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https://www.readbyqxmd.com/read/28912253/physiologically-based-pharmacokinetic-model-predictions-of-panobinostat-lbh589-as-a-victim-and-perpetrator-of-drug-drug-interactions
#1
Heidi J Einolf, Wen Lin, Christina S Won, Lai Wang, Helen Gu, Dung Yu Chun, Handan He, James B Mangold
Panobinostat (Farydak®) is an orally active hydroxamic acid derived histone deacetylase inhibitor for the treatment of relapsed/refractory multiple myeloma. Based upon recombinant cytochrome P450 (CYP) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was found to be primarily mediated by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also shown to be an in vitro reversible and time-dependent inhibitor of CYP3A4/5, and a reversible inhibitor of CYP2D6 and CYP2C19...
September 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28910306/a-quantitative-systems-pharmacology-approach-incorporating-a-novel-liver-model-for-predicting-pharmacokinetic-drug-drug-interactions
#2
Mohammed H Cherkaoui-Rbati, Stuart W Paine, Peter Littlewood, Cyril Rauch
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...
2017: PloS One
https://www.readbyqxmd.com/read/28903490/estimating-methylmercury-intake-for-the-general-population-of-south-korea-using-physiologically-based-pharmacokinetic-modeling
#3
Seungho Lee, Yu-Mei Tan, Martin B Phillips, Jon R Sobus, Sungkyoon Kim
The Korean National Environmental Health Survey (KoNEHS 2009-2011) tracks levels of environmental pollutants in biological samples from the adult Korean population (age 19-88). Recent survey results for blood mercury (Hg) suggest some exceedance above existing blood Hg reference levels. Because total blood Hg represents both organic and inorganic forms, and methylmercury (MeHg) has been specifically linked to several adverse health outcomes, a need exists to quantify MeHg intake for this population. Gender, age, and frequency of fish consumption were first identified as important predictors of KoNEHS blood Hg levels using generalized linear models...
September 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28891201/predicting-drug-concentration-time-profiles-in-multiple-cns-compartments-using-a-comprehensive-physiologically-based-pharmacokinetic-model
#4
Yumi Yamamoto, Pyry A Välitalo, Dymphy R Huntjens, Johannes H Proost, An Vermeulen, Walter Krauwinkel, Margot W Beukers, Dirk-Jan van den Berg, Robin Hartman, Yin Cheong Wong, Meindert Danhof, Johan G C van Hasselt, Elizabeth C M de Lange
Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically-based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration-time profiles from 10 drugs in rat plasma, brain extracellular fluid, two cerebrospinal fluid sites, and total brain tissue...
September 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28890175/effect-of-the-pulmonary-deposition-and-in-vitro-permeability-on-the-prediction-of-plasma-levels-of-inhaled-budesonide-formulation
#5
Sharareh Salar-Behzadi, Shengqian Wu, Annalisa Mercuri, Claudia Meindl, Sandra Stranzinger, Eleonore Fröhlich
The growing interest in the inhalable pharmaceutical products requires advanced approaches to safe and fast product development, such as in silico tools that can be used for estimating the bioavailability and toxicity of developed formulation. GastroPlus™ is one of the few available software packages for in silico simulation of PBPK profile of inhalable products. It contains a complementary module for calculating the lung deposition, the permeability and the systemic absorption of inhalable products. Experimental values of lung deposition and permeability can also be used...
September 7, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28870656/a-two-step-model-of-tio2-nanoparticle-toxicity-in-human-liver-tissue
#6
T Laomettachit, I K Puri, M Liangruksa
We examine the toxicity of titanium dioxide (TiO2) nanoparticles on human liver through a two-step approach, including a physiologically-based pharmacokinetic (PBPK) model and a cell-response model. The PBPK model predicts the bio-distribution of nanoparticles that remain in the human body after exposure, with special attention to their accumulation in liver tissue. The cell-response model predicts liver cell death as a consequence of the accumulated TiO2 nanoparticles by considering cell fate dynamics through the interplay between cellular uptake of the nanoparticles and their dilution due to cell division...
September 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28860113/physiologically-based-pharmacokinetic-pbpk-model-of-the-cyp2d6-probe-atomoxetine-extrapolation-to-special-populations-and-drug-drug-interactions
#7
Weize Huang, Mariko Nakano, Jennifer E Sager, Isabelle Ragueneau-Majlessi, Nina Isoherranen
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...
August 31, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28851254/quantitative-prediction-of-the-extent-of-drug-drug-interaction-using-a-physiologically-based-pharmacokinetic-model-that-includes-inhibition-of-drug-metabolism-determined-in-cryopreserved-hepatocytes
#8
Shinji Iwasaki, Hideki Hirabayashi, Nobuyuki Amano
1. A physiologically based pharmacokinetic (PBPK) model that includes inhibition constant evaluated in cryopreserved hepatocytes was used to predict drug-drug interactions (DDIs) between orally administered nifedipine, a CYP substrate, and fluconazole or ketoconazole, CYP inhibitors, in rats. 2. The Kp,uu, ratio of unbound inhibitor concentration in liver ([I]liver,u) to that in plasma ([I]sys,u), of fluconazole and ketoconazole was 1.0 and 13.0, indicating that ketoconazole accumulates in liver. The ratios of inhibition constants in rat liver microsomes (Ki,mic,u) to that in rat cryopreserved hepatocytes (Ki,hep,u) for fluconazole and ketoconazole were 1...
September 4, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28818579/developing-integrated-pbpk-pd-coupled-mechanistic-pathway-model-mirna-bdnf-an-approach-towards-system-toxicology
#9
Raju Prasad Sharma, Marta Schuhmacher, Vikas Kumar
Integration of a dynamic signal transduction pathway into the tissue dosimetry model is a major advancement in the area of computational toxicology. This paper illustrates the ways to incorporate the use of existing system biological model in the field of toxicology via its coupling to the Physiological based Pharmacokinetics and Pharmacodynamics (PBPK/PD) model. This expansion framework of integrated PBPK/PD coupled mechanistic system pathway model can be called as system toxicology that describes the kinetics of both - the chemicals and - biomolecules, help us to understand the dynamic and steady-state behaviors of molecular pathways under perturbed condition...
August 14, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28817288/in-silico-modeling-approach-for-the-evaluation-of-gastrointestinal-dissolution-supersaturation-and-precipitation-of-posaconazole
#10
Bart Hens, Shriram M Pathak, Amitava Mitra, Nikunjkumar Patel, Bo Liu, Sanjaykumar Patel, Masoud Jamei, Joachim Brouwers, Patrick Augustijns, David B Turner
The aim of this study was to evaluate gastrointestinal (GI) dissolution, supersaturation, and precipitation of posaconazole, formulated as an acidified (pH 1.6) and neutral (pH 7.1) suspension. A physiologically-based pharmacokinetic (PBPK) modeling and simulation tool was applied to simulate GI and systemic concentration-time profiles of posaconazole which were directly compared with intraluminal and systemic data measured in humans. The Advanced Dissolution Absorption and Metabolism (ADAM) model of the Simcyp® Simulator correctly simulated incomplete gastric dissolution and saturated duodenal concentrations of posaconazole in the duodenal fluids following administration of the neutral suspension...
August 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28815392/strategy-for-cyp3a-induction-risk-assessment-from-preclinical-signal-to-human-a-case-example-of-a-late-stage-discovery-compound
#11
Jialin Mao, Peter Fan, Susan Wong, Jianshuang Wang, Moulay Hicham Alaoui Ismaili, Brian Dean, Cornelis E C A Hop, Matthew Wright, Yuan Chen
PURPOSE: The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro induction data to in vivo findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose. METHODS: Pharmacokinetic and induction potency (in vitro and in vivo) of G2917 in monkeys, and the in vitro human induction potency were studied...
August 16, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28811111/cell-cultures-in-drug-discovery-and-development-the-need-of-reliable-in-vitro-in-vivo-extrapolation-for-pharmacodynamics-and-pharmacokinetics-assessment
#12
REVIEW
Karol Jaroch, Alina Jaroch, Barbara Bojko
For ethical and cost-related reasons, use of animals for the assessment of mode of action, metabolism and/or toxicity of new drug candidates has been increasingly scrutinized in research and industrial applications. Implementation of the 3 "Rs"(1); rule (Reduction, Replacement, Refinement) through development of in silico or in vitro assays has become an essential element of risk assessment. Physiologically based pharmacokinetic (PBPK(2)) modeling is the most potent in silico tool used for extrapolation of pharmacokinetic parameters to animal or human models from results obtained in vitro...
July 27, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28808917/development-of-a-translational-physiologically-based-pharmacokinetic-model-for-antibody-drug-conjugates-a-case-study-with-t-dm1
#13
Antari Khot, Jay Tibbitts, Dan Rock, Dhaval K Shah
Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i...
August 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28782239/integration-of-genome-scale-metabolic-networks-and-gene-regulation-of-metabolic-enzymes-with-physiologically-based-pharmacokinetics
#14
Elaina M Maldonado, Vytautas Leoncikas, Ciarán P Fisher, J Bernadette Moore, Nick J Plant, Andrzej M Kierzek
The scope of Physiologically Based Pharmacokinetic (PBPK) modelling can be expanded by assimilation of the mechanistic models of intracellular processes from Systems Biology field. Genome Scale Metabolic Networks (GSMNs) represent a whole set of metabolic enzymes expressed in human tissues. Dynamic models of the gene regulation of key drug metabolism enzymes are available. Here, we introduce GSMNs and review ongoing work on integration of PBPK, GSMNs and metabolic gene regulation. We demonstrate example models...
August 7, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28774813/virtual-bioequivalence-for-achlorhydric-subjects-the-use-of-pbpk-modelling-to-assess-the-formulation-dependent-effect-of-achlorhydria
#15
Kosuke Doki, Adam S Darwich, Nikunjkumar Patel, Amin Rostami-Hodjegan
Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulation more than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on formulations which are pH-sensitive with respect to release or dissolution. We therefore examined achlorhydria-related disparity in bioequivalence of levothyroxine and nifedipine formulations using virtual bioequivalence within a physiologically-based pharmacokinetic (PBPK) modelling framework...
August 1, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28771009/model-based-analysis-of-biopharmaceutic-experiments-to-improve-mechanistic-oral-absorption-modeling-an-integrated-in-vitro-in-vivo-extrapolation-perspective-using-ketoconazole-as-a-model-drug
#16
Shriram M Pathak, Aaron Ruff, Edmund S Kostewicz, Nikunjkumar Patel, David B Turner, Masoud Jamei
Mechanistic modeling of in vitro data generated from metabolic enzyme systems (viz., liver microsomes, hepatocytes, rCYP enzymes, etc.) facilitates in vitro-in vivo extrapolation (IVIV_E) of metabolic clearance which plays a key role in the successful prediction of clearance in vivo within physiologically-based pharmacokinetic (PBPK) modeling. A similar concept can be applied to solubility and dissolution experiments whereby mechanistic modeling can be used to estimate intrinsic parameters required for mechanistic oral absorption simulation in vivo...
August 25, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28759222/a-permeability-limited-physiologically-based-pharmacokinetic-pbpk-model-for-perfluorooctanoic-acid-pfoa-in-male-rats
#17
Weixiao Cheng, Carla A Ng
Physiologically based pharmacokinetic (PBPK) modeling is a powerful in silico tool that can be used to simulate the toxicokinetics and tissue distribution of xenobiotic substances, such as perfluorooctanoic acid (PFOA), in organisms. However, most existing PBPK models have been based on the flow-limited assumption and largely rely on in vivo data for parametrization. In this study, we propose a permeability-limited PBPK model to estimate the toxicokinetics and tissue distribution of PFOA in male rats. Our model considers the cellular uptake and efflux of PFOA via both passive diffusion and transport facilitated by various membrane transporters, association with serum albumin in circulatory and extracellular spaces, and association with intracellular proteins in liver and kidney...
August 18, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28749581/prediction-of-transporter-mediated-drug-drug-interactions-for-baricitinib
#18
Maria M Posada, Ellen A Cannady, Christopher D Payne, Xin Zhang, James A Bacon, Y Anne Pak, J William Higgins, Nazila Shahri, Stephen D Hall, Kathleen M Hillgren
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, undergoes active renal tubular secretion. Baricitinib was not predicted to inhibit hepatic and renal uptake and efflux drug transporters, based on the ratio of the unbound maximum eliminating-organ inlet concentration and the in vitro half-maximal inhibitory concentrations (IC50 ). In vitro, baricitinib was a substrate for organic anion transporter (OAT)3, multidrug and toxin extrusion protein (MATE)2-K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP)...
July 27, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28748626/combining-bottom-up-and-top-down-approaches-to-assess-the-impact-of-food-and-gastric-ph-on-pictilisib-gdc-0941-pharmacokinetics
#19
Tong Lu, Grazyna Fraczkiewicz, Laurent Salphati, Nageshwar Budha, Gena Dalziel, Gillian S Smelick, Kari M Morrissey, John D Davis, Jin Y Jin, Joseph A Ware
Pictilisib, a weakly basic compound, is an orally administered, potent, and selective pan-inhibitor of phosphatidylinositol 3-kinases for oncology indications. To investigate the significance of high-fat food and gastric pH on pictilisib pharmacokinetics (PK) and enable label recommendations, a dedicated clinical study was conducted in healthy volunteers, whereby both top-down [Population PK, (PopPK)] and bottom-up [physiologically-based PK, (PBPK)] approaches were applied to enhance confidence of recommendation and facilitate the clinical development through scenario simulations...
July 27, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28739143/prediction-of-time-integrated-activity-coefficients-in-prrt-using-simulated-dynamic-pet-and-a-pharmacokinetic-model
#20
Deni Hardiansyah, Ali Asgar Attarwala, Peter Kletting, Felix M Mottaghy, Gerhard Glatting
PURPOSE: To investigate the accuracy of predicted time-integrated activity coefficients (TIACs) in peptide-receptor radionuclide therapy (PRRT) using simulated dynamic PET data and a physiologically based pharmacokinetic (PBPK) model. METHODS: PBPK parameters were estimated using biokinetic data of 15 patients after injection of (152±15)MBq of (111)In-DTPAOC (total peptide amount (5.78±0.25)nmol). True mathematical phantoms of patients (MPPs) were the PBPK model with the estimated parameters...
July 21, 2017: Physica Medica: PM
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