title: Effect of different durations and formulations of diltiazem on the single-dose pharmacokinetics of midazolam: how long do we go?
abstract: 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.
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey, USA.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Friedman
authors.forename: Iain P
authors.initials: IP
authors.lastname: Fraser
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Wang
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Bergman
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Li
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Larson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chodakewitz
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004110:Diltiazem / Q000008:administration & dosage*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008875:Middle Aged; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; D004110:Diltiazem; D008874:Midazolam; D007654:Ketoconazole