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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
#1
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
#2
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
#3
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
#4
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-biopharmaceutical-experiments-to-improve-mechanistic-oral-absorption-modelling-an-integrated-in-vitro-in-vivo-extrapolation-iviv_e-perspective-using-ketoconazole-as-a-model-drug
#5
Shriram M Pathak, Aaron Ruff, Edmund Kostewicz, Nikunjkumar Patel, David B Turner, Masoud Jamei
Mechanistic modelling 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) modelling. A similar concept can be applied to solubility and dissolution experiments whereby mechanistic modelling can be used to estimate intrinsic parameters required for mechanistic oral absorption simulation in vivo...
August 3, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28759222/a-permeability-limited-physiologically-based-pharmacokinetic-pbpk-model-for-perfluorooctanoic-acid-pfoa-in-male-rats
#6
Weixiao Cheng, Carla 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 parameterization. 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...
July 31, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28749581/prediction-of-transporter-mediated-drug-drug-interactions-for-baricitinib
#7
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
#8
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
#9
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
https://www.readbyqxmd.com/read/28738449/pbpk-modeling-of-the-effect-of-reduced-kidney-function-on-the-pharmacokinetics-of-drugs-excreted-renally-by-organic-anion-transporters
#10
C-H Hsueh, V Hsu, P Zhao, L Zhang, K M Giacomini, S-M Huang
Altered pharmacokinetics (PK) in subjects with chronic kidney disease (CKD) may lead to dosing adjustment of certain drugs in subjects with CKD. It can be valuable to quantitatively predict PK in CKD for the management of drug dosing in these subjects. We developed physiologically based pharmacokinetic (PBPK) models of seven renally eliminated drugs: adefovir, avibactam, entecavir, famotidine, ganciclovir, oseltamivir carboxylate, and sitagliptin. These drugs are all substrates of renal organic anion transporters (OATs)...
July 24, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28715785/prenatal-exposure-estimation-of-bpa-and-dehp-using-integrated-external-and-internal-dosimetry-a-case-study
#11
M A Martínez, J Rovira, R Prasad Sharma, M Nadal, M Schuhmacher, V Kumar
Prenatal exposure to Endocrine disruptors (EDs), such as Bisphenol A (BPA) and di (2-ethylhexyl) phthalate (DEHP), has been associated with obesity and diabetes diseases in childhood, as well as reproductive, behavioral and neurodevelopment problems. The aim of this study was to estimate the prenatal exposure to BPA and DEHP through food consumption for pregnant women living in Tarragona County (Spain). Probabilistic calculations of prenatal exposure were estimated by integrated external and internal dosimetry modelling, physiologically based pharmacokinetic (PBPK) model, using a Monte-Carlo simulation...
July 14, 2017: Environmental Research
https://www.readbyqxmd.com/read/28710684/utility-of-physiologically-based-pharmacokinetic-absorption-modeling-to-predict-the-impact-of-salt-to-base-conversion-on-prasugrel-hcl-product-bioequivalence-in-the-presence-of-proton-pump-inhibitors
#12
Jianghong Fan, Xinyuan Zhang, Liang Zhao
Prasugrel HCl may convert to prasugrel base during manufacturing or storage. It was reported that formulations with different ratios of salt to base were bioequivalent in healthy subjects, but formulations with a higher extent of conversion were not bioequivalent in subjects taking proton pump inhibitor (PPI) whose stomach pH is elevated. The objective of this study was to assess the magnitude of impact of salt-to-base conversion on prasugrel HCl products BE evaluation in healthy subjects on PPI. A physiologically based pharmacokinetic (PBPK) absorption model was constructed to predict pharmacokinetic (PK) profiles of active metabolite after oral administration of prasugrel HCl products containing various fractions of base based on the prasugrel salt and base intrinsic solubility...
July 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28688108/a-physiologically-based-pharmacokinetic-modeling-approach-to-predict-buprenorphine-pharmacokinetics-following-intravenous-sublingual-administration
#13
Hari V Kalluri, Hongfei Zhang, Steve N Caritis, Raman Venkataramanan
INTRODUCTION: Opioid dependence is associated with high morbidity and mortality. Buprenorphine(BUP) is approved by the FDA to treat opioid dependence. There is a lack of clear consensus on appropriate dosing of BUP due to inter-patient physiological differences in absorption/disposition, subjective response assessment and other patient comorbidities. The objective of this study is to build and validate robust physiologically-based-pharmacokinetic(PBPK) models for intravenous(IV) and Sublingual(SL) BUP as a first-step to optimize BUP pharmacotherapy...
July 8, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28684146/physiologically-based-pharmacokinetic-modeling-of-human-exposure-to-perfluorooctanoic-acid-suggests-historical-non-drinking-water-exposures-are-important-for-predicting-current-serum-concentrations
#14
Rachel Rogers Worley, Xiaoxia Yang, Jeffrey Fisher
Manufacturing of perfluorooctanoic acid (PFOA), a synthetic chemical with a long half-life in humans, peaked between 1970 and 2002, and has since diminished. In the United States, PFOA is detected in the blood of >99% of people tested, but serum concentrations have decreased since 1999. Much is known about exposure to PFOA in drinking water; however, the impact of non-drinking water PFOA exposure on serum PFOA concentrations is not well characterized. The objective of this research is to apply physiologically based pharmacokinetic (PBPK) modeling and Monte Carlo analysis to evaluate the impact of historic non-drinking water PFOA exposure on serum PFOA concentrations...
September 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28681680/evolution-of-chemical-specific-adjustment-factors-csaf-based-on-recent-international-experience-increasing-utility-and-facilitating-regulatory-acceptance
#15
Virunya S Bhat, M E Bette Meek, Mathieu Valcke, Caroline English, Alan Boobis, Richard Brown
The application of chemical-specific toxicokinetic or toxicodynamic data to address interspecies differences and human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared with the use of traditional default or categorically-based uncertainty factors. The present review summarizes the state-of-the-science since the introduction of the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) guidance on chemical-specific adjustment factors (CSAF) in 2005 and the availability of recent applicable guidance including the WHO/IPCS guidance on physiologically-based pharmacokinetic (PBPK) modeling in 2010 as well as the U...
July 6, 2017: Critical Reviews in Toxicology
https://www.readbyqxmd.com/read/28676206/manganese-testing-under-a-clean-air-act-test-rule-and-the-application-of-resultant-data-in-risk-assessments
#16
Darcie Smith, George M Woodall, Annie M Jarabek, William K Boyes
In the 1990's, the proposed use of methylcyclopentadienyl manganese tricarbonyl (MMT) as an octane-enhancing gasoline fuel additive led to concerns for potential public health consequences from exposure to manganese (Mn) combustion products in automotive exhaust. After a series of regulatory/legal actions and negotiations, the U.S. Environmental Protection Agency (EPA) issued under Clean Air Act (CAA) section 211(b) an Alternative Tier 2 Test Rule that required development of scientific information intended to help resolve uncertainties in exposure or health risk estimates associated with MMT use...
July 1, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28672700/using-exposure-prediction-tools-to-link-exposure-and-dosimetry-for-risk-based-decisions-a-case-study-with-phthalates
#17
Marjory Moreau, Jeremy Leonard, Katherine A Phillips, Jerry Campbell, Salil N Pendse, Chantel Nicolas, Martin Phillips, Miyoung Yoon, Yu-Mei Tan, Sherrie Smith, Harish Pudukodu, Kristin Isaacs, Harvey Clewell
A few different exposure prediction tools were evaluated for use in the new in vitro-based safety assessment paradigm using di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. Daily intake of each phthalate was estimated using both high-throughput (HT) prediction models such as the HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors...
October 2017: Chemosphere
https://www.readbyqxmd.com/read/28669739/an-evidence-based-recommendation-to-increase-the-dosing-frequency-of-buprenorphine-during-pregnancy
#18
Steve N Caritis, Jaime R Bastian, Hongfei Zhang, Hari Kalluri, Dennis English, Michael England, Stephanie Bobby, Raman Venkataramanan
BACKGROUND: Dose-adjusted plasma concentrations of buprenorphine are significantly decreased during pregnancy compared with the nonpregnant state. This observation suggests that pregnant women may need a higher dose of buprenorphine than nonpregnant individuals to maintain similar drug exposure (plasma concentrations over time after a dose). The current dosing recommendations for buprenorphine during pregnancy address the total daily dose of buprenorphine to be administered, but the frequency of dosing is not clearly addressed...
June 29, 2017: American Journal of Obstetrics and Gynecology
https://www.readbyqxmd.com/read/28663311/the-use-of-physiology-based-pk-and-pd-modeling-in-the-discovery-of-the-dual-orexin-receptor-antagonist-act-541468
#19
Alexander Treiber, Ruben de Kanter, Catherine Roch, John Gatfield, Christoph Boss, Markus von Raumer, Benno Schindelholz, Clemens Muehlan, Joop van Gerven, Francois Jenck
The identification of new sleep drugs poses particular challenges in drug discovery due to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging in case inter-species differences are prominent...
June 29, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28640606/pharmacokinetics-of-mequindox-and-its-marker-residue-1-4-bisdesoxymequindox-in-swine-following-multiple-oral-gavage-and-intramuscular-administration-an-experimental-study-coupled-with-population-physiologically-based-pharmacokinetic-modeling
#20
Dongping Zeng, Zhoumeng Lin, Binghu Fang, Miao Li, Ronette Gehring, Jim E Riviere, Zhenling Zeng
Mequindox (MEQ) is a quinoxaline-N,N-dioxide antibiotic used in food-producing animals. MEQ residue in animal-derived foods is a food safety concern. The tissue distribution of MEQ and its marker residue 1,4-bisdesoxymequindox (M1) were determined in swine following oral gavage or intramuscular injection twice daily for 3 days. The experimental data were used to construct a flow-limited physiologically based pharmacokinetic (PBPK) model. The model predictions correlated with available data well. Monte Carlo analysis showed that the times needed for M1 concentrations to fall below limit of detection (5 μg/kg) in liver for the 99th percentile of the population were 27 and 34 days after oral gavage and intramuscular administration twice daily for 3 days, respectively...
July 19, 2017: Journal of Agricultural and Food Chemistry
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