Manitpisitkul Prasarn, Brandt Michael, Flores Christopher M, Kenigs Velga, Moyer John A, Romano Gary, Shalayda Kevin, Mayorga Arthur J
Neuroscience Department, Janssen Research & Development, LLC, Titusville, NJ, USA.
Pain Rep. 2016 Oct 30;1(4):e576. doi: 10.1097/PR9.0000000000000576. eCollection 2016 Oct.
This double-blind, randomized, placebo-controlled, sequential group, phase 1 study was designed to assess in healthy men, the safety, tolerability, pharmacokinetics, and translational pharmacodynamics of JNJ-39439335 (mavatrep), a transient receptor potential vanilloid subtype 1 antagonist; it was preceded by a translational preclinical study which assessed the ability of JNJ-39439335 to block capsaicin-induced flare in rats, providing predictive pharmacokinetic and pharmacodynamic data that informed the subsequent phase 1 clinical study. The clinical study consisted of 2 parts: part 1 assessed pharmacokinetics and pharmacodynamics, including heat pain detection threshold and heat pain tolerance, of JNJ-39439335, and part 2 assessed pharmacodynamic effect of JNJ-39439335 on capsaicin-induced flare and sensory testing on naïve and UVB-sensitized skin in humans. Plasma concentrations of JNJ-39439335 peaked at approximately 2 to 4 hours postdose, then declined multiexponentially, with a prolonged terminal phase (half-life: 30-86 hours). Renal clearance of JNJ-39439335 was negligible. JNJ-39439335 treatment resulted in clear, consistent dose-related increases in heat pain detection threshold, heat pain tolerance, and heat pain latency. JNJ-39439335 reduced the capsaicin-induced flare area and flare intensity, with complete blocking observed in the 50-mg dose group at 144 hours postdose. This was consistent with the capsaicin flare results observed with JNJ-39439335 in rats. The most common adverse events observed in the clinical study were related to increases in body temperature after JNJ-39439335 treatment; these were predominately mild to moderate in severity with no evidence of exposure dependence up to 225 mg. JNJ-39439335 was well tolerated at single doses up to 225 mg, recommending its suitability for further clinical development.
这项双盲、随机、安慰剂对照、序贯分组的1期研究旨在评估瞬时受体电位香草酸亚型1拮抗剂JNJ-39439335（mavatrep）在健康男性中的安全性、耐受性、药代动力学和转化药效学；在此之前进行了一项转化临床前研究，评估JNJ-39439335阻断大鼠辣椒素诱导的潮红的能力，提供了预测性药代动力学和药效学数据，为后续的1期临床研究提供了参考。临床研究包括2个部分：第1部分评估JNJ-39439335的药代动力学和药效学，包括热痛检测阈值和热痛耐受性，第2部分评估JNJ-39439335对辣椒素诱导的潮红的药效学作用以及对人类未致敏和紫外线B致敏皮肤的感觉测试。JNJ-39439335的血浆浓度在给药后约2至4小时达到峰值，然后呈多指数下降，终末相延长（半衰期：30 - 86小时）。JNJ-39439335的肾清除率可忽略不计。JNJ-39439335治疗导致热痛检测阈值、热痛耐受性和热痛潜伏期明显、一致的剂量相关增加。JNJ-39439335减少了辣椒素诱导的潮红面积和潮红强度，在给药后144小时的50 mg剂量组中观察到完全阻断。这与在大鼠中用JNJ-39439335观察到的辣椒素潮红结果一致。临床研究中观察到的最常见不良事件与JNJ-39439335治疗后体温升高有关；这些不良事件大多为轻度至中度，在高达225 mg的剂量下没有暴露依赖性的证据。JNJ-39439335在高达225 mg的单剂量下耐受性良好，表明其适合进一步的临床开发。
