Cain, Meredith, Vemula, Janardhana Rao, Zollinger, Markus, Umehara, Ken-Ichi , Elbast, Walid and Erpenbeck, Veit (2020) A study of the effect of cyclosporine on fevipiprant pharmacokinetics and its absolute bioavailability using an intravenous microdose approach. Drug Metabolism and Disposition, 48 (10). pp. 917-924. ISSN 1521009X

Abstract

This drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/ mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios [90% confidence interval (CI)] for oral fevipiprant with or without cyclosporine were 3.02 (2.38, 3.82) for Cmax, 2.50 (2.17, 2.88) for AUClast, and 2.35 (1.99, 2.77) for AUCinf. The geometric mean ratios (90% CI) for fevipiprant intravenous microdose with or without cyclosporine were 1.04 (0.86, 1.25) for Cmax, 2.04 (1.83, 2.28) for AUClast, and 1.95 (1.76, 2.16) for AUCinf. The absolute bioavailability for fevipiprant was approximately 0.3 to 0.4 in the absence and 0.5 in the presence of cyclosporine. The intravenous microdose allowed differentiation between systemic and presystemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately twofold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant, whereas P-gp does not have a relevant effect on oral absorption.

Item Type:	Article
Date Deposited:	01 Dec 2020 00:45
Last Modified:	01 Dec 2020 00:45
URI:	https://oak.novartis.com/id/eprint/39033