Metabotropic glutamate receptor 5 negative modulation in phase I clinical trial: potential impact of circadian rhythm on the neuropsychiatric adverse reactions-do hallucinations matter?

ISRN Psychiatry Pub Date : 2014-03-04 eCollection Date: 2014-01-01 DOI:10.1155/2014/652750
Khalid Abou Farha, Richard Bruggeman, Corine Baljé-Volkers
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引用次数: 16

Abstract

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.

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I期临床试验中代谢性谷氨酸受体5负调节:昼夜节律对神经精神不良反应的潜在影响——幻觉重要吗?
代谢性谷氨酸受体5 (mGluR5)负变构调节剂(NAMs)可能在某些精神疾病如焦虑和抑郁中起作用。mGluR5-NAMs的药代动力学特征和药效学作用此前已有报道。我们对18名接受mGluR5-NAM与单相口服避孕药之间药物相互作用研究的年轻健康女性受试者的药理学和临床数据进行了回顾性分析。mGluR5-NAM按每日递增剂量水平设计给药。OC与mGluR5-NAM之间没有相互作用。早晨的mGluR5-NAM血浆浓度高于晚上的浓度。大多数观察到的具有临床意义的神经精神不良反应发生在夜间,包括视觉(伪)幻觉、伴有继发性行为障碍的失眠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明显不成比例的药代动力学-药效学关系。我们建议在评估精神药物基本药代动力学特性的临床试验中考虑潜在药物的时间药代动力学。这可能有助于剂量优化和减少严重的神经精神不良反应,在脆弱的精神病人。
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