Absorption, metabolism and excretion of fevipiprant (QAW039) investigated in vivo and in vitro

Introduction Fevipiprant is an oral CRTh2 antagonist in development for treatment of allergic conditions. We report the assessment of absorption, metabolism and excretion, and identification of enzymes and transporters involved in its human pharmacokinetics (PK). Methods Healthy males (n=4) received a single oral dose of 14 C radiolabeled-fevipiprant (200 mg). Blood, plasma, urine and feces collected up to 240 h were analysed for total radioactivity. Extracts were analysed by LC-radioactivity and LC-MS/MS to assess metabolite pattern; fevipiprant and its acylglucuronide metabolite (AG-metabolite) were quantified by LC-MS/MS. Human metabolic enzymes and transporters relevant for fevipiprant PK were investigated in vitro using recombinant cellular models. Results In excreta, 94% of the 14 C dose was detected (42% in urine; 52% in feces). Unchanged fevipiprant was the major component in feces. In urine, 13% and 27% of the dose were detected as fevipiprant and AG-metabolite, respectively. AG-metabolite was the only major metabolite. Plasma radioactivity concentration data indicated the possibility of protein adducts with the AG-metabolite. We demonstrated in vitro that fevipiprant was a substrate of human UDP-glucuronosyltransferases UGT1A3, 2B7 and 2B17, and transporters involved in tubular secretion in the kidney (OAT3), active hepatic uptake (OATP1B3) and biliary excretion (MDR1). Conclusion Fevipiprant is eliminated via various metabolic enzymes and direct excretion. Therefore, fevipiprant has a low probability to be a victim of a strong drug interaction or to display major variability or ethnic sensitivity in PK due to genetic polymorphism.