In vitro assessments for pharmacokinetic drug-drug interaction potential of vornorexant, a novel dual orexin 1/2 receptor antagonist

assessments to evaluate the drug-drug interaction (DDI) potential of vornorexant and its metabolite M3 mediated by CYP enzymes and transporters.Human CYP reaction phenotyping studies indicated that vornorexant and M3 are primarily metabolized by CYP3A4, and to a lesser extent by CYP3A5 and CYP2C8.Vornorexant exhibited weak reversible and time-dependent inhibition of CYP3A. Both vornorexant and M3 showed the potential to induce CYP2B6 and CYP3A4. However, these effects were not considered to have any impact on causing DDIs at these unbound systemic concentrations at the clinical doses of vornorexant.Vornorexant was a weak substrate for P-gp but not for BCRP, OATP1B1, or OATP1B3.Vornorexant and M3 exhibited weak or no inhibitory effects against P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K.These data suggest that while vornorexant might be an object drug of CYP3A precipitants, vornorexant is unlikely to cause clinically relevant DDIs mediated by either CYP enzymes or transporters involved in the metabolism and disposition of concomitantly administered drugs.