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

Abstract

This drug-drug interaction (DDI) study determined the effect of cyclosporine, an inhibitor of OATP1B3 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 (IV) microdose of stable isotopelabeled fevipiprant provided the absolute bioavailability of fevipiprant, as well as mechanistic insights in 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% CI) for oral fevipiprant with or without cyclosporine were: for Cmax, 3.02 (2.38, 3.82); for AUClast, 2.50 (2.17, 2.88); and for AUCinf, 2.35 (1.99, 2.77). The geometric mean ratios (90% CI) for fevipiprant IV microdose with or without cyclosporine were: for Cmax, 1.04 (0.86, 1.25); for AUClast, 2.04 (1.83, 2.28) and for AUCinf, 1.95 (1.76, 2.16). The absolute bioavailability for fevipiprant was approximately 0.3-0.4 in the absence and 0.5 in the presence of cyclosporine. The IV microdose allowed differentiation between systemic and pre-systemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately 2-fold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant while P-gp does not have a relevant effect on oral absorption. Significance statement: The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant, as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied IV microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic DDI understanding.

Clinical Investigation of Metabolic and Renal Clearance Pathways Contributing to the Elimination of Fevipiprant Using Probenecid as Perpetrator

“…In addition, reduced distribution of fevipiprant into the kidney in the presence of probenecid can also contribute to the reduced Vz/F. Previous in vitro and clinical DDI data revealed that OATP1B3-mediated uptake into the liver is a key mechanism of fevipiprant systemic elimination (Weiss et al, 2020). The results from the present study further corroborate that hepatic and renal elimination both contribute approximately 50% to the total systemic clearance of fevipiprant (Figure 4).…”

“…The metabolic and renal effects of probenecid can be distinguished using the following information: plasma concentration data and the urinary excretion of both fevipiprant and its AG metabolite; complementary literature providing in vitro and absorption, distribution, metabolism, and excretion (ADME) data (Pearson et al, 2017); and oral and intravenous (IV) DDI data with and without the OATP1B3 and P-gp inhibitor cyclosporine (Weiss et al, 2020). Based on this, the fractional contribution of OAT and UGT inhibition to the observed effect was estimated and a general disposition scheme for fevipiprant established.…”

“…The systemic clearance (CL) of fevipiprant based on IV data is 19 L/h (Weiss et al, 2020), which allows an estimation of bioavailability (F) of 0.43 using the observed CL/F of 43.7 L/h in this study population. The measured CLr (9.87 L/h) accounts for half of CL (19 L/h) and is comparable to the observed CLr reported previously (9.49 L/h) (Weiss et al, 2020). Inhibition of OAT3-mediated active renal excretion by probenecid reduces CLr by 8.7 L/h (Table 1) and consequently CL to 10.3 L/h (19 L/h -8.7 L/h) and CL/F to 24 L/h (10.3 L/h / 0.43).…”

“…A previous DDI study showed that co-administration of cyclosporine, an inhibitor of OATP1B3 and P-gp, increased oral fevipiprant 150 mg area under the curve (AUC) by 2.5-fold and maximum concentration (C max ) by 3-fold (Weiss et al, 2020). Our study investigates the effect of inhibition of the other relevant clearance pathways of fevipiprant by probenecid i.e.…”

“…Fevipiprant is metabolised to an acyl glucuronide (AG) metabolite (1-O-beta form which can rearrange to isomers), representing the only relevant metabolite in systemic circulation and excreta which is not pharmacologically active. Data from clinical mass balance and drug-drug interaction (DDI) studies revealed that hepatic and renal clearance contribute to the total systemic elimination of fevipiprant and that renal clearance involves an active secretion process (Pearson et al, 2017;Weiss et al, 2020). Because the contributions of both glucuronidation and renal excretion exceed 25% of the clearance of fevipiprant, clinical studies are recommended by health authority guidelines to study the DDI risk in humans (Zhang et al, 2009;European Medicines Agency, 2013; Center for Drug Evaluation and…”