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. 2022 Mar;11(3):406-412.
doi: 10.1002/cpdd.1047. Epub 2021 Nov 24.

Assessment of Pharmacokinetic Interaction Between Gefapixant (MK-7264), a P2X3 Receptor Antagonist, and the OATP1B1 Drug Transporter Substrate Pitavastatin

Jacqueline B McCrea  1 , Azher Hussain  1 , Bennett Ma  1 , Graigory C Garrett  1 , Raymond Evers  1   2 , John E Laabs  3 , S Aubrey Stoch  1 , Marian Iwamoto  1
Affiliations

Assessment of Pharmacokinetic Interaction Between Gefapixant (MK-7264), a P2X3 Receptor Antagonist, and the OATP1B1 Drug Transporter Substrate Pitavastatin

Jacqueline B McCrea et al. Clin Pharmacol Drug Dev. 2022 Mar.

Abstract

Gefapixant (MK-7264, AF-219), a first-in-class P2X3 antagonist, is being developed as oral treatment for refractory or unexplained chronic cough. Based on in vitro data, gefapixant exerts inhibitory activity on the organic anion transporter (OAT) P1B1 transporter. Therefore, a drug-drug interaction study evaluating the potential effects of gefapixant on the OATP1B1 drug transporter, using pitavastatin as a sensitive probe substrate, was conducted. An open-label, 2-period, fixed-sequence study in 20 healthy adults 18 to 55 years old was conducted. In period 1, a 1-mg oral dose of pitavastatin was administered to each participant. After a ≥4-day washout, in period 2 participants received a 45-mg oral dose of gefapixant twice daily on days 1 through 4. On day 2 of period 2, pitavastatin was coadministered with the morning dose of gefapixant. Pitavastatin exposures following single-dose administration with and without multiple doses of gefapixant were similar: geometric mean ratio (90% confidence interval) of pitavastatin area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) (pitavastatin + gefapixant/pitavastatin alone) was 0.97 (0.93-1.02). The ratio of pitavastatin lactone AUC0-∞ to pitavastatin AUC0-∞ was also comparable between treatments. Administration of gefapixant and pitavastatin was generally well tolerated, with no safety findings of concern. These results support that gefapixant has a low potential to inhibit the OATP1B1 transporter.

Keywords: chronic cough; drug-drug interaction; organic anion transporting polypeptide.

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Conflict of interest statement

J.B.M., A.H., B.M., G.C.G., R.E., S.A.S., and M.I. are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, and may own stock/stock options in Merck & Co., Inc.. J.E.L. declares no conflicts of interest.

Figures

Figure 1
Figure 1
Arithmetic mean (± standard error) plasma concentration–time profiles of pitavastatin (A) and pitavastatin lactone (B) following administration of a single oral 1‐mg pitavastatin dose to healthy participants, without (○) or with (△) multiple oral doses of 45‐mg gefapixant twice daily for 4 days (N = 20). The insets show the data plotted on a semilogarithmic scale.
See this image and copyright information in PMC

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