Efavirenz Physiologically Development and Validation as a Moderate CYP3A4 Inducer for Drug-Drug Interaction Predictions

Authors: Darling IM, Owen JS, Lukacova V
Conference: SLP MIDD+
Keywords: drug-drug interactions (DDIs), efavirenz, HIV/AIDS, PBPK model, Physiologically based pharmacokinetic (PBPK) modeling, Post-Approval/Generics, SLP2021MIDD
Division: Clinical Pharmacology and Pharmacometrics (CPP), PBPK

Background/Purpose

  • Efavirenz is an antiretroviral medication used to treat and prevent HIV/AIDS.
  • Efavirenz is eliminated primarily by CYP2B6 and CYP3A4 oxidative metabolism with further glucuronidation to inactive metabolites. Due to substantial induction of both CYP3A4 and CYP2B6 enzyme systems with daily dosing of efavirenz, dose adjustments for many coadministered medications are necessary [1].
  • Strong, moderate, and weak inducers are drugs that decrease the AUC of sensitive index substrates of a given metabolic pathway by ≥ 80%, ≥ 50% to < 80%, and ≥ 20% to < 50%, respectively [2].
  • Efavirenz (dosed at 600 mg QD in adults) is a moderate CYP3A4 inducer. As such, a fully validated physiologically based pharmacokinetic (PBPK) model for efavirenz including validated induction potentials could be a useful standard compound for PBPK drug-drug interaction (DDI) simulations.

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Presented at AAPS PharmSci 360 in 2019

Presented at SLP MIDD+ Virtual Conference March 3-4, 2021