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https://www.readbyqxmd.com/read/28444890/utilizing-pbpk-modeling-to-evaluate-the-potential-of-a-significant-drug-drug-interaction-between-clopidogrel-and-dasabuvir-a-scientific-perspective
#1
V Arya, P Zhao, K S Reynolds, P Mishra, I R Younis
Dasabuvir, a component of VIEKIRA PAK, is a substrate of CYP2C8 enzymes. Prescribing information for VIEKIRA PAK contraindicates gemfibrozil, a strong CYP2C8 inhibitor, because coadministration significantly increases dasabuvir exposures, which may increase the risk of QT prolongation. Clopidogrel may increase dasabuvir exposures primarily due to CYP2C8 inhibition by clopidogrel-acyl-β-D-glucuronide. This commentary outlines the US Food and Drug Administration (FDA) interdisciplinary review team's scientific perspective to address the potential for a significant drug-drug interaction (DDI) between clopidogrel and VIEKIRA PAK...
April 26, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28439684/impact-of-altered-endogenous-igg-on-unspecific-mab-clearance
#2
Saskia Fuhrmann, Charlotte Kloft, Wilhelm Huisinga
Immunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data...
April 24, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28438781/transporter-mediated-disposition-clinical-pharmacokinetics-and-cholestatic-potential-of-glyburide-and-its-primary-active-metabolites
#3
Rui Li, Yi-An Bi, Anna Vildhede, Renato J Scialis, Sumathy Mathialagan, Xin Yang, Lisa D Marroquin, Jian Lin, Manthena V S Varma
Glyburide is widely used for the treatment of type 2 diabetes mellitus. We studied the mechanisms involved in the disposition of glyburide and its pharmacologically active hydroxy metabolites, M1 and M2b; and evaluated their clinical pharmacokinetics and the potential role in glyburide-induced cholestasis employing physiologically based pharmacokinetic (PBPK) modeling. Transport studies of parent and metabolites in human hepatocytes and transfected cell systems imply hepatic uptake mediated by organic anion transporting polypeptides...
April 24, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28412400/prediction-of-losartan-active-carboxylic-acid-metabolite-exposure-following-losartan-administration-using-static-and-physiologically-based-pharmacokinetic-models
#4
Hoa Q Nguyen, Jian Lin, Emi Kimoto, Ernesto Callegari, Susanna Tse, R Scott Obach
The aim of this study was to evaluate a strategy based on static and dynamic physiologically based pharmacokinetic (PBPK) modeling for the prediction of metabolite and parent drug area under the time-concentration curve ratio (AUCm/AUCp) and their PK profiles in humans using in vitro data when active transport processes are involved in disposition. The strategy was applied to losartan and its pharmacologically active metabolite carboxylosartan as test compounds. Hepatobiliary transport including transport-mediated uptake, canilicular and basolateral efflux, and metabolic clearance estimates were obtained from in vitro studies using human liver microsomes and sandwich cultured hepatocytes...
April 12, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28411400/physiologically-based-pharmacokinetic-modeling-suggests-limited-drug-drug-interaction-between-clopidogrel-and-dasabuvir
#5
Mohamad Shebley, Wentao Fu, Prajakta Badri, Daniel A J Bow, Volker Fischer
Dasabuvir, a non-nucleoside 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...
April 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28408153/refinement-of-the-oral-exposure-description-in-the-cyclic-siloxane-pbpk-model-for-rats-and-humans-implications-for-exposure-assessment
#6
Jerry L Campbell, Melvin E Andersen, Cynthia Van Landingham, Robinan Gentry, Elke Jensen, Jean Y Domoradzki, Harvey J Clewell
The multi-compound, and multi-dose (MC-MD) route physiologically based pharmacokinetic (PBPK) model for cyclic siloxanes reported by McMullin et al. (2016) brought together the series of models for octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) in rat and human into a unified code structure that would allow simulation of both compounds following the inhalation and dermal routes of exposure. The refined MC-MD PBPK model presented here expands upon this effort to include representation of rat kinetic data in plasma, tissues and exhaled breath for the parent compounds after oral bolus administration...
April 10, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28402537/performance-assessment-and-translation-of-physiologically-based-pharmacokinetic-models-from-acslx%C3%A2-to-berkeley-madonna%C3%A2-matlab%C3%A2-and-r-language-oxytetracycline-and-gold-nanoparticles-as-case-examples
#7
Zhoumeng Lin, Majid Jaberi-Douraki, Chunla He, Shiqiang Jin, Raymond S H Yang, Jeffrey W Fisher, Jim E Riviere
Many physiologically based pharmacokinetic (PBPK) models for environmental chemicals, drugs, and nanomaterials have been developed to aid risk and safety assessments using acslXTM. However, acslXTM has been rendered sunset since November 2015. Alternative modeling tools and tutorials are needed for future PBPK applications. This forum article aimed to: (1) demonstrate the performance of four PBPK modeling software packages (acslXTM, Berkeley MadonnaTM, MATLAB®, and R language) tested using two existing models (oxytetracycline and gold nanoparticles); (2) provide a tutorial of PBPK model code conversion from acslXTM to Berkeley MadonnaTM, MATLAB®, and R language; (3) discuss the advantages and disadvantages of each software package in the implementation of PBPK models in toxicology, and (4) share our perspective about future direction in this field...
April 8, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28402492/predicting-transport-of-3-5-6-trichloro-2-pyridinol-tcpy-into-saliva-using-a-combination-experimental-and-computational-approach
#8
Jordan Ned Smith, Zana A Carver, Thomas J Weber, Charles Timchalk
A combination experimental and computational approach was developed to predict chemical transport into saliva. A serous-acinar chemical transport assay was established to measure chemical transport with non-physiological (standard cell culture medium) and physiological (using surrogate plasma and saliva medium) conditions using 3,5,6-trichloro-2-pyridinol (TCPy) a metabolite of the pesticide chlorpyrifos. High levels of TCPy protein binding were observed in cell culture medium and rat plasma resulting in different TCPy transport behaviors in the two experimental conditions...
April 11, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28398693/development-and-qualification-of-physiologically-based-pharmacokinetic-models-for-drugs-with-atypical-distribution-behavior-a-desipramine-case-study
#9
T S Samant, V Lukacova, S Schmidt
Desipramine is a secondary tricyclic amine, which is primarily metabolized by cytochrome 2D6. It shows a high volume of distribution (Vss) (10-50 L/kg) due to its high lipophilicity, unspecific phospholipid binding, and lysosomal trapping. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for desipramine, which accounts for the high Vss of the drug following intravenous and oral administration of doses up to 100 mg. The model also accounts for the extended time to reach maximum concentration after oral dosing due to enterocyte trapping...
April 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28397089/virtual-clinical-studies-to-examine-the-probability-distribution-of-the-auc-at-target-tissues-using-physiologically-based-pharmacokinetic-modeling-application-to-analyses-of-the-effect-of-genetic-polymorphism-of-enzymes-and-transporters-on-irinotecan-induced
#10
Kota Toshimoto, Atsuko Tomaru, Masakiyo Hosokawa, Yuichi Sugiyama
PURPOSE: To establish a physiologically-based pharmacokinetic (PBPK) model for analyzing the factors associated with side effects of irinotecan by using a computer-based virtual clinical study (VCS) because many controversial associations between various genetic polymorphisms and side effects of irinotecan have been reported. METHODS: To optimize biochemical parameters of irinotecan and its metabolites in the PBPK modeling, a Cluster Newton method was introduced...
April 10, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28392453/physiologically-based-pharmacokinetic-modeling-of-therapeutic-proteins
#11
Harvey Wong, Timothy W Chow
Biologics or therapeutic proteins are becoming increasingly important as treatments for disease. The most common class of biologics are monoclonal antibodies (mAbs). Recently, there has been an increase in the use of physiologically-based pharmacokinetic (PBPK) modeling in the pharmaceutical industry in drug development. We review PBPK models for therapeutic proteins with an emphasis on mAbs. Due to their size and similarity to endogenous antibodies, there are distinct differences between PBPK models for small molecules and mAbs...
April 6, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28392392/combining-transcriptomics-and-pbpk-modeling-indicates-a-primary-role-of-hypoxia-and-altered-circadian-signaling-in-dichloromethane-carcinogenicity-in-mouse-lung-and-liver
#12
Melvin E Andersen, Michael B Black, Jerry L Campbell, Salil N Pendse, Harvey J Clewell Iii, Lynn H Pottenger, James S Bus, Darol E Dodd, Daniel C Kemp, Patrick D McMullen
Dichloromethane (DCM) is a lung and liver carcinogen in mice at inhalation exposures≥2000ppm. The modes of action (MOA) of these responses have been attributed to formation of genotoxic, reactive metabolite(s). Here, we examined gene expression in lung and liver from female B6C3F1 mice exposed to 0, 100, 500, 2000, 3000 and 4000ppm DCM for 90days. We also simulated dose measures - rates of DCM oxidation to carbon monoxide (CO) in lung and liver and expected blood carboxyhemoglobin (HbCO) time courses with a PBPK model inclusive of both conjugation and oxidation pathways...
April 6, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28392065/quantitative-bias-analysis-of-a-reported-association-between-perfluoroalkyl-substances-pfas-and-endometriosis-the-influence-of-oral-contraceptive-use
#13
Gerard Ngueta, Matthew P Longnecker, Miyoung Yoon, Christopher D Ruark, Harvey J Clewell, Melvin E Andersen, Marc-André Verner
An association between serum levels of perfluoroalkyl substances (PFAS) and endometriosis has recently been reported in an epidemiologic study. Oral contraceptive use to treat dysmenorrhea (pelvic pain associated with endometriosis) could potentially influence this association by reducing menstrual fluid loss, a route of excretion for PFAS. In this study, we aimed to evaluate the influence of differential oral contraceptive use on the association between PFAS and endometriosis. We used a published life-stage physiologically based pharmacokinetic (PBPK) model to simulate plasma levels of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) from birth to age at study participation (range 18-44years)...
April 6, 2017: Environment International
https://www.readbyqxmd.com/read/28391404/physiologically-based-pharmacokinetic-modeling-of-renally-cleared-drugs-in-pregnant-women
#14
André Dallmann, Ibrahim Ince, Juri Solodenko, Michaela Meyer, Stefan Willmann, Thomas Eissing, Georg Hempel
BACKGROUND: Since pregnant women are considerably underrepresented in clinical trials, information on optimal dosing in pregnancy is widely lacking. Physiologically based pharmacokinetic (PBPK) modeling may provide a method for predicting pharmacokinetic changes in pregnancy to guide subsequent in vivo pharmacokinetic trials in pregnant women, minimizing associated risks. OBJECTIVES: The goal of this study was to build and verify a population PBPK model that predicts the maternal pharmacokinetics of three predominantly renally cleared drugs (namely cefazolin, cefuroxime, and cefradine) at different stages of pregnancy...
April 8, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28390843/pbpk-modelling-of-drug-transporters-to-facilitate-individualized-dose-prediction
#15
Aleksandra Galetin, Ping Zhao, Shiew-Mei Huang
Physiologically-based pharmacokinetic (PBPK) modelling is a commonly used strategy in the drug development and regulatory submissions. This commentary provides a critical overview of the current status of PBPK methodologies to predict transporter-mediated pharmacokinetics, in addition to impact of disease and genetics with respect to local and systemic concentration.
April 5, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28389273/improved-physiologically-based-pharmacokinetic-model-for-oral-exposures-to-chromium-in-mice-rats-and-humans-to-address-temporal-variation-and-sensitive-populations
#16
C R Kirman, M Suh, D M Proctor, S M Hays
A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations...
April 5, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28386186/mechanistic-prediction-of-food-effects-for-compound-a-tablet-using-pbpk-model
#17
Xueqing Li, Lei Shi, Xiuling Tang, Qinghui Wang, Lun Zhou, Wei Song, Zhijun Feng, Jie Ge, Jian Kang Li, Lin Yang, Aidong Wen, Yan Zhang
Physiologically based pharmacokinetic (PBPK) modeling has been extensively used to study the factors of effect drug absorption, distribution, metabolize and extraction progress in human. In this study, Compound A(CPD A) is a BCS Class II drug, which has been extensive applied in clinical as lipid-lowering drug, administered orally after food, they displayed positive food effects in human, A PBPK model was built to mechanistic investigate the food effect of CPD A tablet in our study. By using gastroplus™ software, the PBPK models accurately predicted the results of food effects and predicted data were within 2-fold error of the observed results...
March 2017: Saudi Journal of Biological Sciences
https://www.readbyqxmd.com/read/28385615/identification-and-characterisation-of-a-salt-form-of-danirixin-with-reduced-pharmacokinetic-variability-in-patient-populations
#18
Jackie C Bloomer, Claire Ambery, Bruce E Miller, Paul Connolly, Helen Garden, Nick Henley, Neil Hodnett, Sarah Keel, James L Kreindler, Richard S Lloyd, Wayne Matthews, John Yonchuk, Aili L Lazaar
The natural variability of gastric pH or gastric acid reducing medications can result in lower and more variable clinical pharmacokinetics for basic compounds in patient populations. Progressing alternative salt forms with improved solubility and dissolution properties can minimise this concern. This manuscript outlines a nonclinical approach comprising multiple biopharmaceutical, in vitro and physiologically based pharmacokinetic model (PBPK) modelling studies to enable selection of an alternative salt form for danirixin (DNX, GSK1325756), a pharmaceutical agent being developed for chronic obstructive pulmonary disease (COPD)...
April 3, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28385544/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
#19
Akihiro Matsuda, Rudolf Karch, Martin Bauer, Alexander Traxl, Markus Zeitlinger, Oliver Langer
The purpose of this study was to establish physiologically based pharmacokinetic (PBPK) models to predict in humans the brain concentration-time profiles and P-glycoprotein (Pgp)-mediated brain drug-drug interactions (DDIs) 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 (PET) studies in humans...
April 3, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28382001/addressing-adherence-using-genotype-specific-pbpk-modeling-impact-of-drug-holidays-on-tamoxifen-and-endoxifen-plasma-levels
#20
Kristin J R Dickschen, Stefan Willmann, Georg Hempel, Michael Block
Introduction: Tamoxifen is one of the most common treatment opportunities for hormonal positive breast cancer. Despite its good tolerability, patients demonstrate decreasing adherence over years impacting on therapeutic success. PBPK modeling was applied to demonstrate the impact of drug holidays on plasma levels of tamoxifen and its active metabolite endoxifen for different CYP2D6 genotypes. Materials and Methods: A virtual study with 24,000 patients was conducted in order to investigate the development of tamoxifen steady-state kinetics in patient groups of different CYP2D6 genotypes...
2017: Frontiers in Pharmacology
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