Safety, Tolerability, and Pharmacokinetics of Oral Camlipixant: A Randomized First-In-Human Study Using Single and Multiple Ascending Doses.

Camlipixant is a highly selective P2X3 receptor antagonist with demonstrated efficacy in pre-clinical models of evoked cough. We report the safety, tolerability, and pharmacokinetics of camlipixant in healthy participants. This Phase 1, double-blind, randomized study evaluated single ascending doses (SAD; 50/100/200/400/800/1200 mg) and multiple ascending doses (MAD; 100/200/400 mg, twice daily [BID]) of oral camlipixant versus placebo. Ninety participants were included (SAD n =  60; MAD n =  30). Treatment-emergent adverse event (TEAE) incidence was similar between camlipixant (32/72) and placebo (9/18). TEAEs were mostly mild (83%), and the most common with camlipixant was dysgeusia, primarily at doses ≥400 mg (n =  13), versus 50-200 mg (n =  1). Camlipixant was rapidly absorbed (time to maximum plasma concentration SAD: 0.77-2.29 h; MAD: 0.50-2.00 h), with a short half-life (SAD 4.28-6.71 h; MAD 7.60-8.39 h). In both cohorts, maximum plasma concentration (Cmax) increased proportionally with dose. The area under the curve extrapolated to infinity (AUC0-∞) increased proportionally with dose in the SAD cohort; the increase was slightly supra-proportional in the MAD cohort (steady state reached on Day 2). The geometric mean apparent volume of distribution ranged from 44.9 to 70.2 L and clearance from 5.7 to 10.4 L/h in the SAD cohort. Pharmacokinetics were unaffected by food (geometric mean fed/fasted ratio Cmax 91.4% [90% confidence interval, CI, 69.8-119.6]; AUC0-∞ 105.5% [90% CI, 89.8-124.0]). In summary, camlipixant was well tolerated, with pharmacokinetics supporting BID dosing and further clinical development for refractory chronic cough.