Construction and Verification of Physiologically Based Pharmacokinetic Models for Four Drugs Majorly Cleared by Glucuron
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Research Article Construction and Verification of Physiologically Based Pharmacokinetic Models for Four Drugs Majorly Cleared by Glucuronidation: Lorazepam, Oxazepam, Naloxone, and Zidovudine Luca Docci,1,2 Kenichi Umehara,1 Stephan Krähenbühl,2 Stephen Fowler,1 and Neil Parrott1,3
Received 13 July 2020; accepted 24 September 2020 Abstract. Physiologically based pharmacokinetic (PBPK) modeling is less well established for substrates of UDP-glucuronosyltransferases (UGT) than for cytochrome P450 (CYP) metabolized drugs and more verification of simulations is necessary to increase confidence. To address specific challenges of UGT substrates, we developed PBPK models for four drugs cleared majorly via glucuronidation (lorazepam, oxazepam, naloxone, and zidovudine). In vitro to in vivo scaling of intrinsic clearance generated with co-cultured human hepatocytes was applied for hepatic metabolism and extra-hepatic clearance was extrapolated based on relative expression of UGT isoforms in the liver, kidney, and intestine. Non-metabolic clearance and the contributions of individual UGT isoforms to glucuronidation were based on in vitro and in vivo studies taken from the literature and simulations were verified and evaluated with a broad set of clinical pharmacokinetic data. Model evaluation showed systemic clearance predictions within 1.5-fold for all drugs and all simulated parameters were within 2-fold of observed. However, during the verification step, top-down model fitting was necessary to adjust for under-prediction of zidovudine VSS and renal clearance and over estimation of intestinal first pass for lorazepam, oxazepam, and zidovudine. The impact of UGT2B15 polymorphisms on the pharmacokinetics of oxazepam and lorazepam was
Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-020-00513-5) contains supplementary material, which is available to authorized users. 1
Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070, Basel, Switzerland. 2 Department of Biomedicine, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland. 3 To whom correspondence should be addressed. (e–mail: [email protected]) Abbreviations: AUC, Area under the plasma concentration-time curve; CLint, Intrinsic clearance; CNT, Concentrative nucleoside transporter; Cmax, Peak concentration; CYP, Cytochrome P450; ENT, Equilibrative nucleoside transporter; F, Bioavailability; Fa, Fraction of the drug entering the enterocytes; FDp, Fraction of the drug reaching the portal vein; FG, Fraction of the drug that escapes gut metabolism; FH, Fraction of the drug that escapes hepatic firstpass metabolism; fm, Fraction metabolized; fu,ent, Fraction unbound in enterocytes; fu,inc, Fraction unbound in incubation; fu,p, Fraction unbound in plasma; GFR, Glomerular filtration rate; ISEF, Intersystem extrapolation factor; IV, Intravenous; Kp, Tissue:plasma partition coefficients; NCA, Non-compartmental analysis; NDAs, New drug applications; OAT, Organ
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