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https://www.readbyqxmd.com/read/28321831/the-impact-of-gastric-ph-volume-and-emptying-on-the-food-effect-of-ziprasidone-oral-absorption
#1
Steven C Sutton, Richard Nause, Kuan Gandelman
In a recent food effect clinical study, the authors concluded that a meal consisting of ≥500 kcal, regardless of fat content, produced the maximal bioavailability for ziprasidone. Using GastroPlus™, a commercially available pharmacokinetic simulation software, a semiphysiological model-a kind of physiologically based pharmacokinetic (PBPK) absorption model-was developed that could predict the concentration-time profiles when ziprasidone was administered with any one of the five test meals or fasting. Ziprasidone intravenous pharmacokinetics and oral absorption permeability were determined from clinical studies following the intravenous and duodenal infusion of ziprasidone to volunteers...
March 20, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28296193/investigating-transporter-mediated-drug-drug-interactions-using-a-physiologically-based-pharmacokinetic-model-of-rosuvastatin
#2
Q Wang, M Zheng, T Leil
Rosuvastatin is a frequently used probe in transporter-mediated drug-drug interaction (DDI) studies. This report describes the development of a physiologically based pharmacokinetic (PBPK) model of rosuvastatin for prediction of pharmacokinetic (PK) DDIs. The rosuvastatin model predicted the observed single (i.v. and oral) and multiple dose PK profiles, as well as the impact of coadministration with transporter inhibitors. The predicted effects of rifampin and cyclosporine (6.58-fold and 5.07-fold increase in rosuvastatin area under the curve (AUC), respectively) were mediated primarily via inhibition of hepatic organic anion-transporting polypeptide (OATP)1B1 (Inhibition constant (Ki ) ∼1...
March 13, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28290120/development-of-a-pediatric-physiologically-based-pharmacokinetic-model-of-clindamycin-using-opportunistic-pharmacokinetic-data
#3
Christoph P Hornik, Huali Wu, Andrea N Edginton, Kevin Watt, Michael Cohen-Wolkowiez, Daniel Gonzalez
Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool used to characterize maturational changes in drug disposition to inform dosing across childhood; however, its use is limited in pediatric drug development. Access to pediatric pharmacokinetic data is a barrier to widespread application of this model, which impedes its development and optimization. To support the development of a pediatric PBPK model, we sought to leverage opportunistically-collected plasma concentrations of the commonly used antibiotic clindamycin...
March 13, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28286289/mechanistic-investigation-of-the-negative-food-effect-of-modified-release-zolpidem
#4
Cord J Andreas, Xavier Pepin, Constantinos Markopoulos, Maria Vertzoni, Christos Reppas, Jennifer Dressman
AIMS: When administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in Cmax and AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound, in vivo and to simulate the observed plasma profiles using in vitro and in silico methods. METHODS: Pharmacokinetic profiles of zolpidem are presented from a bioavailability (8mg intravenous; 10mg immediate release Stilnox®; 10mg and 12...
March 9, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28281195/microdialysis-the-key-to-physiologically-based-model-prediction-of-human-cns-target-site-concentrations
#5
Yumi Yamamoto, Meindert Danhof, Elizabeth C M de Lange
Despite the enormous research efforts that have been put into the development of central nervous system (CNS) drugs, the success rate in this area is still disappointing. To increase the successful rate in the clinical trials, first the problem of predicting human CNS drug distribution should be solved. As it is the unbound drug that equilibrates over membranes and is able to interact with targets, especially knowledge on unbound extracellular drug concentration-time profiles in different CNS compartments is important...
March 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28277163/predictions-of-bisphenol-a-hepatic-clearance-in-the-isolated-perfused-rat-liver-iprl-impact-of-albumin-binding-and-of-co-administration-with-naproxen
#6
Sara Bounakta, Michel Bteich, Marc Mantha, Patrick Poulin, Sami Haddad
1. This study aimed (i) to characterise hepatic clearance (CL) of bisphenol A (BPA) and naproxen (NAP) administered alone or in binary mixtures to highlight the influence of a binding to albumin (ALB) using an isolated perfused rat liver (IPRL) system; and (ii) to compare results of prediction algorithms with measured clearance rates. 2. The IPRL system and liver microsomes were used to determine the metabolic constants of BPA and NAP either in the presence or absence of ALB. In this study, the IPRL was used as proxy for the in vivo situation...
March 3, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28275201/physiologically-based-pharmacokinetic-model-of-all-trans-retinoic-acid-with-application-to-cancer-populations-and-drug-interactions
#7
Jing Jing, Cara Nelson, Jisun Paik, Yoshiyuki Shirasaka, John K Amory, Nina Isoherranen
All-trans retinoic acid (atRA) is a front-line treatment for acute promyelocytic leukemia (APL). Due to its activity in regulating the cell cycle, it has also been evaluated for the treatment of other cancers. However, the efficacy of atRA has been limited by atRA inducing its own metabolism during therapy, resulting in a decrease of atRA exposure during continuous dosing. Frequent relapse occurs in patients receiving atRA monotherapy. In an attempt to combat therapy resistance, inhibitors of atRA metabolism have been developed...
March 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28268592/a-multiscale-model-based-analysis-of-the-multi-tissue-interplay-underlying-blood-glucose-regulation-in-type-i-diabetes
#8
Federico Wadehn, Stephan Schaller, Thomas Eissing, Markus Krauss, Lars Kupfer
A multiscale model for blood glucose regulation in diabetes type I patients is constructed by integrating detailed metabolic network models for fat, liver and muscle cells into a whole body physiologically-based pharmacokinetic/pharmacodynamic (pBPK/PD) model. The blood glucose regulation PBPK/PD model simulates the distribution and metabolization of glucose, insulin and glucagon on an organ and whole body level. The genome-scale metabolic networks in contrast describe intracellular reactions. The developed multiscale model is fitted to insulin, glucagon and glucose measurements of a 48h clinical trial featuring 6 subjects and is subsequently used to simulate (in silico) the influence of geneknockouts and drug-induced enzyme inhibitions on whole body blood glucose levels...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28260166/population-pbpk-modelling-of-trastuzumab-a-framework-for-quantifying-and-predicting-inter-individual-variability
#9
Paul R V Malik, Abdullah Hamadeh, Colin Phipps, Andrea N Edginton
In this work we proposed a population physiologically-based pharmacokinetic (popPBPK) framework for quantifying and predicting inter-individual pharmacokinetic variability using the anti-HER2 monoclonal antibody (mAb) trastuzumab as an example. First, a PBPK model was developed to account for the possible mechanistic sources of variability. Within the model, five key factors that contribute to variability were identified and the nature of their contribution was quantified with local and global sensitivity analyses...
March 4, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28256717/impact-of-acute-fat-mobilization-on-the-pharmacokinetics-of-the-highly-fat-distributed-compound-tak-357-investigated-by-physiologically-based-pharmacokinetic-pbpk-modeling-and-simulation
#10
Akihiko Goto, Yoshihiko Tagawa, Yuu Moriya, Sho Sato, Yoshiyuki Furukawa, Takeshi Wakabayashi, Tetsuya Tsukamoto, Joost DeJongh, Tamara J van Steeg, Toshiya Moriwaki, Satoru Asahi
In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2-weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data. Using the constructed model, the TAK-357 concentration profile in case of body weight change was simulated. PBPK model-derived simulation suggested that redistribution from adipose tissues to plasma due to loss of body fat caused the observed concentration increase of TAK-357 in dog plasma...
March 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28255999/development-of-a-physiologically-based-pharmacokinetic-model-to-predict-the-effects-of-flavin-containing-monooxygenase-3-fmo3-polymorphisms-on-itopride-exposure
#11
Wangda Zhou, Helen Humphries, Sibylle Neuhoff, Iain Gardner, Eric Masson, Nidal Al-Huniti, Diansong Zhou
Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles...
March 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28254086/biopharmaceutics-data-management-system-for-anonymised-data-sharing-and-curation-first-application-with-orbito-imi-project
#12
Kristin Lacy-Jones, Philip Hayward, Steve Andrews, Ian Gledhill, Mark McAllister, Bertil Abrahamsson, Amin Rostami-Hodjegan, Xavier Pepin
The OrBiTo IMI project was designed to improve the understanding and modelling of how drugs are absorbed. To achieve this 13 pharmaceutical companies agreed to share biopharmaceutics drug properties and performance data, as long as they were able to hide certain aspects of their dataset if required. This data was then used in simulations to test how three in silico Physiological Based Pharmacokinetic (PBPK) tools performed. A unique database system was designed and implemented to store the drug data. The database system was unique, in that it had the ability to make different sections of a dataset visible or hidden depending on the stage of the project...
March 2017: Computer Methods and Programs in Biomedicine
https://www.readbyqxmd.com/read/28238854/use-of-a-probabilistic-pbpk-pd-model-to-calculate-data-derived-extrapolation-factors-for-chlorpyrifos
#13
Torka S Poet, Charles Timchalk, Michael J Bartels, Jordan N Smith, Robin McDougal, Daland R Juberg, Paul S Price
A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model combined with Monte Carlo analysis of inter-individual variation was used to assess the effects of the insecticide, chlorpyrifos and its active metabolite, chlorpyrifos oxon in humans. The PBPK/PD model has previously been validated and used to describe physiological changes in typical individuals as they grow from birth to adulthood. This model was updated to include physiological and metabolic changes that occur with pregnancy. The model was then used to assess the impact of inter-individual variability in physiology and biochemistry on predictions of internal dose metrics and quantitatively assess the impact of major sources of parameter uncertainty and biological diversity on the pharmacodynamics of red blood cell acetylcholinesterase inhibition...
February 24, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28237878/a-tissue-dose-based-comparative-exposure-assessment-of-manganese-using-physiologically-based-pharmacokinetic-modeling-the-importance-of-homeostatic-control-for-an-essential-metal
#14
P Robinan Gentry, Cynthia Van Landingham, William G Fuller, Sandra I Sulsky, Tracy B Greene, Harvey J Clewell, Melvin E Andersen, Harry A Roels, Michael D Taylor, Athena M Keene
A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates...
February 22, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28226770/a-multiscale-model-based-analysis-of-the-multi-tissue-interplay-underlying-blood-glucose-regulation-in-type-i-diabetes
#15
Federico Wadehn, Stephan Schaller, Thomas Eissing, Markus Krauss, Lars Kupfer, Federico Wadehn, Stephan Schaller, Thomas Eissing, Markus Krauss, Lars Kupfer, Federico Wadehn, Markus Krauss, Lars Kupfer, Stephan Schaller, Thomas Eissing
A multiscale model for blood glucose regulation in diabetes type I patients is constructed by integrating detailed metabolic network models for fat, liver and muscle cells into a whole body physiologically-based pharmacokinetic/pharmacodynamic (pBPK/PD) model. The blood glucose regulation PBPK/PD model simulates the distribution and metabolization of glucose, insulin and glucagon on an organ and whole body level. The genome-scale metabolic networks in contrast describe intracellular reactions. The developed multiscale model is fitted to insulin, glucagon and glucose measurements of a 48h clinical trial featuring 6 subjects and is subsequently used to simulate (in silico) the influence of geneknockouts and drug-induced enzyme inhibitions on whole body blood glucose levels...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28221813/transport-glucuronidation-classification-system-and-pbpk-modeling-new-approach-to-predict-the-impact-of-transporters-on-disposition-of-glucuronides
#16
Shufan Ge, Yingjie Wei, Taijun Yin, Beibei Xu, Song Gao, Ming Hu
Glucuronide metabolites require the action of efflux transporters to exit cells due to their hydrophilic properties. In this study, we proposed a transport-glucuronidation classification system and developed a PBPK model to predict the impact of BCRP on systemic exposure of glucuronides. The clearance by UGTs in S9 fractions and the efflux clearance of glucuronides by BCRP in human UGT1A9-overexpressing HeLa cells were incorporated in the classification system and PBPK model. Based on simulations for glucuronide AUC for theoretical compounds in the classification system, it was indicated that BCRP was more important for compounds with greater efflux clearance of their glucuronides by BCRP regardless of differences in clearance by UGTs...
March 13, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28215648/estimation-of-the-minimum-permeability-coefficient-in-rats-for-perfusion-limited-tissue-distribution-in-whole-body-physiologically-based-pharmacokinetics
#17
Yoo-Seong Jeong, Chang-Soon Yim, Heon-Min Ryu, Chi-Kyoung Noh, Yoo-Kyung Song, Suk-Jae Chung
The objective of the current study was to determine the minimum permeability coefficient, P, needed for perfusion-limited distribution in PBPK. Two expanded kinetic models, containing both permeability and perfusion terms for the rate of tissue distribution, were considered: The resulting equations could be simplified to perfusion-limited distribution depending on tissue permeability. Integration plot analyses were carried out with theophylline in 11 typical tissues to determine their apparent distributional clearances and the model-dependent permeabilities of the tissues...
February 12, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28214380/application-of-the-mechpeff-model-to-predict-passive-effective-intestinal-permeability-in-the-different-regions-of-the-rodent-small-intestine-and-colon
#18
D Pade, M Jamei, A Rostami-Hodjegan, D B Turner
A major component of Physiologically-Based Pharmacokinetic (PBPK) models is prediction of the rate and extent of absorption of orally dosed drugs for which knowledge of effective passive intestinal permeability (Peff ) is essential. Single pass intestinal perfusion (SPIP) studies are used to establish effective permeability in vivo but are difficult to perform in rodents while mechanistic models to predict drug Peff in rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict Peff in the rodent intestine based upon knowledge of regional gut physiology and drug-specific physicochemical parameters...
February 18, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28195732/in-vivo-predictive-dissolution-ipd-and-biopharmaceutical-modeling-and-simulation-future-use-of-modern-approaches-and-methodologies-in-a-regulatory-context
#19
H Lennernas, A Lindahl, A Van Peer, C Ollier, T Flanagan, R Lionberger, A Nordmark, S Yamashita, L Yu, G L Amidon, V Fischer, E Sjögren, P Zane, M McAllister, B Abrahamsson
The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo-meeting in 2015 was dedicated to the presentation of the most recent progress in the development of the regulatory use of PBPK in silico modeling, in vivo predictive dissolution (IPD) tests and their application to biowaivers...
February 14, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28193650/interaction-of-rifampicin-and-darunavir-ritonavir-or-darunavir-cobicistat-in-vitro
#20
Owain Roberts, Saye Khoo, Andrew Owen, Marco Siccardi
Treatment of HIV patients co-infected with tuberculosis (TB) is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and anti-TB drugs. The aim of this study was to quantify the effects of cobicistat (COBI), or ritonavir (RTV), in modulating DDIs between darunavir (DRV) and rifampicin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone, or in combination with either COBI or RTV for three days, followed by co-incubation with DRV for one hour...
February 13, 2017: Antimicrobial Agents and Chemotherapy
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