Evidence-Based Guidelines for Drug Interaction Studies: Model-Informed Time Course of Intestinal and Hepatic CYP3A4 Inhibition by Clarithromycin

Asha J. Kapetas, Ahmad Y. Abuhelwa, Michael J. Sorich, Ross A. McKinnon, A. David Rodrigues, Andrew Rowland, Ashley M. Hopkins

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Drug-drug interaction (DDI) studies are mandated in drug development; however, protocols for evaluating the impact of cytochrome P450 (CYP) inhibition on new molecular entities are currently inconsistent. This study utilised validated physiologically based pharmacokinetic (PBPK) software to define the optimal dose, frequency, and duration of clarithromycin to achieve optimal characterisation of CYP3A4 inhibition in a study population. The Simcyp® Simulator (Version 19.0) was used to simulate clarithromycin-mediated CYP3A4 inhibition in healthy virtual cohorts. Between trial variability in magnitude and time course of CYP3A4 activity was assessed following clarithromycin dosing strategies obtained from the University of Washington Drug Interaction Database. Heterogeneity in CYP3A4 inhibition was evaluated across sex, race, and age. Literature review identified 500 mg twice daily for 5 days as the most common clarithromycin dosing protocol for CYP3A4 inhibition studies. On simulation, clarithromycin 500 mg twice daily resulted in the largest steady-state inhibition of hepatic (percent mean inhibition [95%CI] = 80 [77–83]) and small intestine (94 [94–95]) CYP3A4 activity (as compared to 500 mg once daily, 400 mg once/twice daily, or 250 mg once/twice daily). Additionally, 500 mg twice daily was associated with the shortest time for 90% of individuals to reach 90% of their minimum hepatic (4 days) and small intestine (1 days) CYP3A4 activity. The study presented herein supports that clarithromycin dosing protocol of 500 mg twice daily for 5 days is sufficient to achieve maximal hepatic and small intestine CYP3A4 inhibition. These findings were consistent between sex, race, and age differences.

Original languageEnglish
Article number104
Number of pages8
JournalAAPS Journal
Volume23
Issue number5
DOIs
Publication statusPublished - 31 Aug 2021

Keywords

  • clarithromycin
  • CYP3A4 inhibition
  • physiologically based pharmacokinetic modelling
  • study protocol

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