Bhattacharya, Anindya

Biewenga, Jeike

Ceusters, Marc

de Boer, Peter

Furey, Maura

Ravenstijn, Paulien

Timmers, Maarten

Triana-Baltzer, Gallen

van den Boer, Maarten

Van Hemelryck, Sandy

van Nueten, Luc

Xi, Liwen

Abstract: Background: Central nervous system-derived interleukin-1 beta plays a role in mood disorders. P2X7 receptor activation by adenosine-triphosphate leads to the release of interleukin-1 beta. Aims: This first-in-human study evaluated 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 effective concentration (EC)(50) (105 ng/mL) and EC90 (900 ng/mL) values for central nervous system P2X7 receptor binding. Results: Seventy-seven participants received a single oral dose of JNJ-54175446 (n=59) or placebo (n=18). Area under the curve of concentration time extrapolated to infinity (AUC(infinity)) increased dose-proportionally; maximum concentration (C-max) of plasma (C-max,C-plasma) increased less than dose-proportionally following single doses of JNJ-54175446. Because food increases bioavailability of JNJ-54175446, higher doses were given with food to evaluate safety at higher exposures. The highest C-max,C-plasma reached (600 mg, fed) was 1475 +/- 163 ng/mL. JNJ-54175446 C-max in cerebrospinal fluid, a proxy for brain penetration, was seven times lower than in total plasma; unbound C-max,C-plasma and C-max,C-CSF were comparable (88.3 +/- 35.7 vs 114 +/- 39 ng/mL). JNJ-54175446 inhibited lipopolysaccharide/3 '-O-(4-benzoylbenzoyl)-ATP-induced interleukin-1 beta release from peripheral blood in a dose-dependent manner (inhibitory concentration (IC)(50):82 ng/mL; 95% confidence interval: 48-94). Thirty-three of 59 (55.9%) participants reported at least one treatment-emergent adverse event; the most common adverse event being headache (11/59, 18.6%). Conclusion: Plasma exposure of JNJ-54175446 was dose-dependent. No serious adverse events occurred. Single-dose administration of JNJ-54175446>10 mg attenuated ex-vivo lipopolysaccharide-induced interleukin-1 beta release in peripheral blood. Passive brain penetration of JNJ-54175446 was confirmed

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

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

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Institutional Repository Universiteit Antwerpen