, we as well investigate the interaction between constituents and intestinal transporter. We conclude, (1) The synergistic effect of constituents at both levels confirm the mutual reinforcement theory of TCM as it is proven in this work. (2) The effect of main constituents on downstream targets in nuclear need more further investigation. (3) Drug elevating the absorption of rhein, berberine and baicalein can be employed to promote oral bioavailability of SHXXT. PMID:27965575

  11. San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review.

    PubMed

    Wu, Jiasi; Hu, Yingfan; Xiang, Li; Li, Sheng; Yuan, Yi; Chen, Xiaomei; Zhang, Yan; Huang, Wenge; Meng, Xianli; Wang, Ping

    2016-01-01

    Inflammatory disorders underlie varieties of human diseases. San-Huang-Xie-xin-Tang (SHXXT), composed with Rhizoma Rhei (Rheum palmatum L.), Rhizoma Coptidis (Coptis chinensis Franch), and Radix Scutellaria (Scutellaria baicalensis Georgi), is a famous formula which has been widely used in the fight against inflammatory abnormalities. Mutual reinforcement is one of the basic theories of traditional Chinese medicine. Here this article reviewed and analyzed the recent research on (1) How the main constituents of SHXXT impact on inflammation-associated signaling pathway molecules. (2) The interaction between the main constituents and efflux pumps or intestinal transporters. The goal of this work was to, (1) Provide evidence to support the theory of mutual reinforcement. (2) Clarify the key targets of SHXXT and suggest which targets need further investigation. (3) Give advice for the clinical use of SHXXT to elevated the absorption of main constituents and eventually promote oral bioavailability. We search literatures in scientific databases with key words of "each main SHXXT constituent," in combination with "each main inflammatory pathway target molecule" or each main intestinal transporter, respectively. We report the effect of five main constituents on target molecules which lies in three main inflammatory signaling pathways, we as well investigate the interaction between constituents and intestinal transporter. We conclude, (1) The synergistic effect of constituents at both levels confirm the mutual reinforcement theory of TCM as it is proven in this work. (2) The effect of main constituents on downstream targets in nuclear need more further investigation. (3) Drug elevating the absorption of rhein, berberine and baicalein can be employed to promote oral bioavailability of SHXXT.

  12. Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.

    PubMed

    Brodney, Michael A; Beck, Elizabeth M; Butler, Christopher R; Barreiro, Gabriela; Johnson, Eric F; Riddell, David; Parris, Kevin; Nolan, Charles E; Fan, Ying; Atchison, Kevin; Gonzales, Cathleen; Robshaw, Ashley E; Doran, Shawn D; Bundesmann, Mark W; Buzon, Leanne; Dutra, Jason; Henegar, Kevin; LaChapelle, Erik; Hou, Xinjun; Rogers, Bruce N; Pandit, Jayvardhan; Lira, Ricardo; Martinez-Alsina, Luis; Mikochik, Peter; Murray, John C; Ogilvie, Kevin; Price, Loren; Sakya, Subas M; Yu, Aijia; Zhang, Yong; O'Neill, Brian T

    2015-04-09

    In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.

  13. Investigation of drug-drug interaction via mechanism-based inhibition of cytochrome P450 3A by macrolides in dexamethasone-treated female rats.

    PubMed

    Kanazu, Takushi; Sato, Norihito; Kadono, Kyoko; Touchi, Akira; Takeda, Yuri; Yamaguchi, Yoshitaka; Baba, Takahiko

    2012-05-01

    The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism-based inhibition (MBI) by macrolides was investigated using dexamethasone-treated female rats (DEX-female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar inhibition responses were observed between human and DEX-female rat liver microsomes, however, there were fewer effects in intact male rats. The ex vivo study showed that midazolam (MDZ) metabolism in liver microsomes of DEX-female rats was reduced by ERM administration and the inhibitory effect was increased with increasing ERM doses, indicating that metabolite intermediate complex formation caused irreversible inhibition of CYP3A activity in DEX-female rats as well as in humans. In the in vivo studies, ERM and CAM significantly increased the area under the plasma concentration-time curve of MDZ and decreased the total clearance in DEX-female rats. It was concluded that the DDIs via MBI of CYP3A following macrolide administration in humans could be reproduced in female rats, suggesting that DEX-female rats can serve as an in vivo model for assessing this DDI in humans.

  14. Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine.

    PubMed

    Khatri, Amit; Trinh, Roger; Zhao, Weihan; Podsadecki, Thomas; Menon, Rajeev

    2016-10-01

    The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally

  15. Characterization of the Effect of Drug-Drug Interaction on Protein Binding in Concurrent Administration of Sulfamethoxazol and Diclofenac Sodium Using Bovine Serum Albumin

    PubMed Central

    Hossain, Md Kamal; Khatun, Amina; Rahman, Mahmudur; Akter, Md Nahid; Chowdhury, Sadia Afreen; Alam, SM Mahbubul

    2016-01-01

    Purpose: This project was aimed to determine the effect of concurrent administration of sulfamethoxazole and diclofenac sodium. Methods: Equilibrium dialysis method was adopted to study different protein binding aspects of sulfamethoxazole and diclofenac sodium. Results: Sulfamethoxazole showed two types of association constants; high affinity constant 29.0±0.20×106 M-1 with lower number of binding sites of 0.7±1 and low affinity constant 1.13±0.20×106 M-1 with higher number of binding sites of 3.45±1 at pH 7.4 and 40 °C temperature. Diclofenac sodium showed high affinity constant 33.66±0.20×106 M-1 with lower number of binding sites of 1.01±1 and low affinity constant 1.72±0.20×106 M-1 with higher number of binding sites of 6.40±1 at the same condition. Site specific probe displacement data implied that site-I, warfarin sodium site, was the high affinity site, while site-II, diazepam site, was the low affinity site for these drugs. During concurrent administration, sulfamethoxazole increased the free concentration of diclofenac sodium from 17.5±0.14% to 70.0±0.014% in absence and from 22.5±0.07% to 83.0±0.014% in presence of site-I specific probe. Diclofenac sodium also increased the free concentration of sulfamethoxazole from 2.8±0.07% to 52.0±0.14% and from 8.5±0.014% to 64.4±0.07% in absence and presence of site-I specific probe respectively. Conclusion: The study revealed that the concurrent administration of sulfamethoxazole and diclofenac sodium may result drug concentration alteration in blood. PMID:28101466

  16. Cardiac drug-drug interaction between HCV-NS5B pronucleotide inhibitors and amiodarone is determined by their specific diastereochemistry.

    PubMed

    Lagrutta, Armando; Regan, Christopher P; Zeng, Haoyu; Imredy, John P; Koeplinger, Kenneth; Morissette, Pierre; Liu, Liping; Wollenberg, Gordon; Brynczka, Christopher; Lebrón, José; DeGeorge, Joseph; Sannajust, Frederick

    2017-03-22

    Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical in vivo experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl) in vitro and in vivo. Co-applied with amiodarone, L-ala,SP prodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala,RP produgs, including MK-3682, did not. Stereochemical selectivity on emerging bradycardia was confirmed in vivo. Diastereomer pairs entered cells equally well, and there was no difference in intracellular accumulation of L-ala,SP metabolites ± amiodarone, but no D-ala,RP metabolites were detected. Cathepsin A (CatA) inhibitors attenuated L-ala,SP prodrug metabolite formation, yet exacerbated L-ala,SP + amiodarone effects, implicating the prodrugs in these effects. Experiments indicate that pharmacological effects and metabolic conversion to UTP analog are L-ala,SP prodrug-dependent in cardiomyocytes.

  17. Cardiac drug-drug interaction between HCV-NS5B pronucleotide inhibitors and amiodarone is determined by their specific diastereochemistry

    PubMed Central

    Lagrutta, Armando; Regan, Christopher P.; Zeng, Haoyu; Imredy, John P.; Koeplinger, Kenneth; Morissette, Pierre; Liu, Liping; Wollenberg, Gordon; Brynczka, Christopher; Lebrón, José; DeGeorge, Joseph; Sannajust, Frederick

    2017-01-01

    Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical in vivo experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl) in vitro and in vivo. Co-applied with amiodarone, L-ala,SP prodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala,RP produgs, including MK-3682, did not. Stereochemical selectivity on emerging bradycardia was confirmed in vivo. Diastereomer pairs entered cells equally well, and there was no difference in intracellular accumulation of L-ala,SP metabolites ± amiodarone, but no D-ala,RP metabolites were detected. Cathepsin A (CatA) inhibitors attenuated L-ala,SP prodrug metabolite formation, yet exacerbated L-ala,SP + amiodarone effects, implicating the prodrugs in these effects. Experiments indicate that pharmacological effects and metabolic conversion to UTP analog are L-ala,SP prodrug-dependent in cardiomyocytes. PMID:28327633

  18. No Clinically Relevant Drug-Drug Interactions Between Methadone or Buprenorphine/Naloxone and Anti-Viral Combination Glecaprevir and Pibrentasvir.

    PubMed

    Kosloski, Matthew; Zhao, Weihan; Asatryan, Armen; Kort, Jens; Geoffroy, Pierre; Liu, Wei

    2017-08-14

    The combination of glecaprevir (formerly ABT-493), a nonstructural (NS) protein 3/4A protease inhibitor, and pibrentasvir (formerly ABT-530), a NS5A protein inhibitor, is being developed as treatment for HCV genotype 1-6 infection. The pharmacokinetics, pharmacodynamics, safety, and tolerability of methadone or buprenorphine/naloxone when coadministered with the glecaprevir and pibrentasvir combination in HCV-negative subjects on stable opioid maintenance therapy were investigated in a Phase 1, single-center, two-arm, multiple-dose, open-label sequential study. Subjects received methadone (Arm 1) or buprenorphine/naloxone (Arm 2) once daily (QD) as per their existing individual prescriptions alone (days 1-9) and then in combination with glecaprevir 300 mg QD and pibrentasvir120 mg QD (days 10-16) each morning. Dose-normalized exposures were similar with and without glecaprevir and pibrentasvir for R- and S- methadone (≤ 5% difference) and for buprenorphine and naloxone (≤ 24% difference); norbuprenorphine area under the curve was 30% higher, consistent with maximum and trough plasma concentrations that increased by 21% to 25%. No changes in pupil response, short opiate withdrawal scale, or desire for drugs questionnaire were observed when glecaprevir and pibrentasvir were added to methadone or buprenorphine/naloxone therapy. No dose adjustment is required when glecaprevir and pibrentasvir are coadministered with methadone or buprenorphine/naloxone. Copyright © 2017 American Society for Microbiology.

  19. In vitro inhibition of UGT1A3, UGT1A4 by ursolic acid and oleanolic acid and drug-drug interaction risk prediction.

    PubMed

    Xie, Hongbo; Wu, Jie; Liu, Dan; Liu, Mingyi; Zhang, Hong; Huang, Shibo; Xiong, Yuqing; Xia, Chunhua

    2017-09-01

    1. Ursolic acid (UA) and oleanolic acid (OA) may have important activity relevant to health and disease prevention. Thus, we studied the activity of UA and OA on UDP-glucuronosyltransferases (UGTs) and used trifluoperazine as a probe substrate to test UGT1A4 activity. Recombinant UGT-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as a probe reaction for other UGT isoforms. 2. UA and OA inhibited UGT1A3 and UGT1A4 activity but did not inhibit other tested UGT isoforms. 3. UA-mediated inhibition of UGT1A3 catalyzed 4-MU-β-d-glucuronidation was via competitive inhibition (IC50 0.391 ± 0.013 μM; Ki 0.185 ± 0.015 μM). UA also competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC50 2.651 ± 0.201 μM; Ki 1.334 ± 0.146 μM). 4. OA offered mixed inhibition of UGT1A3-mediated 4-MU-β-d-glucuronidation (IC50 0.336 ± 0.013 μM; Ki 0.176 ± 0.007 μM) and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC50 5.468 ± 0.697 μM; Ki 6.298 ± 0.891 μM). 5. Co-administering OA or UA with drugs or products that are substrates of UGT1A3 or UGT1A4 may produce drug-mediated side effects.

  20. Pharmacokinetic Evaluation of CYP3A4-Mediated Drug-Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults.

    PubMed

    Townsend, Robert; Dietz, Albert; Hale, Christine; Akhtar, Shahzad; Kowalski, Donna; Lademacher, Christopher; Lasseter, Kenneth; Pearlman, Helene; Rammelsberg, Diane; Schmitt-Hoffmann, Anne; Yamazaki, Takao; Desai, Amit

    2017-01-01

    This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUCτ ) during a dosing interval by 90% and maximum concentration (Cmax ) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0-∞ ) and Cmax by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 μg/1 mg; CYP3A4 substrate). Following coadministration, AUC0-∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; Cmax increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4. © 2016, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

  1. The consequence of regional gradients of P-gp and CYP3A4 for drug-drug interactions by P-gp inhibitors and the P-gp/CYP3A4 interplay in the human intestine ex vivo.

    PubMed

    Li, Ming; de Graaf, Inge A M; van de Steeg, Evita; de Jager, Marina H; Groothuis, Geny M M

    2017-04-01

    Intestinal P-gp and CYP3A4 work coordinately to reduce the intracellular concentration of drugs, and drug-drug interactions (DDIs) based on this interplay are of clinical importance and require pre-clinical investigation. Using precision-cut intestinal slices (PCIS) of human jejunum, ileum and colon, we investigated the P-gp/CYP3A4 interplay and related DDIs with P-gp inhibitors at the different regions of the human intestine with quinidine (Qi), dual substrate of P-gp and CYP3A4, as probe. All the P-gp inhibitors increased the intracellular concentrations of Qi by 2.1-2.6 fold in jejunum, 2.6-3.8 fold in ileum but only 1.2-1.3 fold in colon, in line with the different P-gp expression in these intestinal regions. The selective P-gp inhibitors (CP100356 and PSC833) enhanced 3-hydroxy-quinidine (3OH-Qi) in jejunum and ileum, while dual inhibitors of P-gp and CYP3A4 (verapamil and ketoconazole) decreased the 3OH-Qi production, despite of the increased intracellular Qi concentration, due to inhibition of CYP3A4. The outcome of DDIs based on P-gp/CYP3A4 interplay, shown as remarkable changes in the intracellular concentration of both the parent drug and the metabolite, varied among the intestinal regions, probably due to the different expression of P-gp and CYP3A4, and were different from those found in rat PCIS, which may have important implications for the disposition and toxicity of drugs and their metabolites.

  2. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney.

    PubMed

    Ito, Sumito; Kusuhara, Hiroyuki; Yokochi, Miyu; Toyoshima, Junko; Inoue, Katsuhisa; Yuasa, Hiroaki; Sugiyama, Yuichi

    2012-02-01

    Cimetidine, an H₂ receptor antagonist, has been used to investigate the tubular secretion of organic cations in human kidney. We report a systematic comprehensive analysis of the inhibition potency of cimetidine for the influx and efflux transporters of organic cations [human organic cation transporter 1 (hOCT1) and hOCT2 and human multidrug and toxin extrusion 1 (hMATE1) and hMATE2-K, respectively]. Inhibition constants (K(i)) of cimetidine were determined by using five substrates [tetraethylammonium (TEA), metformin, 1-methyl-4-phenylpyridinium, 4-(4-(dimethylamino)styryl)-N-methylpyridinium, and m-iodobenzylguanidine]. They were 95 to 146 μM for hOCT2, providing at most 10% inhibition based on its clinically reported plasma unbound concentrations (3.6-7.8 μM). In contrast, cimetidine is a potent inhibitor of MATE1 and MATE2-K with K(i) values (μM) of 1.1 to 3.8 and 2.1 to 6.9, respectively. The same tendency was observed for mouse Oct1 (mOct1), mOct2, and mouse Mate1. Cimetidine showed a negligible effect on the uptake of metformin by mouse kidney slices at 20 μM. Cimetidine was administered to mice by a constant infusion to achieve a plasma unbound concentration of 21.6 μM to examine its effect on the renal disposition of Mate1 probes (metformin, TEA, and cephalexin) in vivo. The kidney- and liver-to-plasma ratios of metformin both were increased 2.4-fold by cimetidine, whereas the renal clearance was not changed. Cimetidine also increased the kidney-to-plasma ratio of TEA and cephalexin 8.0- and 3.3-fold compared with a control and decreased the renal clearance from 49 to 23 and 11 to 6.6 ml/min/kg, respectively. These results suggest that the inhibition of MATEs, but not OCT2, is a likely mechanism underlying the drug-drug interactions with cimetidine in renal elimination.

  3. Bioactivation of a novel 2-methylindole-containing dual chemoattractant receptor-homologous molecule expressed on T-helper type-2 cells/D-prostanoid receptor antagonist leads to mechanism-based CYP3A inactivation: glutathione adduct characterization and prediction of in vivo drug-drug interaction.

    PubMed

    Wong, Simon G; Fan, Peter W; Subramanian, Raju; Tonn, George R; Henne, Kirk R; Johnson, Michael G; Tadano Lohr, Michelle; Wong, Bradley K

    2010-05-01

    The 2-methyl substituted indole, 2MI [2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-3-methoxyphenyl)acetic acid] is a potent dual inhibitor of 1) chemoattractant receptor-homologous molecule expressed on T-helper type-2 cells and 2) d-prostanoid receptor. During evaluation as a potential treatment for asthma and allergic rhinitis, 2MI was identified as a mechanism-based inactivator of CYP3A4 in vitro. The inactivation was shown to be irreversible by dialysis and accompanied by an NADPH-dependent increase in 2MI covalent binding to a 55- to 60-kDa microsomal protein, consistent with irreversible binding to CYP3A4. Two glutathione (GSH) adducts, G1 and G2, were identified in vitro, and the more abundant adduct (G1) was unambiguously determined via NMR to be GSH adducted to the 3-position of the 2-methylindole moiety. The potential for a clinical drug-drug interaction arising from mechanism-based inactivation of CYP3A4 by 2MI was predicted using a steady-state model, and a 4.3- to 7.5-fold increase in the exposure of midazolam was predicted at anticipated therapeutic concentrations. To better assess the potential for in vivo drug-drug interactions, the Sprague-Dawley rat was used as an in vivo model. An excellent in vitro-in vivo correlation was observed for the reduction in enzyme steady-state concentration (E'(ss/Ess)) as well as the change in the exposure of a prototypical CYP3A substrate, indinavir (area under the curve (AUC) for indinavir/AUC). In summary, 2MI was identified as a potent mechanism-based inactivator of CYP3A and was predicted to elicit a clinically relevant drug-drug interaction in humans at an anticipated therapeutic concentration.

  4. Characterization of Contents of Distal Ileum and Cecum to Which Drugs/Drug Products are Exposed During Bioavailability/Bioequivalence Studies in Healthy Adults.

    PubMed

    Reppas, Christos; Karatza, Eleni; Goumas, Constantinos; Markopoulos, Constantinos; Vertzoni, Maria

    2015-10-01

    Characterize the contents of distal ileum and cecum in healthy adults under conditions simulating the bioavailability/bioequivelance studies of drug products in fasted and fed state. Twelve males participated in a two-phase crossover study. Phase I: subjects remained fasted overnight plus 4.5 h in the morning prior to colonoscopy. Phase II: subjects remained fasted overnight, consumed breakfast in the morning, and abstain from food until colonoscopy, 4.5 h after breakfast. Upon sampling, volume, pH and buffer capacity were measured; after ultracentrifugation, supernatant was physicochemically characterized and non-liquid particles diameter was measured. In distal ileum, pH is ~8.1 and size of non-liquid particles is ~200 μm, regardless of dosing conditions; in fed state, liquid fraction was lower whereas osmolality and carbohydrate content were higher. In cecum, the environment was similar with previously characterized environment in the ascending colon; in fasted state, size of non-liquid particles is smaller than in distal ileum (~70 μm). Fluid composition in distal ileum is different from cecum, especially in fasted state. Differences in luminal environment between distal ileum and cecum may impact the performance of orally administered products which deliver drug during residence in lower intestine. Dosing conditions affect cecal environment more than in distal ileum.

  5. Predictors of Illicit Drug/s Use Among University Students in Northern Ireland, Wales and England

    PubMed Central

    Ansari, Walid El; Vallentin-Holbech, Lotte; Stock, Christiane

    2015-01-01

    Introduction: The use of illicit drug/s among university students is a public health concern. Nevertheless, many UK studies investigated a narrow spectrum of variables to explore their association/s with illicit drug/s use. Methods: We assessed the associations between a wide range of socio-demographic, health and wellbeing variables (independent variables) and having used illicit drug/s regularly, occasionally or never in life (dependent variables). Data (3706 students) were collected from seven universities in England, Wales, and Northern Ireland, using a self-administered questionnaire. Results: About 5% of the sample had regularly used illicit drug/s, 25% occasionally, and 70% never. Regular drug use (RDU) was significantly more likely among males aged 21-29 years, daily smokers, those with heavy episodic drinking or possible alcohol dependency (CAGE test), and those who perceived their academic performance better than their peers. RDU was less likely among students with high health awareness and those living with parents. The predictors of occasional drug use (ODU) were similar to those of RDU. However, in addition, students with higher perceived stress were less likely, and students who felt financial burden/s were more likely to report ODU, while no association with academic performance was found. Never use of illicit drug/s was inversely associated with most of the variables listed above, and was positively associated with religiosity. Illicit drug/s use goes along with other substance use (alcohol and smoking). The finding that illicit drug/s use was higher among students reporting good academic performance was surprising and raises the question of whether illicit drug/s may be used as performance enhancing drugs. Conclusion: The factors identified with illicit drug/s use in this study could be utilized to develop appropriate public health policies and preventive measures for the health of students. Multilevel, value based, comprehensive, and strategic

  6. Predictors of illicit drug/s use among university students in Northern Ireland, Wales and England.

    PubMed

    El Ansari, Walid; Vallentin-Holbech, Lotte; Stock, Christiane

    2014-12-16

    The use of illicit drug/s among university students is a public health concern. Nevertheless, many UK studies investigated a narrow spectrum of variables to explore their association/s with illicit drug/s use. We assessed the associations between a wide range of socio-demographic, health and wellbeing variables (independent variables) and having used illicit drug/s regularly, occasionally or never in life (dependent variables). Data (3706 students) were collected from seven universities in England, Wales, and Northern Ireland, using a self-administered questionnaire. About 5% of the sample had regularly used illicit drug/s, 25% occasionally, and 70% never. Regular drug use (RDU) was significantly more likely among males aged 21-29 years, daily smokers, those with heavy episodic drinking or possible alcohol dependency (CAGE test), and those who perceived their academic performance better than their peers. RDU was less likely among students with high health awareness and those living with parents. The predictors of occasional drug use (ODU) were similar to those of RDU. However, in addition, students with higher perceived stress were less likely, and students who felt financial burden/s were more likely to report ODU, while no association with academic performance was found. Never use of illicit drug/s was inversely associated with most of the variables listed above, and was positively associated with religiosity. Illicit drug/s use goes along with other substance use (alcohol and smoking). The finding that illicit drug/s use was higher among students reporting good academic performance was surprising and raises the question of whether illicit drug/s may be used as performance enhancing drugs. The factors identified with illicit drug/s use in this study could be utilized to develop appropriate public health policies and preventive measures for the health of students. Multilevel, value based, comprehensive, and strategic long-term intervention plans are required. This

  7. Pharmacokinetic drug-drug interaction between ethinyl estradiol and gestodene, administered as a transdermal fertility control patch, and two CYP3A4 inhibitors and a CYP3A4 substrate.

    PubMed

    Winkler, Julia; Goldammer, Mark; Ludwig, Matthias; Rohde, Beate; Zurth, Christian

    2015-12-01

    Pharmacokinetic (PK) interactions between the cytochrome P450 3A4 (CYP3A4) pathway and transdermally administered ethinyl estradiol (EE) and gestodene (GSD) were investigated. This paper reports the findings of three open-label, intra-individual, one-way crossover, Phase I trials. In two studies, women used a novel contraceptive patch for 3 weeks during two 4-week study periods; in the second period, the CYP3A4 inhibitors erythromycin (Study 1) or ketoconazole (Study 2) were administered concurrently. In a third study, women received single doses of the CYP3A4 model substrate midazolam, alone and after 3 weeks of concurrent patch application. In each period, the EE/GSD patch (delivering low EE and GSD doses resulting in the same systemic exposure as a combined oral contraceptive containing 0.02 mg EE and 0.06 mg GSD) was applied once weekly for 3 weeks, with one patch-free week. Erythromycin, ketoconazole, and midazolam were administered orally. Main outcome measures were area under the curves (AUCs) and maximum plasma concentration (C max) of EE, and total and unbound GSD (Studies 1 and 2). AUC and C max of midazolam (Study 3). Co-administration of CYP3A4 inhibitors did not affect EE metabolism, and had only weak effects on the PK of total and unbound GSD. The patch had no clinically relevant effect on metabolism of the CYP3A4 substrate midazolam.

  8. Physicians' responses to computerized drug interaction alerts with password overrides.

    PubMed

    Nasuhara, Yasuyuki; Sakushima, Ken; Endoh, Akira; Umeki, Reona; Oki, Hiromitsu; Yamada, Takehiro; Iseki, Ken; Ishikawa, Makoto

    2015-08-28

    Although evidence has suggested that computerized drug-drug interaction alert systems may reduce the occurrence of drug-drug interactions, the numerous reminders and alerts generated by such systems could represent an excessive burden for clinicians, resulting in a high override rate of not only unimportant, but also important alerts. We analyzed physicians' responses to alerts of relative contraindications and contraindications for coadministration in a computerized drug-drug interaction alert system at Hokkaido University Hospital. In this system, the physician must enter a password to override an alert and continue an order. All of the drug-drug interaction alerts generated between December 2011 and November 2012 at Hokkaido University Hospital were included in this study. The system generated a total of 170 alerts of relative contraindications and contraindication for coadministration; 59 (34.7 %) of the corresponding orders were cancelled after the alert was accepted, and 111 (65.3 %) were overridden. The most frequent contraindication alert was for the combination of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and fibrates. No incidents involving drug-drug interactions were reported among patients who were prescribed contraindicated drug pairs after an override. Although computerized drug-drug interaction alert systems that require password overrides appear useful for promoting medication safety, having to enter passwords to override alerts may represent an excessive burden for the prescribing physician. Therefore, both patient safety and physicians' workloads should be taken into consideration in future designs of computerized drug-drug interaction alert systems.

  9. Drug-Drug Multicomponent Solid Forms: Cocrystal, Coamorphous and Eutectic of Three Poorly Soluble Antihypertensive Drugs Using Mechanochemical Approach.

    PubMed

    Haneef, Jamshed; Chadha, Renu

    2017-08-01

    The present study deals with the application of mechanochemical approach for the preparation of drug-drug multicomponent solid forms of three poorly soluble antihypertensive drugs (telmisartan, irbesartan and hydrochlorothiazide) using atenolol as a coformer. The resultant solid forms comprise of cocrystal (telmisartan-atenolol), coamorphous (irbesartan-atenolol) and eutectic (hydrochlorothiazide-atenolol). The study emphasizes that solid-state transformation of drug molecules into new forms is a result of the change in structural patterns, diminishing of dimers and creating new facile hydrogen bonding network based on structural resemblance. The propensity for heteromeric or homomeric interaction between two different drugs resulted into diverse solid forms (cocrystal/coamorphous/eutectics) and become one of the interesting aspects of this research work. Evaluation of these solid forms revealed an increase in solubility and dissolution leading to better antihypertensive activity in deoxycorticosterone acetate (DOCA) salt-induced animal model. Thus, development of these drug-drug multicomponent solid forms is a promising and viable approach to addressing the issue of poor solubility and could be of considerable interest in dual drug therapy for the treatment of hypertension.

  10. Drug-drug interaction of the anti-TFPI aptamer BAX499 and factor VIII: studies of spatial dynamics of fibrin clot formation in hemophilia A.

    PubMed

    Parunov, Leonid A; Soshitova, Natalia P; Fadeeva, Olga A; Balandina, Anna N; Kopylov, Konstantin G; Kumskova, Maria A; Gilbert, James C; Schaub, Robert G; McGinness, Kathleen E; Ataullakhanov, Fazoil I; Panteleev, Mikhail A

    2014-01-01

    In recent years, a number of tissue factor pathway inhibitor (TFPI) antagonists have been developed to serve as bypassing agents to improve hemostasis in hemophilia A. Since TFPI antagonists and FVIII concentrates are procoagulants, their combined effect on spatial clot formation could be potentially pro-thrombotic. To investigate the cooperative effect of TFPI inhibition and supplementation of FVIII in hemophilia A in a spatial, reaction-diffusion experiment in vitro. Plasma was collected at different time points from hemophilia A patients undergoing prophylaxis and was supplemented in vitro with TFPI inhibitor BAX499 (formerly ARC19499) at concentrations from 0 up to 600nM. Clotting propagation in recalcified plasma activated by a surface with immobilized tissue factor (TF) was monitored by videomicroscopy. Increasing concentration of BAX499 improved coagulation for all hemophilia A plasma samples activated with TF at 1.6pmole/m(2) by shortening lag time and increasing initial clot growth velocity and clot size. In contrast, plasma concentration of FVIII had little effect on lag time, but increased spatial clot growth velocity. There was a decrease in the BAX499 efficiency as FVIII concentration increased (lag time shortened by 50% if FVIII:C<5%, but the effect was only 25% if FVIII:C>30%). The results indicate that BAX499 has an effect on clotting in hemophilia A plasma at low FVIII concentrations, however has little effect at high FVIII concentrations. © 2013.

  11. Potential drug interactions in patients given antiretroviral therapy

    PubMed Central

    dos Santos, Wendel Mombaque; Secoli, Silvia Regina; Padoin, Stela Maris de Mello

    2016-01-01

    ABSTRACT Objective: to investigate potential drug-drug interactions (PDDI) in patients with HIV infection on antiretroviral therapy. Methods: a cross-sectional study was conducted on 161 adults with HIV infection. Clinical, socio demographic, and antiretroviral treatment data were collected. To analyze the potential drug interactions, we used the software Micromedex(r). Statistical analysis was performed by binary logistic regression, with a p-value of ≤0.05 considered statistically significant. Results: of the participants, 52.2% were exposed to potential drug-drug interactions. In total, there were 218 potential drug-drug interactions, of which 79.8% occurred between drugs used for antiretroviral therapy. There was an association between the use of five or more medications and potential drug-drug interactions (p = 0.000) and between the time period of antiretroviral therapy being over six years and potential drug-drug interactions (p < 0.00). The clinical impact was prevalent sedation and cardiotoxicity. Conclusions: the PDDI identified in this study of moderate and higher severity are events that not only affect the therapeutic response leading to toxicity in the central nervous and cardiovascular systems, but also can interfere in tests used for detection of HIV resistance to antiretroviral drugs. PMID:27878224

  12. Cephradine antacids interaction studies.

    PubMed

    Arayne, M Saeed; Sultana, Najma; Afzal, M

    2007-07-01

    The present work comprises of interaction studies of cephradine with antacids. Cephradine is included among the first generation cephalosporin, which is active against a wide range of Gram positive and Gram-negative bacteria including penicillinase-producing staphylococci. Since the presence of complexing ligand may affect the bioavailability of a drug in blood or tissues, therefore, in order to study the probable interaction of cephradine with antacids all the reaction conditions were simulated to natural environments. Antacids are commonly used in patients complaining of GI irritations. The behavior of cephradine in presence of seven antacids i.e., simethicone, magaldrate, magnesium carbonate, magnesium hydroxide, magnesium trisilicate, sodium bicarbonate and aluminium hydroxide was studied by using standard dissolution apparatus. Cephradine was monitored both by UV and by high performance liquid chromatography. The results revealed that antacids containing polyvalent cations retarded the in vitro availability of cephradine. Moreover, these studies indicated that cephradine was strongly adsorbed on antacids; magnesium trisilicate and simeco tablets (powdered) exhibited relatively higher adsorption capacities.

  13. Critical Density Interaction Studies

    SciTech Connect

    Young, P; Baldis, H A; Cheung, P; Rozmus, W; Kruer, W; Wilks, S; Crowley, S; Mori, W; Hansen, C

    2001-02-14

    Experiments have been performed to study the propagation of intense laser pulses to high plasma densities. The issue of self-focusing and filamentation of the laser pulse as well as developing predictive capability of absorption processes and x-ray conversion efficiencies is important for numerous programs at the Laboratory, particularly Laser Program (Fast Ignitor and direct-drive ICF) and D&NT (radiography, high energy backlighters and laser cutting). Processes such as resonance absorption, profile modification, linear mode conversion, filamentation and stimulated Brillouin scattering can occur near the critical density and can have important effects on the coupling of laser light to solid targets. A combination of experiments have been used to study the propagation of laser light to high plasma densities and the interaction physics of intense laser pulses with solid targets. Nonparaxial fluid codes to study nonstationary behavior of filamentation and stimulated Brillouin scattering at high densities have also been developed as part of this project.

  14. Design, Characterization, and Optimization of Controlled Drug Delivery System Containing Antibiotic Drug/s

    PubMed Central

    Shelate, Pragna; Dave, Divyang

    2016-01-01

    The objective of this work was design, characterization, and optimization of controlled drug delivery system containing antibiotic drug/s. Osmotic drug delivery system was chosen as controlled drug delivery system. The porous osmotic pump tablets were designed using Plackett-Burman and Box-Behnken factorial design to find out the best formulation. For screening of three categories of polymers, six independent variables were chosen for Plackett-Burman design. Osmotic agent sodium chloride and microcrystalline cellulose, pore forming agent sodium lauryl sulphate and sucrose, and coating agent ethyl cellulose and cellulose acetate were chosen as independent variables. Optimization of osmotic tablets was done by Box-Behnken design by selecting three independent variables. Osmotic agent sodium chloride, pore forming agent sodium lauryl sulphate, and coating agent cellulose acetate were chosen as independent variables. The result of Plackett-Burman and Box-Behnken design and ANOVA studies revealed that osmotic agent and pore former had significant effect on the drug release up to 12 hr. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of the optimization procedure in successful development of porous osmotic pump tablets containing antibiotic drug/s by using sodium chloride, sodium lauryl sulphate, and cellulose acetate as key excipients. PMID:27610247

  15. Application of Caco-2 Cell Line in Herb-Drug Interaction Studies: Current Approaches and Challenges

    PubMed Central

    Awortwe, C.; Fasinu, P.S.; Rosenkranz, B.

    2015-01-01

    The Caco-2 model is employed in pre-clinical investigations to predict the likely gastrointestinal permeability of drugs because it expresses cytochrome P450 enzymes, transporters, microvilli and enterocytes of identical characteristics to the human small intestine. The FDA recommends this model as integral component of the Biopharmaceutics Classification System (BCS). Most dedicated laboratories use the Caco-2 cell line to screen new chemical entities through prediction of its solubility, bioavailability and the possibility of drug-drug or herb-drug interactions in the gut lumen. However, challenges in the inherent characteristics of Caco-2 cell and inter-laboratory protocol variations have resulted to generation of irreproducible data. These limitations affect the extrapolation of data from pre-clinical research to clinical studies involving drug-drug and herb-drug interactions. This review addresses some of these caveats and enumerates the plausible current and future approaches to reduce the anomalies associated with Caco-2 cell line investigations focusing on its application in herb-drug interactions. PMID:24735758

  16. Arc electrode interaction study

    NASA Technical Reports Server (NTRS)

    Zhou, X.; Berns, D.; Heberlein, J.

    1994-01-01

    The project consisted of two parts: (1) the cathode interaction studies which were a continuation of previous work and had the objective of increasing our understanding of the microscopic phenomena controlling cathode erosion in arc jet thrusters, and (2) the studies of the anode attachment in arc jet thrusters. The cathode interaction studies consisted of (1) a continuation of some modeling work in which the previously derived model for the cathode heating was applied to some specific gases and electrode materials, and (2) experimental work in which various diagnostics was applied to the cathode. The specific diagnostics used were observation of the cathode tip during arcing using a Laser Strobe Video system in conjunction with a tele-microscope, a monochromator with an optical multichannel analyzer for the determination of the cathode temperature distribution, and various ex situ materials analysis methods. The emphasis of our effort was shifted to the cathode materials analysis because a parallel project was in place during the second half of 1993 with a visiting scientist pursuing arc electrode materials studies. As a consequence, the diagnostic investigations of the arc in front of the cathode had to be postponed to the first half of 1994, and we are presently preparing these measurements. The results of last year's study showed some unexpected effects influencing the cathode erosion behavior, such as increased erosion away from the cathode tip, and our understanding of these effects should improve our ability to control cathode erosion. The arc jet anode attachment studies concentrated on diagnostics of the instabilities in subsonic anode attachment arc jet thrusters, and were supplemental measurements to work which was performed by one of the authors who spent the summer as an intern at NASA Lewis Research Center. A summary of the results obtained during the internship are included because they formed an integral part of the study. Two tasks for 1994, the

  17. Studies on Strong Interactions

    NASA Astrophysics Data System (ADS)

    Coriano, Claudio

    Five studies, four in Quantum field theory and one in fermionic molecular dynamics are presented. In the first study, introduced in chapter one and developed in chapter two of this dissertation, we formulate an extension of QCD sum rules to Compton scattering of the pion at intermediate energy. The chapter is based on the research paper Fixed angle pion Compton scattering and QCD sum rules by Prof. George Sterman and the author, which has been submitted for publication as a regular article. In chapter 3 we discuss the relation between traditional bosonic exchange models of nuclear strong interaction and soliton models, in the particular case of the sine-Gordon model. The chapter is based on the research paper "Scattering in soliton models and bosonic exchange descriptions", by R. R. Parwani, H. Yamagishi, I. Zahed and the author, and is published in Phys. Rev. D 45 (1992), 2542. A preprint of this paper (Preprint 1) has been included as an Appendix to the Chapter. In Chapter 4 we discuss aspects of the propagation of quantized fields in classical backgrounds, using the light-cone expansion of the propagator. The chapter is based on the research papers "Electrodynamics in the presence of an axion", published by the author in Modern Physics Letters A 7 (1992), 1253, and on the paper "Singularity of Green's function and the effective action in massive Yang Mills theories, by Prof. H. Yamagishi and the author. This last paper is published in Physical Review D 41 (1990), 3226 and its reprint appears in the final part of the Chapter (Reprint 1). In chapter 5, entitled "On the time dependent Rayleigh-Ritz equations", we discuss aspects of the variational approach to fermionic molecular dynamics. This investigation by R. Parwani, H. Yamagishi and the author has been published in Nucl. Physics A 522 (1991), 591. A preprint of this research paper has been inserted in the final part of the Chapter (Preprint 2).

  18. The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis.

    PubMed

    Hou, Mei-Ling; Lin, Chi-Hung; Lin, Lie-Chwen; Tsai, Tung-Hu

    2015-10-01

    Clozapine, an atypical antipsychotic agent, is highly effective in treatment-resistant schizophrenia; however, its major side effect is constipation. Instead of laxatives, rhein is a pharmacologically active component found in Rheum palmatum L., a medicinal herbal remedy for constipation. The purpose of this study is to determine whether rhein impacts the pharmacokinetics (PK) and pharmacodynamics (PD) of clozapine in brain when used to relieve clozapine-induced constipation. Here, we have investigated not only the PK of clozapine in blood but also the effects of rhein on the PK of clozapine in blood and in brain extracellular fluid together with the PD effects on neurotransmitters in extracellular fluid. The concentrations of clozapine and norclozapine in biologic samples were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The drug-drug effects of rhein on extracellular neurotransmitter efflux in the rat medial prefrontal cortex (mPFC) produced by clozapine were assayed by high-performance liquid chromatography-electrochemical detection. The results demonstrate that the clozapine PK was nonlinear. Pretreatment with rhein for 7 days increased the total blood concentration of clozapine, but significantly reduced the unbound clozapine concentrations in the mPFC by approximately 3-fold. Furthermore, 7 days of rhein pretreatment thoroughly abolished the efflux of dopamine and its metabolite (3,4-dihydroxyphenylacetic acid) and altered the profile of homovanillic acid, another metabolite of dopamine, in the mPFC. In conclusion, rhein was found to substantially decrease clozapine and norclozapine concentrations in the mPFC dialysate, and this is accompanied by lower concentrations in the neurotransmitters in the same biophase. These findings suggest that a detailed clinical study for drug-drug interactions is recommended.

  19. The Pharmacokinetic Interaction Study between Carvedilol and Bupropion in Rats.

    PubMed

    Abrudan, Maria Bianca; Muntean, Dana Maria; Gheldiu, Ana Maria; Neag, Maria Adriana; Vlase, Laurian

    2017-01-01

    The effects of multiple-dose bupropion on the pharmacokinetics of single-dose carvedilol were investigated in order to evaluate this possible drug-drug interaction. A preclinical study was conducted among white male Wistar rats. Each rat was cannulated on the femoral vein prior to being connected to BASi Culex ABC®. During the reference period, each rat received an intravenous and an oral dose of 3.57 mg/kg body weight (b.w.) carvedilol, at 2 days distance. After 5 days of pretreatment with 21.42 mg/kg b.w. bupropion (by oral route, twice a day - given in order to reach the steady state), during the sixth day, 3.57 mg/kg b.w. carvedilol and 21.42 mg/kg b.w. bupropion were orally co-administrated (test period). After each administration of carvedilol, several samples of 200 µL blood were collected. The pharmacokinetic parameters of carvedilol were analyzed by the noncompartmental method. The 5 days pretreatment with bupropion increased the exposure to carvedilol in rats by 180%, considering the modifications observed in the area under the curve of carvedilol. Carvedilol was shown to have higher plasma concentrations, delay in maximum concentration, and a prolonged half-life, after being pretreated with bupropion. The administration of multiple-dose bupropion influences the pharmacokinetics of carvedilol (single oral dose) in rats. © 2017 S. Karger AG, Basel.

  20. A current review of cytochrome P450 interactions of psychotropic drugs.

    PubMed

    Madhusoodanan, Subramoniam; Velama, Umamaheswararao; Parmar, Jeniel; Goia, Diana; Brenner, Ronald

    2014-05-01

    The number of psychotropic drugs has expanded tremendously over the past few decades with a proportional increase in drug-drug interactions. The majority of psychotropic agents are biotransformed by hepatic enzymes, which can lead to significant drug-drug interactions. Most drug-drug interactions of psychotropics occur at metabolic level involving the hepatic cytochrome P450 enzyme system. We searched the National Library of Medicine, PsycINFO, and Cochrane reviews from 1981 to 2012 for original studies including clinical trials, double-blind, placebo-controlled studies, and randomized controlled trials. In addition, case reports, books, review articles, and hand-selected journals were utilized to supplement this review. Based on the clinical intensity of outcome, cytochrome interactions can be classified as severe, moderate, and mild. Severe interactions include effects that might be acutely life threatening. They are mainly inhibitory interactions with cardiovascular drugs. Moderate interactions include efficacy issues. Mild interactions include nonserious side effects, such as somnolence. Psychotropic drugs may interact with other prescribed medications used to treat concomitant medical illnesses. A thorough understanding of the most prescribed medications and patient education will help reduce the likelihood of potentially fatal drug-drug interactions.

  1. HIV/HCV Antiviral Drug Interactions in the Era of Direct-acting Antivirals

    PubMed Central

    Rice, Donald P.; Faragon, John J.; Banks, Sarah; Chirch, Lisa M.

    2016-01-01

    Abstract Therapy for human immunodeficiency virus (HIV) and chronic hepatitis C has evolved over the past decade, resulting in better control of infection and clinical outcomes; however, drug-drug interactions remain a significant hazard. Joint recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America regarding drug-drug interactions between HIV antiretroviral agents and direct-acting antiviral agents for treatment of hepatitis C virus (HCV) infection are reviewed here. This review is oriented to facilitate appropriate selection of an antiviral therapy regimen for HCV infection based on the choice of antiretroviral therapy being administered and, if necessary, switching antiretroviral regimens. PMID:27777891

  2. Studies of food drug interactions.

    PubMed

    Aman, Syed Faisal; Hassan, Fouzia; Naqvi, Baqar S; Hasan, Syed Muhammmad Farid

    2010-07-01

    Medicines can treat and alleviate many diseases provided that they must be taken properly to ensure that they are safe and useful. One issue related with the medicines is that whether to take on empty stomach or with food. The present work gives information regarding food-drug interactions that were studied by collecting seventy five prescriptions from various hospitals. In most of the collected prescriptions, food-drug interactions were detected using the literature available. It was also found that only few studies have been carried out so far on the effect of food on drug disposition in the Asian population. Thus more studies on food-drug interactions particularly in the local population is recommended in order to determine the effect of food and food components on drug disposition and to the kinetics of the drugs which has not yet well highlighted in this part of the world.

  3. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies.

    PubMed

    Hill, George; Cihlar, Tomas; Oo, Charles; Ho, Edmund S; Prior, Ken; Wiltshire, Hugh; Barrett, Jo; Liu, Baulian; Ward, Penny

    2002-01-01

    Oseltamivir is an ester prodrug of the active metabolite [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a potent and selective inhibitor of neuraminidase enzyme of influenza virus. Oseltamivir is rapidly hydrolyzed by hepatic carboxylesterases to Ro 64-0802, which is then exclusively excreted by glomerular filtration and active tubular secretion without further metabolism. In vivo and in vitro studies were conducted to evaluate the renal drug-drug interaction potential of oseltamivir. Crossover studies were conducted in healthy subjects in which oral oseltamivir was administered alone and coadministered with probenecid, cimetidine, or amoxicillin. Probenecid completely blocked the renal secretion of Ro 64-0802, increasing systemic exposure (area under the curve) by 2.5-fold, but no interaction was observed with cimetidine or amoxicillin. These in vivo data show that Ro 64-0802 is secreted via an organic anion pathway, but Ro 64-0802 does not inhibit amoxicillin renal secretion. In vitro effects of Ro 64-0802 on the human renal organic anionic transporter 1 (hOAT1) were investigated using novel Chinese hamster ovary cells stably transfected with hOAT1. Ro 64-0802 was found to be a low-efficiency substrate for hOAT1 and a very weak inhibitor of hOAT1-mediated transport of p-aminohippuric acid (PAH). Ro 64-0802 did not inhibit the hOAT1-mediated transport of amoxicillin. In contrast, probenecid effectively inhibited the transport of PAH, Ro 64-0802, and amoxicillin via hOAT1. These in vitro observations are consistent with the in vivo data, validating the usefulness of the in vitro system for evaluating such drug-drug interaction. The study results demonstrate that oseltamivir has a low drug-drug interaction potential at the renal tubular level due to inhibition of hOAT1.

  4. The role of competitive binding to human serum albumin on efavirenz-warfarin interaction: a nuclear magnetic resonance study.

    PubMed

    Wanke, Riccardo; Harjivan, Shrika G; Pereira, Sofia A; Marques, M Matilde; Antunes, Alexandra M M

    2013-11-01

    The potential for co-prescription of the anti-human immunodeficiency virus (anti-HIV) drug efavirenz (EFV) and the oral anticoagulant warfarin (WAR) is currently high as EFV is a drug of choice for HIV type 1 infection and because cardiovascular disease is increasing among HIV-infected individuals. However, clinical reports of EFV-WAR interaction, leading to WAR overdosing, call for elucidation of the mechanisms involved in this drug-drug interaction. Here we present the first report demonstrating competition of the two drugs for the same binding site of human serum albumin. Using ligand-based nuclear magnetic resonance experiments, this study proves that EFV has an effect on the concentration of free WAR. This previously unidentified EFV-WAR interaction represents a potential risk factor that should be taken into account when considering treatment options. Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  5. Elucidation of the biochemical basis for a clinical drug-drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), a subtype selective agonist of the peroxisome proliferator-activated receptor alpha.

    PubMed

    Kalgutkar, Amit S; Chen, Danny; Varma, Manthena V; Feng, Bo; Terra, Steven G; Scialis, Renato J; Rotter, Charles J; Frederick, Kosea S; West, Mark A; Goosen, Theunis C; Gosset, James R; Walsky, Robert L; Francone, Omar L

    2013-11-01

    1. 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans. 2. The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (n = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778875 (1.0 mg QD) on days 5-12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778875. Subjects in group B (n = 29) received CP-778875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5-12. 3. Mean maximum serum concentration (Cmax) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778875. Statistically significant increases in the systemic exposure of ortho- and para-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778875. CP-778875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin. 4.  Inhibition of organic anion transporting polypeptide 1B1 by CP-778875 (IC50 = 2.14 ± 0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin.

  6. Extraterrestrial Studies Using Nuclear Interactions

    NASA Technical Reports Server (NTRS)

    Reedy, Robert C.

    2003-01-01

    Cosmogenic nuclides were used to study the recent histories of the aubrite Norton County and the pallasite Brenham using calculated production rates. Calculations were done of the rates for making cosmogenic noble-gas isotopes in the Jovian satellite Europa by the interactions of galactic cosmic rays and especially trapped Jovian protons. Cross sections for the production of cosmogenic nuclides were reported and plans made to measure additional cross sections. A new code, MCNPX, was used to numerically simulate the interactions of cosmic rays with matter and the subsequent production of cosmogenic nuclides. A review was written about studies of extraterrestrial matter using cosmogenic radionuclides. Several other projects were done. Results are reviewed here with references to my recent publications for details.

  7. IRAS study of interacting galaxies

    NASA Astrophysics Data System (ADS)

    Allam, S.

    1998-04-01

    Interacting galaxies are ideal laboratories for studying the influence of gravitational forces on galaxies. From theoretical and observational studies, we know how sensitive galaxies are to tidal interaction, from the formation of tidal tails, bridges, bursts of star formation up to a complete merging of the galaxies. The Far Infrared (FIR) properties of interacting galaxies give information on the dynamical and physical properties of these systems. Several earlier studies using the IRAS point source catalogue (IPSC) and IRAS Faint Source Survey (FSS), showed that the FIR emission from interacting/merging galaxies is enhanced with respect to isolated non-interacting galaxies; moreover, that high density environments have more influence in producing enhanced FIR emission over isolated interacting systems. In general the ratio of FIR to optical luminosity in interacting systems was found to be enhanced. It is regarded as an increased star formation (SF) rate in these systems. Later on, due to the rather high IPSC detection threshold, and its low resolution, several contradictory results have been reported. In this thesis the FIR emission from interacting galaxies is studied by using the high resolution IRAS software introduced by Bontekoe et al. (1994). This soft ware package uses a Maximum Entropy method (hereafter MaxEnt). The MaxEnt formulation is rooted in Bayesian probability theory. The raw IRAS data contains the Point Spread Function (PSF) of both the telescope mirror (60 cm --> 1 arcmin at 60 μm) and the PSF of the detectors (≃ 5 arcmin). Since there is much redundancy in the data, the MaxEnt routine can be used to remove the 5 arcmin PSF from the detectors. For many interacting galaxies this is enough to resolve them. The size of the images was chosen such that the objects could be studied including their surroundings. The absolute position calibration and flux estimates for the MaxEnt images are described in Allam et al. (1996). Because of the high

  8. Water-module interaction studies

    NASA Technical Reports Server (NTRS)

    Mon, G.; Wen, L.; Ross, R., Jr.

    1988-01-01

    Mechanisms by which moisture enters photovoltaic modules and techniques for reducing such interactions are reported. Results from a study of the effectiveness of various module sealants are given. Techniques for measuring the rate and quantity of moisture ingress are discussed. It is shown that scribe lines and porous frit bridging conductors provide preferential paths for moisture ingress and that moisture diffusion by surface/interfacial paths is considerably more rapid than diffusion by bulk paths, which implies that thin-film substrate and supersubstrate modules are much more vulnerable to moist environments than are bulk-encapsulated crystalline-silicon modules. Design approaches that reduce moisture entry are discussed.

  9. Effect of ketoconazole on the pharmacokinetics of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor ABT-384 and its two active metabolites in healthy volunteers: population analysis of data from a drug-drug interaction study.

    PubMed

    An, Guohua; Liu, Wei; Katz, David A; Marek, Gerard; Awni, Walid; Dutta, Sandeep

    2013-05-01

    ABT-384 [1-piperazineacetamide, N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]-α,α-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-,stereoisomer] is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). ABT-384 has been shown to be safe and well tolerated in humans at doses up to 100 mg daily, and to fully inhibit both peripheral and brain HSD-1 at a dose of 2 mg daily. The effect of ketoconazole on the pharmacokinetics of ABT-384 and its two active metabolites, A-1331480 and A-847082, was investigated in healthy volunteers. When 10 mg of ABT-384 was coadministered with ketoconazole, ABT-384 exposures increased 18-fold for area under the plasma concentration-time curve from time 0 to infinity and 3.5-fold for Cmax. The results suggest that ABT-384 is a sensitive substrate of CYP3A. After ketoconazole coadministration, exposures of A-1331480 and A-847082 were also greatly increased. A population pharmacokinetic model was constructed for ABT-384 and its metabolites using NonMEM. A two-compartment model with three transit absorption compartments best described ABT-384 data. The model predicted a 69.3% decrease in ABT-384 clearance and 91.1% increase in the volume of distribution of ABT-384 in the presence of ketoconazole. A-1331480 was shown to be formation rate-limited and A-847082 was elimination rate-limited. Both metabolites were characterized by a one-compartment model with first-order rate constants of formation and elimination. Overall the model adequately captured the concentration-time profiles of ABT-384, A-1331480, and A-847082 in both ABT-384-alone and ketoconazole-coadministration conditions. Although ABT-384 exposures were greatly increased in the presence of ketoconazole, coadministration of ABT-384 with ketoconazole or other strong/moderate CYP3A inhibitors is not expected to contribute to any major clinical safety issues considering the favorable safety profile of ABT-384.

  10. Allosteric cross-talk in chromatin can mediate drug-drug synergy

    NASA Astrophysics Data System (ADS)

    Adhireksan, Zenita; Palermo, Giulia; Riedel, Tina; Ma, Zhujun; Muhammad, Reyhan; Rothlisberger, Ursula; Dyson, Paul J.; Davey, Curt A.

    2017-03-01

    Exploitation of drug-drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug-drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.

  11. Allosteric cross-talk in chromatin can mediate drug-drug synergy.

    PubMed

    Adhireksan, Zenita; Palermo, Giulia; Riedel, Tina; Ma, Zhujun; Muhammad, Reyhan; Rothlisberger, Ursula; Dyson, Paul J; Davey, Curt A

    2017-03-30

    Exploitation of drug-drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug-drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.

  12. Drug interactions with levothyroxine therapy in patients with hypothyroidism: observational study in gen