Single‐ and Multiple‐Dose Pharmacokinetics of Gefapixant (MK‐7264), a P2X3 Receptor Antagonist, in Healthy Adults.

Gefapixant (MK‐7264, RO4926219, AF‐219) is a first‐in‐class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single‐ and multiple‐dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials. Following single‐dose administration of 10‐450 mg, the pharmacokinetic (PK) profile of gefapixant in plasma and urine demonstrated low inter‐subject variability and a dose‐proportional exposure. Following administration of multiple doses twice daily, the plasma exposures were dose‐proportional at doses ranging from 7.5 to 50 mg and less than dose‐proportional at doses ranging from 100 to 1800 mg. The time to mean peak drug concentration ranged from 2 to 3 h post‐dose, and steady state was achieved by 7 days after dosing, with an accumulation ratio of approximately 2, comparing data from day 1 to steady state. The mean apparent terminal half‐life ranged from 8.2 to 9.6 h. Gefapixant was primarily excreted unmodified in urine. Gefapixant was well tolerated following single‐dose administration up to 1800 mg and multiple doses up to 1800 mg twice daily; there were no serious adverse events (AEs) reported. The most common AE reported was dysgeusia. The PK profile supports a twice‐daily dosing regimen. [ABSTRACT FROM AUTHOR]