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

Abstract

Background: Central nervous system-derived interleukin-1β plays a role in mood disorders. P2X7 receptor activation by adenosine-triphosphate leads to the release of interleukin-1β. Aims: This first-inhuman 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 EC 90 (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∞) increased dose-proportionally; maximum concentration (C max) of plasma (C max,plasma) increased less than doseproportionally 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,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,plasma and C max,CSF were comparable (88.3±35.7 vs 114±39 ng/mL). JNJ-54175446 inhibited lipopolysaccharide/3′-O-(4-benzoylbenzoyl)-ATP-induced interleukin-1β release from peripheral blood in a dosedependent 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-1β release in peripheral blood. Passive brain penetration of JNJ-54175446 was confirmed.

Translational Model‐Informed Dose Selection for a Human Positron Emission Tomography Imaging Study of JNJ‐54175446, a P2X7 Receptor Antagonist

“…Like most Biopharmaceutics Classification System class II compounds, JNJ‐54175446 showed a positive food effect on its systemic exposure due to an increased solubility in fed state. The model‐predicted food effects (60–70% increase in exposure with food) were consistent with the clinical observations of JNJ‐54175446 that C max and area under the curve (AUC) increased by 50–70% after a 50 mg dose and by 50% to 111% after a 300 mg dose, in the presence of a high‐fat meal …”

“…The assumption is based on the following considerations: (i) unbound drug concentration in plasma approximates pharmacologically active free concentration in the brain; and (ii) free but not bound drug binds to receptors in the brain. JNJ‐54175446 is CNS‐penetrating and its drug concentration in cerebrospinal fluid was comparable to the unbound plasma concentration . Therefore, it is reasonable to extrapolate EC 50,RO from monkey to human after adjusting for differences in protein binding.…”

“…Plasma JNJ‐54175446 concentrations were quantified using liquid chromatographic‐mass spectrometry/mass spectrometry . For SAD/MAD and PET studies, the lowest quantifiable concentration was 0.500 ng/mL and 2.50 ng/mL, respectively.…”

“…4 P2X7 receptor is hypothesized to be critical in mediating brain inflammation and CNS neuron-glia signaling leading to neurodegenerative and psychiatric diseases. [5][6][7] JNJ-54175446 has been tested in single ascending dose (SAD; NCT02475148) 8 and multiple ascending dose (MAD; NCT02515955) studies in healthy subjects and is well-tolerated up to 600 mg single dose and 450 mg once daily following oral administration. The median time to achieve maximal concentration (T max ) ranged from 2-4 hours under fasted conditions, and the elimination halflife was ~ 35 hours.…”

“…Food effect was shown with higher exposure under fed compared with fasted condition. Passive CNS penetration was confirmed as drug concentrations in cerebrospinal fluid corresponded well to the free drug concentrations in plasma …”