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

• Published in: Journal of clinical pharmacology Vol. 51; no. 11; p. 1561
• Main Authors: Friedman, Evan J, Fraser, Iain P, Wang, Ying-Hong, Bergman, Arthur J, Li, Chi-Chung, Larson, Patrick J, Chodakewitz, Jeffrey, Wagner, John A, Stoch, S Aubrey
• Format: Journal Article
• Language: English
• Published: England 01.11.2011
• Subjects: 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
• ISSN: 1552-4604
• DOI: 10.1177/0091270010387141

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.