Quantitative evaluation of pharmacokinetic inhibition of CYP3A substrates by ketoconazole: a simulation study

J Clin Pharmacol. 2009 Mar;49(3):351-9. doi: 10.1177/0091270008331196.


The US Food and Drug Administration draft drug interaction guidance recommends that 400 mg ketoconazole (KTZ) be administered once daily for several days (QD400) for maximal CYP3A inhibition. Some investigators suggest that a single dose of 400 mg (SD400) KTZ is sufficient given its short half-life (t(1/2) approximately 3-5 hr). To determine the impact of KTZ regimens on CYP3A inhibition, we simulated AUC fold-change (AUCR) in the presence of SD400, QD400, or 200 mg twice-daily (BID200) KTZ for theoretical CYP3A substrates. Ratios of AUCR (AUCR(QD400)/AUCR(SD400) and AUCR(BID200) AUCR(QD400)) increase with increasing bioavailability and increasing substrate t(1/2). The SD400 KTZ regimen may provide maximal inhibition only for a subset of substrates (ie, low bioavailability and short t(1/2)). For substrates with t(1/2) longer than that of KTZ, multiple KTZ dosing is critical and BID200 appears to provide greater inhibition than QD400. Also, timing of KTZ administration should be optimized to allow maximal presystemic enzyme inhibition prior to substrate administration.

MeSH terms

  • Adult
  • Aged
  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacokinetics*
  • Antifungal Agents / pharmacology
  • Area Under Curve
  • Biological Availability
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Female
  • Half-Life
  • Humans
  • Ketoconazole / metabolism
  • Ketoconazole / pharmacokinetics*
  • Ketoconazole / pharmacology
  • Male
  • Middle Aged
  • Models, Biological*
  • Time Factors
  • Young Adult


  • Antifungal Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 CYP3A
  • Ketoconazole