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https://www.readbyqxmd.com/read/27910730/retrospective-use-of-pbpk-modelling-to-understand-a-clinical-drug-drug-interaction-between-dextromethorphan-and-gsk1034702
#1
Michael J Hobbs, Jackie Bloomer, Gordon Dear
: 1. PURPOSE: In a clinical trial, a strong drug-drug interaction (DDI) was observed between dextromethorphan (DM, the object or victim drug) and GSK1034702 (the precipitant or perpetrator drug), following single and repeat doses. This study determined the inhibition parameters of GSK1034702 in vitro and applied PBPK modelling approaches to simulate the clinical observations and provide mechanistic hypotheses to understand the DDI. 2. METHODS: In vitro assays were conducted to determine the inhibition parameters of human CYP2D6 by GSK1034702...
December 2, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27909650/pbpk-modeling-and-simulation-in-drug-research-and-development
#2
REVIEW
Xiaomei Zhuang, Chuang Lu
Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug-drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development...
September 2016: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/27895113/age-dependent-absolute-abundance-of-hepatic-carboxylesterases-ces1-and-ces2-by-lc-ms-ms-proteomics-application-to-pbpk-modeling-of-oseltamivir-in-vivo-pharmacokinetics-in-infants
#3
Mikael Boberg, Marc Vrana, Aanchal Mehrotra, Robin E Pearce, Andrea Gaedigk, Deepak Kumar Bhatt, J Steven Leeder, Bhagwat Prasad
The age-dependent absolute protein abundance of carboxylesterase 1 and 2 (CES1 and CES2) in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by LC-MS/MS proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards...
November 28, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27885372/treatment-planning-in-prrt-based-on-simulated-pet-data-and-a-pbpk-model-determination-of-accuracy-using-a-pet-noise-model
#4
Deni Hardiansyah, Wei Guo, Ali Asgar Attarwala, Peter Kletting, Felix M Mottaghy, Gerhard Glatting
AIM: To investigate the accuracy of treatment planning in peptide-receptor radionuclide therapy (PRRT) based on simulated PET data (using a PET noise model) and a physiologically based pharmacokinetic (PBPK) model. METHODS: The parameters of a PBPK model were fitted to the biokinetic data of 15 patients. True mathematical phantoms of patients (MPPs) were the PBPK model with the fitted parameters. PET measurements after bolus injection of 150 MBq (68)Ga-DOTATATE were simulated for the true MPPs...
November 25, 2016: Nuklearmedizin. Nuclear Medicine
https://www.readbyqxmd.com/read/27865610/assessment-of-bioequivalence-of-weak-base-formulations-under-various-dosing-conditions-using-physiologically-based-pharmacokinetic-simulations-in-virtual-populations-case-examples-ketoconazole-and-posaconazole
#5
Rodrigo Cristofoletti, Nikunjkumar Patel, Jennifer B Dressman
Postabsorptive factors which can affect systemic drug exposure are assumed to be dependent on the active pharmaceutical ingredient (API), and thus independent of formulation. In contrast, preabsorptive factors, for example, hypochlorhydria, might affect systemic exposure in both an API and a formulation-dependent way. The aim of this study was to evaluate whether the oral absorption of 2 poorly soluble, weakly basic APIs, ketoconazole (KETO) and posaconazole (POSA), would be equally sensitive to changes in dissolution rate under the following dosing conditions-coadministration with water, with food, with carbonated drinks, and in drug-induced hypochlorhydria...
November 16, 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27862160/in-vitro-and-pbpk-based-assessment-of-drug-drug-interaction-potential-of-canagliflozin
#6
Rao N V S Mamidi, Shannon Dallas, Carlo Sensenhauser, Heng Keang Lim, Ellen Scheers, Peter Verboven, Filip Cuyckens, Laurent Leclercq, David C Evans, Michael F Kelley, Mark D Johnson, Jan Snoeys
AIMS: Canagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug-drug interactions (DDIs) was assessed. METHODS: DDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters. Basic predictive approaches were applied to determine potential interaction in vivo. A physiologically-based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of CYP inhibition by canagliflozin...
November 11, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27858342/physiologically-based-pharmacokinetic-pbpk-modeling-of-pitavastatin-and-atorvastatin-to-predict-drug-drug-interactions-ddis
#7
Peng Duan, Ping Zhao, Lei Zhang
BACKGROUND: The disposition of statins varies and involves both metabolizing enzymes and transporters, making predictions of statin drug-drug interactions (DDIs) challenging. Physiologically based pharmacokinetic (PBPK) models have, however, demonstrated ability to predict complex DDIs. OBJECTIVE: In this study, PBPK models of two statins (pitavastatin and atorvastatin) were developed and applied to predict pitavastatin and atorvastatin associated DDIs. METHOD: Pitavastatin and atorvastatin PBPK models were developed using in vitro and human pharmacokinetic data in a population-based PBPK software (SimCYP(®)) by considering the contribution of both metabolizing enzymes and transporters to their overall pharmacokinetics...
November 17, 2016: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27856526/extrapolation-of-elementary-rate-constants-of-p-glycoprotein-mediated-transport-from-mdckii-hmdr1-to-caco-2-cells
#8
Zhou Meng, Harma Ellens, Joe Bentz
The best parameters for incorporation into mechanistic PBPK models for transporters are system independent kinetic parameters and active (not total) transporter levels. Previously, we determined the elementary rate constants for P-gp mediated transport (on- and off- rate constants from membrane to P-gp binding pocket and efflux rate constant into apical chamber) using the structural mass action kinetic model in confluent MDCKII-hMDR1-NKI cell monolayers. In the present work, we extended the kinetic analysis to Caco-2 cells for the first time and showed that the elementary rate constants are very similar compared to MDCKII-hMDR1-NKI cells, suggesting they primarily depend on the interaction of the compound with P-gp and are therefore mostly independent of the in vitro system used...
November 16, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27836941/target-site-investigation-for-the-plasma-prolactin-response-mechanism-based-pharmacokinetic-pharmacodynamic-analysis-of-risperidone-and-paliperidone-in-the-rat
#9
Shinji Shimizu, Sandra M den Hoedt, Victor Mangas Sanjuan, Sinziana Cristea, Jana K Geuer, Dirk-Jan van den Berg, Robin Hartman, Francisco Bellanti, Elizabeth C M de Lange
In order to understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semi-physiologically-based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). A microdialysis study in rats was performed to obtain detailed plasma, brain extracellular fluid (brainECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-gp functioning on brain distribution, experiments were performed in absence or presence of the P-glycoprotein (P-gp) inhibitor tariquidar (TQD)...
November 11, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27834047/physiologically-based-pharmacokinetic-pbpk-modeling-of-pharmaceutical-nanoparticles
#10
Min Li, Peng Zou, Katherine Tyner, Sau Lee
With the great interests in the discovery and development of drug products containing nanoparticles, there is a great demand of quantitative tools for assessing quality, safety, and efficacy of these products. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches provide excellent tools for describing and predicting in vivo absorption, distribution, metabolism, and excretion (ADME) of nanoparticles administered through various routes. PBPK modeling of nanoparticles is an emerging field, and more than 20 PBPK models of nanoparticles used in pharmaceutical products have been published in the past decade...
November 10, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27822600/clarithromycin-midazolam-and-digoxin-application-of-pbpk-modeling-to-gain-new-insights-into-drug-drug-interactions-and-co-medication-regimens
#11
Daniel Moj, Nina Hanke, Hannah Britz, Sebastian Frechen, Tobias Kanacher, Thomas Wendl, Walter Emil Haefeli, Thorsten Lehr
Clarithromycin is a substrate and mechanism-based inhibitor of cytochrome P450 (CYP) 3A4 as well as a substrate and competitive inhibitor of P-glycoprotein (P-gp) and organic anion-transporting polypeptides (OATP) 1B1 and 1B3. Administered concomitantly, clarithromycin causes drug-drug interactions (DDI) with the victim drugs midazolam (CYP3A4 substrate) and digoxin (P-gp substrate). The objective of the presented study was to build a physiologically based pharmacokinetic (PBPK) DDI model for clarithromycin, midazolam, and digoxin and to exemplify dosing adjustments under clarithromycin co-treatment...
November 7, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27821435/what-can-be-learned-from-recent-new-drug-applications-a-systematic-review-of-drug-interaction-data-for-drugs-approved-by-the-u-s-fda-in-2015
#12
Jingjing Yu, Zhu Zhou, Katie H Owens, Tasha K Ritchie, Isabelle Ragueneau-Majlessi
As a follow-up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, PK, and DDI data available in the 33 NDAs and 12 BLAs approved by the FDA in 2015, using the University of Washington Drug Interaction Database©, and to highlight the significant findings. All of the NDAs were well-characterized with regard to drug metabolism, transport, and/or organ impairment, 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 DME or transporter...
November 7, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27820679/malathion-dermal-permeability-in-relation-to-dermal-load-assessment-by-physiologically-based-pharmacokinetic-modeling-of-in-vivo-human-data
#13
Kenneth T Bogen, Ankur Singhal
Estimates of dermal permeability (Kp), obtained by fitting an updated human PBPK model for malathion to previously reported data on excreted urinary metabolites after 29 volunteers were dermally exposed to measured values of [(14)C]malathion dermal load (L), were used to examine the empirical relationship between Kp and L. The PBPK model was adapted from previously reported human biokinetic and PBPK models for malathion, fit to previously reported urinary excretion data after oral [(14)C]malathion intake by volunteers, and then augmented to incorporate a standard Kp approach to modeling dermal-uptake kinetics...
November 7, 2016: Journal of Environmental Science and Health. Part. B, Pesticides, Food Contaminants, and Agricultural Wastes
https://www.readbyqxmd.com/read/27816841/heavy-metals-pb-cd-as-and-mehg-as-risk-factors-for-cognitive-dysfunction-a-general-review-of-metal-mixture-mechanism-in-brain
#14
REVIEW
Venkatanaidu Karri, Marta Schuhmacher, Vikas Kumar
Human exposure to toxic heavy metals is a global challenge. Concurrent exposure of heavy metals, such as lead (Pb), cadmium (Cd), arsenic (As) and methylmercury (MeHg) are particularly important due to their long lasting effects on the brain. The exact toxicological mechanisms invoked by exposure to mixtures of the metals Pb, Cd, As and MeHg are still unclear, however they share many common pathways for causing cognitive dysfunction. The combination of metals may produce additive/synergetic effects due to their common binding affinity with NMDA receptor (Pb, As, MeHg), Na(+) - K(+) ATP-ase pump (Cd, MeHg), biological Ca(+2) (Pb, Cd, MeHg), Glu neurotransmitter (Pb, MeHg), which can lead to imbalance between the pro-oxidant elements (ROS) and the antioxidants (reducing elements)...
December 2016: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/27816631/imi-oral-biopharmaceutics-tools-project-evaluation-of-bottom-up-pbpk-prediction-success-part-2-an-introduction-to-the-simulation-exercise-and-overview-of-results
#15
Alison Margolskee, Adam S Darwich, 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, Loic Laplanche, 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
Orally administered drugs are subject to a number of barriers impacting bioavailability (Foral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp®, and GastroPlus™) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise...
November 2, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27799216/efavirenz-is-predicted-to-accumulate-in-brain-tissue-an-in-silico-in-vitro-and-in-vivo-investigation
#16
Paul Curley, Rajith K R Rajoli, Darren M Moss, Neill J Liptrott, Scott Letendre, Andrew Owen, Marco Siccardi
INTRODUCTION: Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to supress viral replication but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate efavirenz distribution into the cerebrospinal fluid (CSF) and brain using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. METHODS: Efavirenz CNS distribution was calculated using a permeability-limited model in a virtual cohort of 100 patients receiving efavirenz (600 mg once-daily)...
October 31, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27781273/forecasting-oral-absorption-across-biopharmaceutics-classification-system-classes-with-physiologically-based-pharmacokinetic-models
#17
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...
December 2016: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/27770430/physiologically-based-pharmacokinetic-modelling-in-regulatory-decision-making-at-the-european-medicines-agency
#18
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
https://www.readbyqxmd.com/read/27766562/a-physiologically-based-pharmacokinetic-model-to-predict-human-fetal-exposure-for-a-drug-metabolized-by-several-cyp450-pathways
#19
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
https://www.readbyqxmd.com/read/27760784/quantitative-assessment-of-population-variability-in-hepatic-drug-metabolism-using-a-perfused-3d-human-liver-microphysiological-system
#20
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
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