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.