PII-097 - AN INTEGRATED ASSESSMENT OF THE AME PROPERTIES OF SELTOREXANT UTILIZING PRECLINICAL IN VITRO, IN VIVO, AND HUMAN ADME DATA.

D. Devineni¹, S. Xu¹, V. Sinha¹, I. Wynant², S. Ballentine¹, C. Sensenhauser¹, J. Snoeys², S. Mesens²; ¹Janssen Research & Development, LLC, ²Janssen Research & Development, Beerse, Belgium.

Background: Seltorexant (JNJ-42847922) is a potent and selective orexin-2 receptor (OX2R) antagonist being developed as a treatment for major depressive disorder (MDD). We herein report an assessment integrating the absorption, metabolism, and excretion results across species to understand the clearance pathways of seltorexant.

Methods: A single dose of 14C-Seltorexant was orally administered to rats (30 mg/kg) and dogs (15 mg/kg) (in 0.5% hypromellose), as well as healthy subjects (40 mg, oral solution). Seltorexant and its metabolites in plasma, urine, and feces were analyzed using liquid chromatography coupled to radioflow detection and tandem mass spectrometry (LC-RAD-MS/MS). Cytochrome P450 (CYP) phenotyping study was conducted in vitro.

Results: Following single oral administration of 14C-seltorexant to rats, dogs and humans, absorption was fast in all species with a tmax of ~2 hours. Oral absorption was estimated to be high with >96% in rats and >69% in dogs and almost complete (~100%) in humans. Seltorexant was extensively metabolized in rats, dogs and humans, and the major metabolites in the feces were oxidation products. In rat plasma, the major circulating components were unchanged drug (UD), M12 (hydroxymethyl-UD), M16 (hydroxy-UD), and M17 (dihydroxy-UD), while in dog plasma, M16 was the predominant circulating component, followed by UD. In human plasma, the major circulating components were UD and M12, with M16 and M23 (carboxy-UD) as minor circulating metabolites. In humans, seltorexant was predominantly metabolized by CYP3A4 (to M16) and CYP2C9 (to M12).
In rats, dogs and humans, ~90%, 64%, 44% of the dose was recovered in feces and 11%, 33% and 56% was recovered in urine, respectively. UD was a major component in dog feces (~28% of the dose) and a minor component in feces from rats (~4% of the dose) and humans ( < 1% of the dose), and a minor component in urine ( < 1% of the dose) across all species.

Conclusion: Seltorexant is well absorbed and cleared primarily via oxidative metabolism across species.