Towards a Best Practice Approach in PBPK Modeling: Case Example of Developing a Unified Efavirenz Model Accounting for Induction of CYPs 3A4 and 2B6

Abstract

In this study, we present efavirenz physiologically based pharmacokinetic (PBPK) model development as an example of our best practice approach that uses a stepwise approach to verify the different components of the model. First, a PBPK model for efavirenz incorporating in vitro and clinical pharmacokinetic (PK) data was developed to predict exposure following multiple dosing (600 mg q.d.). Alfentanil i.v. and p.o. drug‐drug interaction (DDI) studies were utilized to evaluate and refine the CYP3A4 induction component in the liver and gut. Next, independent DDI studies with substrates of CYP3A4 (maraviroc, atazanavir, and clarithromycin) and CYP2B6 (bupropion) verified the induction components of the model (area under the curve [AUC] ratios within 1.0–1.7‐fold of observed). Finally, the model was refined to incorporate the fractional contribution of enzymes, including CYP2B6, propagating autoinduction into the model (Racc 1.7 vs. 1.7 observed). This validated mechanistic model can now be applied in clinical pharmacology studies to prospectively assess both the victim and perpetrator DDI potential of efavirenz.

Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations

“…Input parameters for all drugs other than olaparib, dexamethasone, and raltegravir used reference values from the Simcyp compound library ( Table , Table S2). Simulated PK profiles after oral administration of multiple doses of itraconazole, OH‐itraconazole, rifampicin, efavirenz, fluvoxamine, or single doses of midazolam, simvastatin, and digoxin were consistent with the observed literature data from clinical studies and verification summary reports can be found in the Simcyp members area (https://members.simcyp.com/account/libraryFiles/). Verification of dexamethasone and raltegravir are detailed in Pilla Reddy et al ., 2018 and Hartman et al ., 2013 .…”

Predicting Efavirenz Concentrations in the Brain Tissue of HIV‐Infected Individuals and Exploring their Relationship to Neurocognitive Impairment

“…Of note, the lowered plasma concentrations were observed 96 hours after the first dose. This is early for EFV autoinduction (predicted to occur in humans a week after dosing 32 ), although early auto-induction effect has been shown for some other drugs. 33 The four animals that showed lower C24h were predicted to have higher peak concentration after the first dose compared with the other animals (> 2,200 vs. < 1,500 ng/mL), and auto-induction may occur earlier with higher concentration of the inducing agent.…”

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

“…PK models describing the disposition of efavirenz in plasma have been reported previously (3,(10)(11)(12)(13). A single study reported a PK model comprising both the parent drug (EFV) and the metabolite (8OHEFV) in plasma after a single dose that was lower than the recommended dose of efavirenz in 17 healthy Korean male subjects (14).…”