Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Grenzacherstrasse 124, Basel, Switzerland.
PRA Health Sciences (PRA) - Early Development Services, Van Swietenlaan 6 Clinical Site, Groningen, the Netherlands.
Br J Clin Pharmacol. 2018 Mar;84(3):445-455. doi: 10.1111/bcp.13466. Epub 2017 Dec 18.
The objectives of this first-in-human study were to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, and maximum tolerated dose (MTD) of single ascending oral doses of RG7342, a positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGlu5) for the treatment of schizophrenia, in healthy male subjects.
This was a single-centre, randomized, double-blind, adaptive study of 37 subjects receiving single ascending oral doses of RG7342 (ranging from 0.06-1.2 mg, n = 27) or placebo (n = 10). A modified continual reassessment method, with control for the probability of overdosing based on the occurrence of dose-limiting events (DLEs), was applied to inform the subsequent dose decisions for RG7342.
DLEs consisted of dizziness, nausea and vomiting, and the incidence and severity of these adverse events increased in a concentration-dependent manner. RG7342 doses of 1.2 mg under fasting conditions, which reached a mean maximum plasma concentration (C ) of 10.2 ng ml , were not tolerated (four out of six subjects experienced DLEs). RG7342 showed dose-proportional pharmacokinetics, with rapid absorption and a biphasic decline, and a mean terminal half-life estimated to be >1000 h.
Single oral doses of RG7342 were generally tolerated up to 0.6 mg under fasting and 0.9 mg under fed conditions in healthy subjects. Bayesian adaptive methods describing the probability of DLEs were applied effectively to support dose escalation. MTDs (fasting, fed) were associated with a C of 6.5 ng ml . The development of RG7342 was discontinued owing to the potential challenges associated with a long half-life in context of the observed adverse events.
这项首次人体研究的目的是评估单剂量递增口服 RG7342（一种用于治疗精神分裂症的代谢型谷氨酸受体 5 正变构调节剂（PAM））在健康男性受试者中的安全性和耐受性、药代动力学和药效学以及最大耐受剂量（MTD）。
这是一项在单一中心进行的、随机的、双盲的、适应性研究，共纳入 37 名受试者，他们接受了单剂量递增口服 RG7342（范围为 0.06-1.2mg，n=27）或安慰剂（n=10）。采用改良的连续再评估方法，并根据剂量限制事件（DLE）的发生控制发生过度用药的概率，来为后续 RG7342 剂量的确定提供信息。
DLEs 包括头晕、恶心和呕吐，这些不良反应的发生率和严重程度呈浓度依赖性增加。在禁食条件下，RG7342 剂量达到 1.2mg（C 平均值为 10.2ng/ml）时不可耐受（6 名受试者中有 4 名发生 DLEs）。RG7342 表现出剂量比例的药代动力学特征，吸收迅速，呈双相下降，估计终末半衰期大于 1000h。
在健康受试者中，空腹时口服 RG7342 高达 0.6mg，进食时口服 RG7342 高达 0.9mg，通常可耐受。描述 DLE 发生概率的贝叶斯自适应方法被有效地应用于支持剂量递增。MTD（禁食，进食）与 C 为 6.5ng/ml 相关。由于观察到的不良反应与较长半衰期相关，因此开发 RG7342 被停止。
