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


First published in European Journal of Clinical Pharmacology on 2019 Feb.
Eur J Clin Pharmacol. 2019 Feb;75(2):195-205. doi: 10.1007/s00228-018-2559-5. Epub 2018 Oct 4

Authors: Boof ML, Alatrach A, Ufer M, Dingemanse J



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.


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.


Moderate CYP3A4 inhibition by diltiazem (240 mg/day) increased the Cmax and AUC0-∞ 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 t½ by 80% (90% CI: 60-90) without affecting tmax. 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 Cmax and AUC within bioequivalence criteria and by an unchanged tmax. After a high-fat high-calorie breakfast, the pharmacokinetic profile of 25 mg ACT-541468 showed a decrease of Cmax by 24% (90% CI: 17-31) and a delay of tmax by approximately 2 h (90% CI: 1.4-2.4), whereas t½ and AUC0-24 remained essentially unchanged. ACT-541468 given alone or in combination with diltiazem, midazolam, or food was safe and well tolerated.


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.


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