Interaction potential of the dual orexin receptor antagonist ACT-541468 with CYP3A4 and food: results from two interaction studies.

PURPOSE

ACT-541468 is a novel dual orexin receptor antagonist (DORA) under development for the treatment of insomnia. In vitro studies suggested a significant role of CYP3A4 in ACT-541468 metabolism and an impact on CYP3A4 activity.

METHODS

Subsequently, two clinical cross-over studies investigated the victim (n = 14 healthy subjects) and perpetrator (n = 20) potential of 25 mg ACT-541468 with respect to CYP3A4. The effect of food intake on the pharmacokinetics of ACT-541468 was also investigated.

RESULTS

Moderate CYP3A4 inhibition by diltiazem (240 mg/day) increased the C and AUC of ACT-541468 by 1.4-fold (90% confidence interval (CI): 1.2-1.6) and 2.4-fold (90% CI: 2.0-2.8), respectively, and prolonged t by 80% (90% CI: 60-90) without affecting t. Single- and multiple-dose administration of 25 mg ACT-541468 had no impact on the pharmacokinetics of the sensitive substrate midazolam and its main metabolite 1-hydroxy midazolam indicated by 90% CI of the geometric mean ratios of C and AUC within bioequivalence criteria and by an unchanged t. After a high-fat high-calorie breakfast, the pharmacokinetic profile of 25 mg ACT-541468 showed a decrease of C by 24% (90% CI: 17-31) and a delay of t by approximately 2 h (90% CI: 1.4-2.4), whereas t and AUC remained essentially unchanged. ACT-541468 given alone or in combination with diltiazem, midazolam, or food was safe and well tolerated.

CONCLUSIONS

Overall, ACT-541468 has been determined as CYP3A4 substrate but without any perpetrator drug-drug interaction potential regarding CYP3A4 in humans. Food affected ACT-541468 absorption without modifying overall exposure.