1 Janssen Research and Development, Beerse, Belgium.
2 Reference Centre for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium.
J Psychopharmacol. 2018 Dec;32(12):1341-1350. doi: 10.1177/0269881118800067. Epub 2018 Sep 27.
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.
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.
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) (105 ng/mL) and EC (900 ng/mL) values for central nervous system P2X7 receptor binding.
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) of plasma (C) 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 reached (600 mg, fed) was 1475±163 ng/mL. JNJ-54175446 C in cerebrospinal fluid, a proxy for brain penetration, was seven times lower than in total plasma; unbound C and C 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 dose-dependent manner (inhibitory concentration (IC):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%).
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.
中枢神经系统衍生的白细胞介素-1β在情绪障碍中发挥作用。三磷酸腺苷激活 P2X7 受体导致白细胞介素-1β释放。
本项首次人体研究评估了新型中枢神经系统穿透性 P2X7 受体拮抗剂 JNJ-54175446 在健康参与者中的安全性、耐受性、药代动力学和药效学。
该研究分为三个部分：禁食参与者的递增剂量研究（0.5-300mg JNJ-54175446）；进食参与者的递增剂量研究（50-600mg）；和脑脊液研究（300mg）。基于中枢神经系统 P2X7 受体结合的估计血浆有效浓度（EC）（105ng/mL）和 EC（900ng/mL）值，确定目标血浆浓度。
77 名参与者接受了单次口服 JNJ-54175446（n=59）或安慰剂（n=18）。浓度时间外推至无穷大的曲线下面积（AUC）呈剂量比例增加；JNJ-54175446 单剂量后，血浆（C）的最大浓度（C）的增加小于剂量比例。由于食物增加了 JNJ-54175446 的生物利用度，因此给予更高剂量的食物以评估更高暴露量的安全性。达到的最高 C（600mg，进食）为 1475±163ng/mL。脑脊液中的 JNJ-54175446 C，是穿透大脑的替代物，比总血浆低 7 倍；未结合的 C 和 C 相当（88.3±35.7 vs 114±39ng/mL）。JNJ-54175446 以剂量依赖性方式抑制脂多糖/3'-O-（4-苯甲酰苯甲酰）-ATP 诱导的外周血白细胞介素-1β释放（抑制浓度（IC）：82ng/mL；95%置信区间：48-94）。59 名参与者中有 33 名（55.9%）报告了至少 1 次治疗后出现的不良事件；最常见的不良事件是头痛（11/59，18.6%）。
JNJ-54175446 的血浆暴露与剂量有关。没有发生严重不良事件。单次给药 JNJ-54175446>10mg 可减轻外周血中脂多糖诱导的白细胞介素-1β释放。证实了 JNJ-54175446 的被动脑穿透。
