Physiologically based pharmacokinetic (PBPK) modeling of meloxicam in different CYP2C9 genotypes

2021 ◽  
Author(s):  
Chang‑Keun Cho ◽  
Hye-Jung Park ◽  
Pureum Kang ◽  
Sungmin Moon ◽  
Yun Jeong Lee ◽  
...  
Keyword(s):  
Pbpk Modeling ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

scholarly journals A Physiologically-Based Pharmacokinetic Framework for Prediction of Drug Exposure in Malnourished Children

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 204
Author(s):  
Erik Sjögren ◽  
Joel Tarning ◽  
Karen I. Barnes ◽  
E. Niclas Jonsson
Keyword(s):  
Body Composition ◽  
Drug Exposure ◽  
Drug Disposition ◽  
Pediatric Population ◽  
Model Performance ◽  
Vulnerable Population ◽  
Pbpk Modeling ◽  
Malnourished Children ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Malnutrition in children is a global health problem, particularly in developing countries. The effects of an insufficient supply of nutrients on body composition and physiological functions may have implications for drug disposition and ultimately affect the clinical outcome in this vulnerable population. Physiologically-based pharmacokinetic (PBPK) modeling can be used to predict the effect of malnutrition as it links physiological changes to pharmacokinetic (PK) consequences. However, the absence of detailed information on body composition and the limited availability of controlled clinical trials in malnourished children complicates the establishment and evaluation of a generic PBPK model in this population. In this manuscript we describe the creation of physiologically-based bridge to a malnourished pediatric population, by combining information on (a) the differences in body composition between healthy and malnourished adults and (b) the differences in physiology between healthy adults and children. Model performance was confirmed using clinical reference data. This study presents a physiologically-based translational framework for prediction of drug disposition in malnourished children. The model is readily applicable for dose recommendation strategies to address the urgent medicinal needs of this vulnerable population.

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

scholarly journals 1315. No Dose Adjustment of Metformin with Fostemsavir Coadministration Based on Mechanistic Static and Physiologically Based Pharmacokinetic Models

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S669-S669
Author(s):  
Dung N Nguyen ◽  
Xiusheng Miao ◽  
Mindy Magee ◽  
Guoying Tai ◽  
Peter D Gorycki ◽  
...  
Keyword(s):  
Dose Adjustment ◽  
Pbpk Model ◽  
Systemic Exposure ◽  
Multidrug Resistant ◽  
Pbpk Modeling ◽  
Repeat Dose ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Abstract Background Fostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines. Methods Metformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMR Results TMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposure Conclusion Based on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTR Disclosures Xiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)

Database for Physiologically Based Pharmacokinetic (PBPK) Modeling: Physiological Data for Healthy and Health-Impaired Elderly

2009 ◽  
Vol 12 (1) ◽  
pp. 1-24 ◽  
Author(s):  
Chad M. Thompson ◽  
Douglas O. Johns ◽  
Babasaheb Sonawane ◽  
Hugh A. Barton ◽  
Dale Hattis ◽  
...  
Keyword(s):  
Pbpk Modeling ◽  
Physiological Data ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Translating dosimetry of Dibenzo[def,p]chrysene (DBC) and metabolites across dose and species using physiologically based pharmacokinetic (PBPK) modeling

2021 ◽  
pp. 115830
Author(s):  
Paritosh Pande ◽  
Erin P. Madeen ◽  
David E. Williams ◽  
Susan R. Crowell ◽  
Ted J. Ognibene ◽  
...  
Keyword(s):  
Pbpk Modeling ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

scholarly journals Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs

2020 ◽  
Author(s):  
Armin Sadighi ◽  
Lorenzo Leggio ◽  
Fatemeh Akhlaghi
Keyword(s):  
Pbpk Model ◽  
Organ Damage ◽  
Time Profile ◽  
Sensitivity Analyses ◽  
Pbpk Modeling ◽  
Time Curve ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

Abstract Aims A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions. Methods A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted. Results Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss). Conclusions The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies.

Physiologically based pharmacokinetic (PBPK) modeling of human lactational transfer of methylmercury in China

2018 ◽  
Vol 115 ◽  
pp. 180-187 ◽  
Author(s):  
Langbo Ou ◽  
Huanhuan Wang ◽  
Cen Chen ◽  
Long Chen ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Pbpk Modeling ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Lactational Transfer
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