p450 - publications
Pharmacokinetic interactions of almorexant with midazolam and simvastatin, two CYP3A4 model substrates, in healthy male subjects.
Eur J Clin Pharmacol. 2012 Sep 19;
Authors: Hoch M, Hoever P, Alessi F, Theodor R, Dingemanse J
PURPOSE: Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 model substrates. METHODS: Fourteen healthy male subjects were enrolled in an open-label, randomized, two-way crossover study. Treatment period A consisted of a single oral dose of 2 mg midazolam on day 1 and 40 mg simvastatin on day 3. In treatment period B, subjects received 200 mg almorexant once daily for 9 days together with a single oral dose of midazolam on day 7 and simvastatin on day 9. RESULTS: Concomitant administration of midazolam with almorexant at steady-state levels, achieved within 4-5 days, resulted in an increase of 1.2-fold [90 % confidence interval (CI) 1.0-1.4], 1.4-fold (90 % CI 1.2-1.6), and 1.3-fold (90 % CI 1.2-1.4) in the maximum plasma concentration (C(max)), area under the concentration-time curve from time 0 to infinity (AUC(0-∞)), and terminal half-life (t(1/2)), respectively, of midazolam; the time to peak plasma concentration (t(max)) was unchanged. Whereas C(max) and t(max) were not influenced by almorexant, the AUC(0-∞) of hydroxy-midazolam increased by 1.2-fold (90 % CI 1.1-1.4) and the t(1/2) by 1.3-fold (90 % CI 1.0-1.5). Concomitant administration of simvastatin with almorexant at steady-state resulted in an increase of 2.7-fold (90 % CI 2.0-3.7) and 3.4-fold (90 % CI 2.6-4.4) in C(max) and AUC(0-∞), respectively, for simvastatin; the t(1/2) and t(max) were unchanged. The C(max) and AUC(0-∞) of hydroxyacid simvastatin both increased by 2.8-fold, with 90 % CIs of 2.3-3.5 and 2.2-3.5, respectively; the t(max) increased by 2 h and the t(1/2) was unchanged. The urinary 6-β-hydroxycortisol/cortisol ratio was unaffected by almorexant. CONCLUSIONS: Our results suggest that the observed interaction was caused by the inhibition of CYP3A4 activity, most probably at the gut level.
PMID: 22990330 [PubMed - as supplied by publisher]