Clinical pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-54175446, a brain permeable P2X7 antagonist, in a randomised single-ascending dose study in healthy participants

Background:Central nervous system-derived interleukin-1β plays a role in mood disorders. P2X7 receptor activation by adenosine-triphosphateleads to the release of interleukin-1β.Aims:This first-in- human studyevaluated safety, tolerability, pharmacokinetics and pharmacodynamics of a novel central nervous system-penetrant P2X7 receptor antagonist, JNJ-54175446, in healthy participants.Methods:The study had three parts: an ascending-dose study in fasted participants (0.5–300 mg JNJ-54175446); an ascending-dose study in fed participants (50–600 mg); and a cerebrospinal fluid study (300 mg). Target plasma concentrations were based on estimated plasma effectiveconcentration (EC)50 (105 ng/mL) and EC90 (900 ng/mL) values for central nervous systemP2X7 receptor binding.Results:Seventy-seven participants received a single oral dose of JNJ-54175446 (n=59) or placebo (n=18). Area underthe curveof concentration time extrapolated to infinity (AUC∞) increased dose-proportionally; maximum concentration ( Cmax) of p...