Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro.
David Pearson,H. Markus Weiss,Yi Jin,Jan Jaap van Lier,Veit J. Erpenbeck,Ulrike Glaenzel,Peter End,Ralph Woessner,Fabian Eggimann,Gian Camenisch +9 more
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Elimination of fevipiprant occurs via glucuronidation by several uridine 5′-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion, resulting in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.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), multidrug 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.read more
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The impact of the prostaglandin D2 receptor 2 and its downstream effects on the pathophysiology of asthma.
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New treatments for asthma: From the pathogenic role of prostaglandin D2 to the therapeutic effects of fevipiprant.
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TL;DR: Fevipiprant appears to be safe and effective, especially in consideration of its ability to inhibit eosinophilic bronchial inflammation and improve forced expiratory volume in one second (FEV1).
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