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Simone Hansmann, Adam Darwich, Alison Margolskee, Leon Aarons, Jennifer Dressman
OBJECTIVES: The aim of this study was (1) to determine how closely physiologically based pharmacokinetic (PBPK) models can predict oral bioavailability using a priori knowledge of drug-specific properties and (2) to examine the influence of the biopharmaceutics classification system class on the simulation success. METHODS: Simcyp Simulator, GastroPlus(™) and GI-Sim were used. Compounds with published Biowaiver monographs (bisoprolol (BCS I), nifedipine (BCS II), cimetidine (BCS III), furosemide (BCS IV)) were selected to ensure availability of accurate and reproducible data for all required parameters...
October 26, 2016: Journal of Pharmacy and Pharmacology
Elisa Luzon, Kevin Blake, Susan Cole, Anna Nordmark, Carolien Versantvoort, Eva Gil Berglund
Physiologically-Based Pharmacokinetic (PBPK) modelling is a valuable tool in drug development and regulatory assessment, as it offers the opportunity to simulate the pharmacokinetics of a compound, with a mechanistic understanding, in a variety of populations and situations. This work reviews the use and impact of such modelling in selected regulatory procedures submitted to the European Medicines Agency (EMA) before the end of 2015, together with its subsequent reflection in public documents relating to the assessment of these procedures...
October 22, 2016: Clinical Pharmacology and Therapeutics
Maïlys De Sousa Mendes, Gabrielle Lui, Yi Zheng, Claire Pressiat, Deborah Hirt, Elodie Valade, Naïm Bouazza, Frantz Foissac, Stephane Blanche, Jean-Marc Treluyer, Saik Urien, Sihem Benaboud
BACKGROUND: Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. METHODS: A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK)...
October 21, 2016: Clinical Pharmacokinetics
Nikolaos Tsamandouras, Tomasz Kostrzewski, Cynthia L Stokes, Linda G Griffith, David J Hughes, Murat Cirit
In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from 5 different donors cultured in a perfused 3D human liver microphysiological system and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of 6 compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability (LDH release, albumin and urea production)...
October 19, 2016: Journal of Pharmacology and Experimental Therapeutics
Lisa M Sweeney, Michael L Gargas
To help develop a comprehensive, quantitative understanding of the hazards of 1,2-dichloroethane (ethylene dichloride, EDC, CAS No. 107-06-2) exposure by the inhalation route, the results of existing subchronic studies and an extended one-generation reproductive toxicity (EOGRT) study recently conducted by the oral route in rats were extrapolated using a physiologically based pharmacokinetic (PBPK) model. The no observed adverse effects levels (NOAELs) for the endpoints of neurotoxicity and reproductive/developmental toxicity were the highest tested doses of 169 and 155 mg/kg-day, respectively...
October 15, 2016: Regulatory Toxicology and Pharmacology: RTP
Iftekhar Mahmod, Tasneem Ahmad, Najia Mansoor, S M Sharib
The objective of this study was to evaluate the predictive performances of allometric models and a physiologically based pharmacokinetic model (PBPK) to predict clearance of glucuronidated drugs in neonates (≤3 months of age). From the literature, clearance values for 9 drugs (glucuronidated) for neonates and adults were obtained. Three allometric models were used to predict clearances of these glucuronidated drugs. A PBPK model was developed using the physicochemical, biopharmaceutical, and metabolic properties together with known pediatric physiology and enzymatic ontogeny...
October 4, 2016: Journal of Clinical Pharmacology
Raju Prasad Sharma, Marta Schuhmacher, Vikas Kumar
Endocrine disruptor compounds (EDCs) are environment chemicals that cause harmful effects through multiple mechanisms, interfering with hormone system resulting in alteration of homeostasis, reproduction and developmental effect. Many of these EDCs have concurrent exposure with crosstalk and common mechanisms which may lead to dynamic interactions. To carry out risk assessment of EDCs' mixture, it is important to know the detailed toxic pathway, crosstalk of receptor and other factors like critical window of exposure...
September 30, 2016: Environment International
Jee Sun Min, Doyun Kim, Jung Bae Park, Hyunjin Heo, Soo Hyeon Bae, Jae Hong Seo, Euichaul Oh, Soo Kyung Bae
BACKGROUND: Evaluating the potential risk of metabolic drug-drug interactions (DDIs) is clinically important. OBJECTIVE: To develop a physiologically based pharmacokinetic (PBPK) model for sarpogrelate hydrochloride and its active metabolite, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1), in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP) 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine...
2016: Drug Design, Development and Therapy
Adam S Darwich, Alison Margolskee, Xavier Pepin, Leon Aarons, Aleksandra Galetin, Amin Rostami-Hodjegan, Sara Carlert, Maria Hammarberg, Constanze Hilgendorf, Pernilla Johansson, Eva Karlsson, Dónal Murphy, Christer Tannergren, Helena Thörn, Mohammed Yasin, Florent Mazuir, Olivier Nicolas, Sergej Ramusovic, Christine Xu, Shriram M Pathak, Timo Korjamo, Johanna Laru, Jussi Malkki, Sari Pappinen, Johanna Tuunainen, Jennifer Dressman, Simone Hansmann, Edmund Kostewicz, Handan He, Tycho Heimbach, Fan Wu, Carolin Hoft, Yan Pang, Michael B Bolger, Eva Huehn, Viera Lukacova, James M Mullin, Ke X Szeto, Chester Costales, Jian Lin, Mark McAllister, Sweta Modi, Charles Rotter, Manthena Varma, Mei Wong, Amitava Mitra, Jan Bevernage, Jeike Biewenga, Achiel Van Peer, Richard Lloyd, Carole Shardlow, Peter Langguth, Irina Mishenzon, Mai Anh Nguyen, Jonathan Brown, Hans Lennernäs, Bertil Abrahamsson
Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp® Simulator, and GastroPlus™) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (Foral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information...
September 28, 2016: European Journal of Pharmaceutical Sciences
Alison Margolskee, Adam S Darwich, Xavier Pepin, Shriram M Pathak, Michael B Bolger, Leon Aarons, Amin Rostami-Hodjegan, Jonas Angstenberger, Franziska Graf, Loic Laplanche, Thomas Müller, Sara Carlert, Pankaj Daga, Dónal Murphy, Christer Tannergren, Mohammed Yasin, Susanne Greschat-Schade, Wolfgang Mück, Uwe Muenster, Dorina van der Mey, Kerstin Julia Frank, Richard Lloyd, Lieve Adriaenssen, Jan Bevernage, Loeckie De Zwart, Dominique Swerts, Christophe Tistaert, An Van Den Bergh, Achiel Van Peer, Stefania Beato, Anh-Thu Nguyen-Trung, Joanne Bennett, Mark McAllister, Mei Wong, Patricia Zane, Céline Ollier, Pascale Vicat, Markus Kolhmann, Alexander Marker, Priscilla Brun, Florent Mazuir, Stéphane Beilles, Marta Venczel, Xavier Boulenc, Petra Loos, Hans Lennernäs, Bertil Abrahamsson
Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study...
September 23, 2016: European Journal of Pharmaceutical Sciences
Clara Hartmanshenn, Megerle Scherholz, Ioannis P Androulakis
Personalized medicine strives to deliver the 'right drug at the right dose' by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses...
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
Marios Spanakis, Eleftherios Kontopodis, Sophie Van Cauter, Vangelis Sakkalis, Kostas Marias
Dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI) is used for detailed characterization of pathology of lesions sites, such as brain tumors, by quantitative analysis of tracer's data through the use of pharmacokinetic (PK) models. A key component for PK models in DCE-MRI is the estimation of the concentration-time profile of the tracer in a nearby vessel, referred as Arterial Input Function (AIF). The aim of this work was to assess through full body physiologically-based pharmacokinetic (PBPK) model approaches the PK profile of gadoteric acid (Gd-DOTA) and explore potential application for parameter estimation in DCE-MRI based on PBPK-derived AIFs...
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
I E Templeton, Y Chen, J Mao, J Lin, H Yu, S Peters, M Shebley, M V Varma
This subteam under the Drug Metabolism Leadership Group (Innovation and Quality Consortium) investigated the quantitative role of circulating inhibitory metabolites in drug-drug interactions using physiologically based pharmacokinetic (PBPK) modeling. Three drugs with major circulating inhibitory metabolites (amiodarone, gemfibrozil, and sertraline) were systematically evaluated in addition to the literature review of recent examples. The application of PBPK modeling in drug interactions by inhibitory parent-metabolite pairs is described and guidance on strategic application is provided...
September 19, 2016: CPT: Pharmacometrics & Systems Pharmacology
James P Sluka, Xiao Fu, Maciej Swat, Julio M Belmonte, Alin Cosmanescu, Sherry G Clendenon, John F Wambaugh, James A Glazier
We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level...
2016: PloS One
Andrés Olivares-Morales, Avijit Ghosh, Leon Aarons, Amin Rostami-Hodjegan
A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart...
September 8, 2016: AAPS Journal
Xun Wang, Wen-Xiong Wang
Copper (Cu) is an essential yet potentially toxic metal, thus delicate homeostatic controls are developed in the fish. In this study, a physiologically based pharmacokinetic (PBPK) model was developed to simulate the homeostatic regulation of Cu in a marine fish (Terapon jarbua) under dietary and waterborne exposures. In this model, fish were schematized as a six-compartment model, with the intestine being divided into two sub-compartments (chyme and gut wall). The blood was assumed to be the "carrier" distributing Cu into different compartments...
November 2016: Environmental Pollution
Rangaraj Narayanan, Matthew Hoffmann, Gondi Kumar
BACKGROUND: Oncology therapy typically involves drug combinations since monotherapy seldom provides the desired outcome. But combination therapy presents the potential for drug-drug interactions (DDIs). Due to the narrow window between therapeutic concentrations and onset of toxicity often observed with oncology therapeutics, managing DDIs with combination therapy in cancer is critical. Physiologically based pharmacokinetic (PBPK) modeling can be effectively used for predicting DDIs and guiding dose-selection, but requires development of PBPK models of cancer drugs...
July 29, 2016: Drug Metabolism Letters
Kazumi Mori, Ryuta Saito, Yoshinobu Nakamaru, Makiko Shimizu, Hiroshi Yamazaki
Canagliflozin is a recently developed sodium-glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic-pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized...
September 7, 2016: Biopharmaceutics & Drug Disposition
Andy Z X Zhu, Ming-Chih David Ho, Christopher K Gemski, Bei-Ching Chuang, Mingxiang Liao, Cindy Q Xia
For many orally administered basic drugs with pH-dependent solubility, concurrent administration with acid-reducing agents (ARAs) can significantly impair their absorption and exposure. In this study, pH-dependent drug-drug interaction (DDI) prediction methods, including in vitro dissolution-permeation chamber (IVDP) and physiologically based pharmacokinetic (PBPK) modeling, were evaluated for their ability to quantitatively predict the clinical DDI observations using 11 drugs with known clinical pH-dependent DDI data...
September 6, 2016: AAPS Journal
Catia Marzolini, Rajith Rajoli, Manuel Battegay, Luigia Elzi, David Back, Marco Siccardi
BACKGROUND: Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously. METHODS: This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs...
September 7, 2016: Clinical Pharmacokinetics
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