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Construction and Verification of Physiologically Based Pharmacokinetic Models for Four Drugs Majorly Cleared by Glucuronidation: Lorazepam, Oxazepam, Naloxone, and Zidovudine

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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 simulated and glucuronide metabolites were also simulated for all four drugs. To increase confidence in predicting extra-hepatic clearance, improvement of enzyme phenotyping for UGT substrates and more quantitative tissue expression levels of UGT enzymes are both needed. Prediction of glucuronide disposition is also challenging when active transport processes play a major role.

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Abbreviations

AUC:

Area under the plasma concentration-time curve

CLint :

Intrinsic clearance

CNT:

Concentrative nucleoside transporter

C max :

Peak concentration

CYP:

Cytochrome P450

ENT:

Equilibrative nucleoside transporter

F :

Bioavailability

F a :

Fraction of the drug entering the enterocytes

FDp :

Fraction of the drug reaching the portal vein

F G :

Fraction of the drug that escapes gut metabolism

F H :

Fraction of the drug that escapes hepatic first-pass metabolism

f m :

Fraction metabolized

f u,ent :

Fraction unbound in enterocytes

f u,inc :

Fraction unbound in incubation

f u,p :

Fraction unbound in plasma

GFR:

Glomerular filtration rate

ISEF:

Inter-system extrapolation factor

IV:

Intravenous

K p :

Tissue:plasma partition coefficients

NCA:

Non-compartmental analysis

NDAs:

New drug applications

OAT:

Organic anion transporter

OCT:

Organic cation transporter

PBPK modeling:

Physiologically based pharmacokinetic modeling

PK:

Pharmacokinetics

PO:

Oral administration

PSA:

Parameter sensitivity analysis

RAF:

Relative activity factor

SCHH:

Sandwich-cultured hepatocytes

T max :

Time of peak concentration

UGT:

UDP-glucuronosyltransferases

rhUGT:

Recombinant human UGT

V SS :

Volume of distribution at steady state

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Authors and Affiliations

  1. Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070, Basel, Switzerland

    Luca Docci, Kenichi Umehara, Stephen Fowler & Neil Parrott

  2. Department of Biomedicine, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland

    Luca Docci & Stephan Krähenbühl

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  1. Luca Docci
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  2. Kenichi Umehara
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  3. Stephan Krähenbühl
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  4. Stephen Fowler
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  5. Neil Parrott
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Correspondence to Neil Parrott.

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Docci, L., Umehara, K., Krähenbühl, S. et al. Construction and Verification of Physiologically Based Pharmacokinetic Models for Four Drugs Majorly Cleared by Glucuronidation: Lorazepam, Oxazepam, Naloxone, and Zidovudine. AAPS J 22, 128 (2020). https://doi.org/10.1208/s12248-020-00513-5

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