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https://www.readbyqxmd.com/read/29150544/estimation-of-circulating-drug-metabolite-exposure-in-human-using-in-vitro-data-and-physiologically-based-pharmacokinetic-modelling-example-of-a-high-metabolite-parent-drug-ratio
#1
R Scott Obach, Jian Lin, Emi Kimoto, Sridhar Duvvuri, Timothy Nicholas, Eugene P Kadar, Larry M Tremaine, Aarti Sawant Basak
TBPT ((R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol), a serotonin-4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product (M1) and a cyclized oxazolidine structure (M2). After administration to humans, the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent ratios for M1 and M2 was attempted, using in vitro metabolism, binding, and permeability data in static and dynamic PBPK models...
November 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29150543/toxicokinetics-and-physiologically-based-pharmacokinetic-modeling-of-the-shellfish-toxin-domoic-acid-in-nonhuman-primates
#2
Jing Jing, Rebekah Petroff, Sara Shum, Brenda Crouthamel, Ariel R Topletz, Kimberly S Grant, Thomas M Burbacher, Nina Isoherranen
Domoic acid (DA), a neurotoxin, is produced by marine algae and has caused toxications worldwide in animals and humans. However, the toxicokinetics of DA has not been fully evaluated, and information is missing on the disposition of DA following oral exposures at doses that are considered safe for human consumption. In this study, toxicokinetics of DA were investigated in cynomolgus monkeys, following single doses of 5 µg/kg DA iv, 0.075 mg/kg DA po and 0.15 mg/kg DA po. Following iv dosing, DA had a systemic clearance of 124 ± 71 ml/hr/kg, volume of distribution at steady state of 131±71 ml/kg and elimination half-life of 1...
November 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29143853/sex-specific-risk-assessment-of-pfhxs-using-a-physiologically-based-pharmacokinetic-model
#3
Sook-Jin Kim, Hwajin Shin, Yong-Bok Lee, Hea-Young Cho
Perfluorohexanesulfonate (PFHxS), which belongs to the group of perfluoroalkyl and polyfluoroalkyl substances (PFASs), has been extensively used in industry and subsequently detected in the environment. Its use may be problematic, as PFHxS is known to induce neuronal cell death, and has been associated with early onset menopause in women and with attention deficit/hyperactivity disorder. Due to these impending issues, the aim of this study is to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for PFHxS in male and female rats, and apply this to a human health risk assessment...
November 16, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29134635/ribociclib-bioavailability-is-not-affected-by-gastric-ph-changes-or-food-intake-in-silico-and-clinical-evaluations
#4
Tanay S Samant, Shyeilla Dhuria, Yasong Lu, Marc Laisney, Shu Yang, Arnaud Grandeury, Martin Mueller-Zsigmondy, Kenichi Umehara, Felix Huth, Michelle Miller, Caroline Germa, Mohamed Elmeliegy
Ribociclib (KISQALI®), a cyclin-dependent kinase 4/6 inhibitor approved for the first-line treatment of HR+/HER2- advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH-elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using (1) biorelevant media solubility, (2) physiologically based pharmacokinetic (PBPK) modeling, (3) non-compartmental analysis (NCA) of clinical trial data, and (4) population PK (PopPK) analysis...
November 14, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29133240/prediction-of-human-cns-pharmacokinetics-using-a-physiologically-based-pharmacokinetic-modeling-approach
#5
Yumi Yamamoto, Pyry A Välitalo, Yin Cheong Wong, Dymphy R Huntjens, Johannes H Proost, An Vermeulen, Walter Krauwinkel, Margot W Beukers, Hannu Kokki, Merja Kokki, Meindert Danhof, Johan G C van Hasselt, Elizabeth C M de Lange
Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration-time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin). Values of the system-specific parameters in the rat CNS PBPK model were replaced by corresponding human values...
November 10, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29119333/physiologically-based-pharmacokinetic-modelling-of-cytochrome-p450%C3%A2-2c9-related-tolbutamide-drug-interactions-with-sulfaphenazole-and-tasisulam
#6
Everett J Perkins, Maria Posada, P Kellie Turner, Jill Chappell, Wee Teck Ng, Chris Twelves
BACKGROUND AND OBJECTIVES: Cytochrome P450 2C9 (CYP2C9) is involved in the biotransformation of many commonly used drugs, and significant drug interactions have been reported for CYP2C9 substrates. Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80-90% of the total clearance. Therefore, these models are not useful for predicting the magnitude of CYP2C9 drug-drug interactions (DDIs)...
November 8, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29117990/simultaneous-physiologically-based-pharmacokinetic-pbpk-modeling-of-parent-and-active-metabolites-to-investigate-complex-cyp3a4-drug-drug-interaction-potential-a-case-example-of-midostaurin
#7
Helen Gu, Catherine Dutreix, Sam Rebello, Taoufik Ouatas, Lai Wang, Dung Yu Chun, Heidi J Einolf, Handan He
Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (advSM). It is extensively metabolized by cytochrome P450 (CYP) 3A4 to form 2 major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or advSM...
November 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29111469/an-in-silico-approach-to-determine-challenges-in-the-bioavailability-of-ciprofloxacin-a-poorly-soluble-weak-base-with-borderline-solubility-and-permeability-characteristics
#8
Simone Hansmann, Yoshihiro Miyaji, Jennifer Dressman
Ciprofloxacin is administered as the hydrochloride salt in immediate release formulations for the treatment of various infectious diseases in different patient populations. Due to its weakly basic properties and poor solubility, the in vivo behaviour of this compound could be influenced by both physicochemical and physiological factors. The first aim of this study was to investigate the behaviour of ciprofloxacin (Ciprobay® 500 mg tablets) in the human gastro-intestinal tract with in vitro dissolution, transfer and two-stage experiments...
October 27, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/29102550/a-physiologically-based-pharmacokinetic-modeling-approach-to-predict-drug-drug-interactions-of-buprenorphine-after-subcutaneous-administration-of-cam2038-with-perpetrators-of-cyp3a4
#9
Tao Liu, Jogarao V S Gobburu
CAM2038, FluidCrystral (FC) injection depot, is an extended release formulation of buprenorphine given subcutaneously every 1 week (Q1W) or every 4 weeks (Q4W). The purpose of this research is to predict the magnitude of drug-drug interaction (DDI) after coadministration of a strong CYP3A4 inducer or inhibitor using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model was developed for CAM2038 based on the previously published buprenorphine PBPK model after intravenous (IV) and sublingual (SL) administration and the PK profiles after SC administration of CAM2038 from two Phase I clinical trials...
November 1, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29079968/prediction-of-drug-drug-interaction-potential-using-physiologically-based-pharmacokinetic-modeling
#10
REVIEW
Jee Sun Min, Soo Kyung Bae
The occurrence of drug-drug interactions (DDIs) can significantly affect the safety of a patient, and thus assessing DDI risk is important. Recently, physiologically based pharmacokinetic (PBPK) modeling has been increasingly used to predict DDI potential. Here, we present a PBPK modeling concept and strategy. We also surveyed PBPK-related articles about the prediction of DDI potential in humans published up to October 10, 2017. We identified 107 articles, including 105 drugs that fit our criteria, with a gradual increase in the number of articles per year...
October 27, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/29077203/evaluation-of-model-based-prediction-of-pharmacokinetics-in-the-renal-impairment-population
#11
Ka Lai Yee, Mengyao Li, Tamara Cabalu, Vaishali Sahasrabudhe, Jian Lin, Ping Zhao, Pravin Jadhav
Dose recommendations for specific populations are not always provided and, when available, typically rely on empirical derivation from a small fraction of the general population. In this study, a prediction/confirmation framework was applied to 2 model-based methods, physiologically based pharmacokinetics (PBPK) and a static model, to evaluate their ability to predict clearance in mild, moderate, and severe renal impairment populations and to inform dosing recommendations in these populations. Simulated renal impairment/healthy subject AUC ratios (AUCRs) from PBPK and static models were compared with observed AUCRs from dedicated clinical studies in renal impairment subjects for 7 drugs eliminated primarily by renal clearance...
October 27, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29068158/development-of-an-adult-physiologically-based-pharmacokinetic-model-of-solithromycin-in-plasma-and-epithelial-lining-fluid
#12
Sara N Salerno, Andrea Edginton, Michael Cohen-Wolkowiez, Christoph P Hornik, Kevin M Watt, Brian D Jamieson, Daniel Gonzalez
Solithromycin is a fluoroketolide antibiotic under investigation for community-acquired bacterial pneumonia (CABP). We developed a whole-body physiologically based pharmacokinetic (PBPK) model for solithromycin in adults using PK-Sim and MoBi version 6.2, which incorporated time-dependent CYP3A4 auto-inhibition. The model was developed and evaluated using plasma and epithelial lining fluid (ELF) concentration data from 100 healthy subjects and 22 patients with CABP (1,966 plasma, 30 ELF samples). We performed population simulations and calculated the number of observations falling outside the 90% prediction interval...
October 25, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29066968/prediction-of-a-therapeutic-dose-for-buagafuran-a-potent-anxiolytic-agent-by-physiologically-based-pharmacokinetic-pharmacodynamic-modeling-starting-from-pharmacokinetics-in-rats-and-human
#13
Fen Yang, Baolian Wang, Zhihao Liu, Xuejun Xia, Weijun Wang, Dali Yin, Li Sheng, Yan Li
Physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) models can contribute to animal-to-human extrapolation and therapeutic dose predictions. Buagafuran is a novel anxiolytic agent and phase I clinical trials of buagafuran have been completed. In this paper, a potentially effective dose for buagafuran of 30 mg t.i.d. in human was estimated based on the human brain concentration predicted by a PBPK/PD modeling. The software GastroPlus(TM) was used to build the PBPK/PD model for buagafuran in rat which related the brain tissue concentrations of buagafuran and the times of animals entering the open arms in the pharmacological model of elevated plus-maze...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29064106/integration-of-mechanistic-and-pharmacokinetic-information-to-derive-oral-reference-dose-and-margin-of-exposure-values-for-hexavalent-chromium
#14
Chad M Thompson, Christopher R Kirman, Sean M Hays, Mina Suh, Seneca E Harvey, Deborah M Proctor, Julia E Rager, Laurie C Haws, Mark A Harris
The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg(-1)  day(-1) , is based on a no-observable-adverse-effect-level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as "low." A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non-neoplastic lesions from the 2 year cancer bioassay were modeled in a three-step process...
October 24, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/29060463/development-of-a-physiologically-based-pharmacokinetic-model-of-paraquat
#15
Manupat Lohitnavy, Arnon Chitsakhon, Kritsada Jomprasert, Ornrat Lohitnavy, Brad Reisfeld
Paraquat (N, N'-dimethyl-4,4'-bipyridium dichloride) is a potent and widely used herbicide in agricultural countries, including Thailand. The presence of this chemical in the body can lead to toxic effects in the liver, kidney, and lung. Pulmonary toxicity has been identified as the main cause of acute toxicity in animals and humans. Chronic exposure to paraquat is associated with Parkinson's disease in humans. Paraquat is transported into the lungs by neutral amino acid transporter. Therefore, a physiologically based pharmacokinetic (PBPK) model of paraquat was developed with a description of the protein transporter mechanism...
July 2017: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/29060462/a-physiologically-based-pharmacokinetic-model-of-methotrexate-incorporating-hepatic-excretion-via-multidrug-resistance-associated-protein-2-mrp2-in-mice-rats-dogs-and-humans
#16
Manupat Lohitnavy, Yasong Lu, Ornrat Lohitnavy, Raymond S H Yang
An updated physiologically-based pharmacokinetic (PBPK) model of methotrexate (MTX) was built based on an earlier model developed by Bischoff et al. (1971). MTX has been known to be a substrate of multidrug-resistance-associated protein 2 (Mrp2). A three-dimensional quantitative structure-activity relationship model (3D-QSAR) of Mrp2 was developed by Hirono et al. (2005). In our updated PBPK model of MTX, using the computational chemistry-derived binding affinity (Km), a Mrp2-mediated biliary excretion process was incorporated as the MTX excretory pathway...
July 2017: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/29054499/coupled-in-silico-platform-computational-fluid-dynamics-cfd-and-physiologically-based-pharmacokinetic-pbpk-modelling
#17
Aleksandra Vulović, Tijana Šušteršič, Sandra Cvijić, Svetlana Ibrić, Nenad Filipović
One of the critical components of the respiratory drug delivery is the manner in which the inhaled aerosol is deposited in respiratory tract compartments. Depending on formulation properties, device characteristics and breathing pattern, only a certain fraction of the dose will reach the target site in the lungs, while the rest of the drug will deposit in the inhalation device or in the mouth-throat region. The aim of this study was to link the Computational fluid dynamics (CFD) with physiologically-based pharmacokinetic (PBPK) modelling in order to predict aerolisolization of different dry powder formulations, and estimate concomitant in vivo deposition and absorption of amiloride hydrochloride...
October 17, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29053169/whole-body-physiologically-based-modelling-of-beta-blockers-in-the-rat-events-in-tissues-and-plasma-following-an-intravenous-bolus-dose
#18
S Y A Cheung, T Rodgers, L Aarons, I Gueorguieva, G L Dickinson, S Murby, C Brown, B Collins, M Rowland
BACKGROUND AND PURPOSE: Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and human. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible. EXPERIMENTAL APPROACH: Prior PBPK model development of enantiomers of a series of seven racemic betablockers, namely acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state...
October 20, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29038231/evaluation-of-clinical-drug-interaction-potential-of-clofazimine-using-static-and-dynamic-modeling-approaches
#19
Ramachandra Sangana, Helen Gu, Dung Yu Chun, Heidi J Einolf
The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (CYP) inhibitor in vitro, a CYP-mediated drug interaction may be likely when clofazimine is co-administered with substrates of these enzymes. The CYP-mediated drug interaction potential of clofazimine was evaluated using both static (estimation of "R1" and area under the plasma concentration-time curve ratio [AUCR] values) and dynamic (physiologically based pharmacokinetic [PBPK]) modeling approaches...
October 16, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29034770/association-with-polymorphic-marmoset-cytochrome-p450-2c19-of-in-vivo-hepatic-clearances-of-chirally-separated-r-omeprazole-and-s-warfarin-using-individual-marmoset-physiologically-based-pharmacokinetic-models
#20
Takashi Kusama, Akiko Toda, Makiko Shimizu, Shotaro Uehara, Takashi Inoue, Yasuhiro Uno, Masahiro Utoh, Erika Sasaki, Hiroshi Yamazaki
1. Simulated clearances of R-warfarin and efavirenz were recently reported for individual cynomolgus monkeys genotyped for cytochrome P450 2C19 and 2C9, respectively. To expand and verify this modeling procedure, simulations of R/S-omeprazole and R/S-warfarin clearances after oral administrations in individual marmosets were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling consisting of gut, liver, and central compartments. 2. Pharmacokinetics of R/S-omeprazole were chirally determined using the previously reported plasma microsamples in this study...
October 16, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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