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Effect of Different Durations and Formulations of Diltiazem on the Single‐Dose Pharmacokinetics of Midazolam: How Long Do We Go?
Author(s) -
Friedman Evan J.,
Fraser Iain P.,
Wang YingHong,
Bergman Arthur J.,
Li ChiChung,
Larson Patrick J.,
Chodakewitz Jeffrey,
Wagner John A.,
Stoch S. Aubrey
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010387141
Subject(s) - midazolam , diltiazem , cyp3a , pharmacokinetics , dosing , pharmacology , confidence interval , extended release , drug interaction , medicine , anesthesia , chemistry , cytochrome p450 , metabolism , sedation , calcium
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.