| Sumario: | 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), area under the concentration-time curve from time 0 to infinity (AUC), and terminal half-life (t), respectively, of midazolam; the time to peak plasma concentration (t) was unchanged. Whereas C and t were not influenced by almorexant, the AUC of hydroxy-midazolam increased by 1.2-fold (90 % CI 1.1-1.4) and the t 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 and AUC, respectively, for simvastatin; the t and t were unchanged. The C and AUC 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 increased by 2 h and the t 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.
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