First-in-human study of eliapixant (BAY 1817080), a highly selective P2X3 receptor antagonist: Tolerability, safety and pharmacokinetics

Aims Neuronal hypersensitisation due to adenosine triphosphate-dependent P2X3 receptor signalling plays a significant role in several disorders including chronic cough and endometriosis. This first-in-human study of eliapixant (BAY 1817080) investigated the tolerability, safety and pharmacokinetics (PK) of single doses of eliapixant, including the effect of food and coadministration with a CYP3A inhibitor on eliapixant relative bioavailability. Methods In this randomised, double-blind phase I study (NCT02817100), 88 healthy male subjects received single ascending doses of immediate-release eliapixant (10-800 mg) tablets or placebo under fasted conditions, with food (low-fat continental or high-fat American breakfast) or with itraconazole (fasted state). PK parameters, dose proportionality, adverse events and taste assessments (taste strips; dysgeusia questionnaire) were evaluated. Results Eliapixant had a long half-life (23.5-58.9 h [fasted state]; 32.8-43.8 h [high-fat breakfast]; 38.9-46.0 h [low-fat breakfast]). Less than dose-proportional increases in maximum plasma concentrations (C-max) and area under the concentration-time curve from time 0 to infinity (AUC([0-inf])) were observed with ascending eliapixant doses. We observed a pronounced food effect with the high-fat breakfast (4.1-fold increased C-max; 2.7-fold increased AUC([0-inf])), a smaller food effect with the low-fat breakfast and a mild-to-moderate effect of itraconazole coadministration on eliapixant (1.1-1.2-fold increased C-max; 1.7-fold increased AUC from 0 to 72 h). Eliapixant was well tolerated with minimal impact on taste perception. Conclusion The PK profile, particularly the long half-life, and favourable tolerability with no taste-related adverse events, supports the further development of eliapixant in disorders with underlying P2X3 receptor-mediated neuronal hypersensitisation.