Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro

Abstract

Fevipiprant is a novel oral prostaglandin D receptor 2 (DP; 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 [C]-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.

A Study of the Effect of Cyclosporine on Fevipiprant Pharmacokinetics and its Absolute Bioavailability Using an Intravenous Microdose Approach

“…Renal clearance and hepatic elimination via glucuronidation and/or biliary secretion contribute to the elimination of fevipiprant; IV PK data can help to estimate the contributions of these clearance pathways more quantitatively. In a human absorption, distribution, metabolism and excretion (ADME) study of fevipiprant the fraction of the oral dose absorbed from the intestine was estimated to be at least 43.5% (42.1% of the total radioactive dose recovered from urine and 1.4% as metabolites in feces) (Pearson et al, 2017). However, the absolute bioavailability, DMD # 90852 i.e.…”

“…In vitro data indicate that fevipiprant is taken up via organic anion transporting polypeptide 1B3 (OATP1B3) into the liver, followed by formation of an acyl glucuronide (AG) metabolite by several uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. Of note, the AG metabolite is the only major circulating metabolite of fevipiprant and is not pharmacologically active (Pearson et al, 2017). Organic anion transporter 3 (OAT3) is responsible for the active renal excretion of fevipiprant (Pearson et al, 2017).…”

“…Of note, the AG metabolite is the only major circulating metabolite of fevipiprant and is not pharmacologically active (Pearson et al, 2017). Organic anion transporter 3 (OAT3) is responsible for the active renal excretion of fevipiprant (Pearson et al, 2017).…”

“…Because fevipiprant is a substrate of P-glycoprotein (P-gp or multidrug resistance protein 1; MDR1) and UGT enzymes, intestinal efflux and metabolism could have an impact on its absorption and first-pass metabolism, respectively (Pearson et al, 2017). In addition, the hepatic first-pass extraction by OATP1B3-mediated uptake may influence the bioavailability of fevipiprant.…”

The impact of the prostaglandin D2 receptor 2 and its downstream effects on the pathophysiology of asthma

“…Pharmacological studies have shown that fevipiprant is a competitive inhibitor of DP 2 receptor‐mediated responses involved in asthma . Furthermore, fevipiprant has a short time to peak plasma concentration, has a long half‐life, does not interact with food and is excreted through multiple pathways reducing the risk of drug‐drug interactions and pharmacogenetic or ethnic variability …”