PI-062 - EFFECT OF ACT-539313, A SELECTIVE OREXIN-1 RECEPTOR ANTAGONIST, ON THE CYTOCHROME P450 2C9, 2C19, AND 3A4 SUBSTRATES FLURBIPROFEN, OMEPRAZOLE, AND MIDAZOLAM USING A COCKTAIL APPROACH.

B. Berger¹, P. Kaufmann¹, M. Berse², N. Grignaschi¹, J. Dingemanse¹; ¹Idorsia Pharmaceuticals Ltd,, Allschwil, Switzerland, ²CRS Berlin GmbH, Berlin, Germany.

Background: Orexin neuropeptides regulate feeding behavior and compulsive reactions by activating the orexin-1 receptor (OX1R) [1]. ACT-539313, a selective OX1R antagonist, has recently been assessed in the treatment of binge eating disorder [2].

Methods: A single-center, open-label, fixed-sequence study was performed to explore the effect of single- and repeated-dose twice daily administration (for 8 days) of 100 mg ACT-539313 on the pharmacokinetics (PK) of 50 mg flurbiprofen (FLU, cytochrome P450 [CYP] 2C9), 20 mg omeprazole (OME, CYP2C19), 2 mg midazolam (MDZ, CYP3A4), and their main metabolites in healthy adults. PK sampling in plasma was performed over 24 h on Day 1 (Treatment [Trt] A), 8 (Trt B), and 15 (Trt D).

Results: In 22 subjects, exposure to FLU, OME, and MDZ was generally higher during concomitant single- and repeated-dose ACT-539313 administration compared to the cocktail administered alone (Table 1). The most frequently reported adverse event was somnolence (mild/moderate intensity). No treatment-related effects on vital signs, clinical laboratory, or ECG were observed.

Conclusion: According to FDA guidance [3], ACT-539313 is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after one day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after repeated b.i.d. administration of 100 mg.

[1] Sakurai T. The role of orexin in motivated behaviours. Nat Rev Neurosci. 15, 719-31 (2014).
[2] ClinicalTrials.gov Identifier: NCT04753164. https://clinicaltrials.gov/ct2/show/NCT04753164?term=NCT04753164&draw=2&rank=1 (2022). Accessed 14 September 2022.
[3] FDA. Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Drug Interactions Guidance for Industry. FDA Guide Doc. 2020;1(January):1-27. https://www.fda.gov/media/134581/download (2020). Accessed 14 September 2022.

Table 1. Summary of flurbiprofen, omeprazole, and midazolam PK parameters.