Metabotropic glutamate receptor 5 negative modulation in phase I clinical trial: potential impact of circadian rhythm on the neuropsychiatric adverse reactions-do hallucinations matter?
Metabotropic glutamate receptor 5 negative modulation in phase I clinical trial: potential impact of circadian rhythm on the neuropsychiatric adverse reactions-do hallucinations matter?
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DOI：
10.1155/2014/652750
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Baljé-Volkers C
中科院分区：
文献类型：
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作者：
Abou Farha K;Bruggeman R;Baljé-Volkers C
代谢型谷氨酸受体5（mGluR 5）负变构调节剂（NAM）可能在一些精神疾病如焦虑和抑郁中发挥作用。mGluR 5-NAMs的药代动力学特征和药效学效应先前已有报道。我们对18名年轻健康女性受试者的药理学和临床数据进行了事后分析，这些受试者在mGluR 5 NAM和双相口服避孕药之间的I期药物相互作用研究中接受了mGluR 5-NAM。mGluR 5-NAM以递增的二倍剂量水平设计施用。OC和mGluR 5-NAM之间没有相互作用。发现早晨mGluR 5-NAM血浆浓度高于晚上浓度。大多数观察到的具有临床意义的神经精神不良反应均发生在夜间，包括视觉（假性）幻觉、失眠伴继发性行为障碍和严重程度足以干扰日常功能的认知功能障碍症状。 药物吸收和处置的昼夜节律相关的生理变化可以解释这种药代动力学-药效学明显不成比例的关系。我们建议临床试验评估精神科药物的基本药代动力学特性时考虑潜在药物的时间药代动力学。这可能有助于剂量优化，并最大限度地减少脆弱的精神病患者的严重神经精神不良反应。
Metabotropic Glutamate Receptor 5 (mGluR5) negative allosteric modulators (NAMs) may play a role in some psychiatric disorders such as anxiety and depression. The pharmacokinetic profile and pharmacodynamics effects of mGluR5-NAMs have been previously reported. We performed a post hoc analysis of pharmacological and clinical data obtained from 18 young healthy female subjects who received a mGluR5-NAM in the context of a phase I drug-drug interaction study between a mGluR5 NAM and a monophasic oral contraceptive. mGluR5-NAM was administered in an escalating bidaily dose level design. There was no interaction between the OC and mGluR5-NAM. Higher morning mGluR5-NAM plasma concentrations were found compared to evening concentrations. Most of the observed clinically significant neuropsychiatric adverse reactions occurred nocturnally and included visual (pseudo) hallucinations, insomnia accompanied by secondary behavioural disorders, and cognitive dysfunction symptoms of sufficient severity to interfere with daily functioning. Circadian rhythm-related physiological variations in drug absorption and disposition may explain this pharmacokinetics-pharmacodynamics apparently disproportionate relationship. We suggest that clinical trials evaluating basic pharmacokinetic properties of psychiatric medications consider potential drug's chronopharmacokinetics. This may assist with dose optimization and minimize serious neuropsychiatric adverse reactions in the vulnerable psychiatric patient.