title: Effect of different durations of ketoconazole dosing on the single-dose pharmacokinetics of midazolam: shortening the paradigm.
abstract: Given the prominent role of cytochrome P450 3A (CYP3A) in the metabolism of drugs, it is critical to determine whether new chemical entities will be affected by the inhibition of this enzyme system and result in clinically relevant drug interactions. Ketoconazole interaction studies are frequently performed to determine a given compound's sensitivity to CYP3A metabolism. The present study evaluated whether probing a sensitive substrate (midazolam) with a potent inhibitor (ketoconazole) at earlier time points (days 1 or 2) might be used to reliably gauge the magnitude of a meaningful interaction. The geometric mean ratios (ketoconazole+midazolamday 5/ketoconazole+midazolamday 1 and ketoconazole+midazolamday 5/ketoconazole+midazolamday 2) for midazolam AUC0-infinity were 1.36 and 1.06 with corresponding 90% confidence intervals of (1.17, 1.57) and (0.83, 1.23), respectively. These findings suggest that short-term drug-drug interaction studies can predict the magnitude of change in AUC as reliably as studies using longer duration treatments.
authors.affiliation: Merck & Co, Inc, Whitehouse Station, NJ, USA. aubrey_stoch@merck.com
authors.forename: S A
authors.initials: SA
authors.lastname: Stoch
authors.forename: E
authors.initials: E
authors.lastname: Friedman
authors.forename: A
authors.initials: A
authors.lastname: Maes
authors.forename: K
authors.initials: K
authors.lastname: Yee
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: P
authors.initials: P
authors.lastname: Larson
authors.forename: M
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: J
authors.initials: J
authors.lastname: Chodakewitz
authors.forename: J A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: D000328:Adult; D001682:Biological Availability; D003198:Computer Simulation; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D008962:Models, Theoretical; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D008874:Midazolam; D007654:Ketoconazole