Weiss, Markus, Cain, Meredith, Langenickel, Thomas, Kulkarni, Swarupa, Shah, Bharti, Rahmanzadeh, Gholamreza, Poller, Birk and Vemula, Janardhana Rao (2021) Clinical investigation of metabolic and renal clearance pathways contributing to the elimination of fevipiprant using probenecid as perpetrator. Drug metabolism and disposition, 49 (5). pp. 389-394. ISSN 1521-009X

Abstract

Fevipiprant, an oral, non-steroidal, highly selective, reversible, and competitive antagonist of the prostaglandin D2 receptor 2, is eliminated by glucuronidation, and by direct renal excretion. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and organic anion transporter (OAT) 3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite.. This was a single-center, open-label, single sequence, two-period, crossover study in healthy subjects. Liquid chromatography with tandem mass spectrometry was used to measure concentrations of fevipiprant and its AG metabolite in plasma and urine. In the presence of probenecid, the mean maximum concentration of fevipiprant increased approximately 1.7-fold, and the area under the curve (AUC)last and AUCinf increased approximately 2.5-fold, while the mean apparent volume of distribution as well as the AG metabolite-fevipiprant ratio decreased. The apparent systemic clearance decreased by approximately 60% and the renal clearance decreased by approximately 88% in the presence of probenecid. Using the data from this study and previous studies, the relative contribution of OAT and UGT inhibition to the overall effect of probenecid was determined. This allowed to establish a general disposition scheme for fevipiprant and to estimate quantitative contributions for the involved pathways: OATP1B1-mediated hepatic uptake, OAT3-mediated renal excretion and glucuronidation via UGT1A3, UGT2B7 and UGT2B17.

Item Type:	Article
Date Deposited:	11 May 2021 00:45
Last Modified:	11 May 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43600