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Absorption, distribution, metabolism and excretion of the oral prostaglandin D2 receptor 2 (DP2) antagonist fevipiprant (QAW039) in healthy volunteers and in vitro

Pearson, David and Weiss, Markus and Jin, Yi and van Lier, Jan Jaap and Erpenbeck, Veit and Glaenzel, Ulrike and End, Peter and Woessner, Ralph and Camenisch, Gian P. and Eggimann, Fabian (2017) Absorption, distribution, metabolism and excretion of the oral prostaglandin D2 receptor 2 (DP2) antagonist fevipiprant (QAW039) in healthy volunteers and in vitro. Drug Metabolism and Disposition. ISSN 0090-95561521-009X

Abstract

Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200 mg oral dose of [14C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multi-drug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes, as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.

Item Type: Article
Date Deposited: 20 Jun 2017 00:45
Last Modified: 20 Jun 2017 00:45
URI: https://oak.novartis.com/id/eprint/32505

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