1. Single- and Multiple-Dose Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist, in Healthy Adults.
- Author
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Nussbaum JC, Hussain A, Butera P, Ford AP, Kitt MM, O'Neill EA, Smith S, Vargas G, O'Reilly T, Wynne C, Stoch SA, and Iwamoto M
- Subjects
- Humans, Male, Adult, Female, Middle Aged, Young Adult, Dose-Response Relationship, Drug, Double-Blind Method, Healthy Volunteers, Adolescent, Drug Administration Schedule, Half-Life, Sulfonamides pharmacokinetics, Sulfonamides administration & dosage, Sulfonamides adverse effects, Pyrimidines pharmacokinetics, Pyrimidines administration & dosage, Pyrimidines adverse effects, Benzenesulfonamides, Purinergic P2X Receptor Antagonists pharmacokinetics, Purinergic P2X Receptor Antagonists administration & dosage, Purinergic P2X Receptor Antagonists adverse effects
- Abstract
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., (© 2024 Merck Sharp & Dohme LLC and The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
- Published
- 2024
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