Effect of different durations and formulations of diltiazem on the single-dose pharmacokinetics of midazolam: how long do we go?

J Clin Pharmacol. 2011 Nov;51(11):1561-70. doi: 10.1177/0091270010387141. Epub 2011 Jan 5.


Understanding how inhibition of cytochrome P4503A (CYP3A) affects the metabolism of a new drug is critical in determining if a clinically relevant drug interaction will occur. Diltiazem interaction studies assess a given compound's sensitivity to moderate CYP3A inhibition. The present study compared the effect different durations and formulations of diltiazem (extended release [XR] and conventional release [CR]) had on the single-dose pharmacokinetics of midazolam. The geometric mean ratio (GMR; midazolam + diltiazem(XR × 5 days)/midazolam + diltiazem(XR × 2 days)) for midazolam AUC(0-∞) was 0.98 (90% confidence interval [CI], 0.87, 1.10). The GMR (midazolam + diltiazem(XR × 2 days)/midazolam + diltiazem(CR × 2 days)) for midazolam AUC(0-∞) was 0.82 (90% CI, 0.73, 0.92). Simcyp simulations accurately predicted the observed clinical results only when a hepatic CYP3A degradation rate (k(deg)) different from that provided by the software was used. The data suggest that dosing diltiazem XR for 2 days predicts the change in midazolam AUC as reliably as 5 days of XR dosing and 2 days of CR dosing. In addition, the authors believe that a hepatic CYP3A kdeg of 0.03 h(-1) should be considered for future Simcyp studies.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Area Under Curve
  • Chemistry, Pharmaceutical / methods
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors
  • Diltiazem / administration & dosage*
  • Drug Interactions
  • Female
  • Humans
  • Ketoconazole / administration & dosage
  • Male
  • Midazolam / administration & dosage*
  • Midazolam / pharmacokinetics*
  • Middle Aged
  • Sensitivity and Specificity
  • Young Adult


  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 CYP3A
  • Diltiazem
  • Midazolam
  • Ketoconazole