Centre for Human Drug Research, Leiden, The Netherlands.
Leiden University Medical Centre, Leiden, The Netherlands.
J Clin Pharmacol. 2021 Nov;61(11):1466-1478. doi: 10.1002/jcph.1913. Epub 2021 Jul 29.
Selective M muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition-enhancing effects in early-phase clinical development in healthy subjects is difficult. A challenge with the M mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M mAChR agonists. The aim of this study was to develop such a model. To this end, 12 healthy elderly subjects participated in a randomized, placebo-controlled, 3-way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK-PD model was developed. Four milligrams of biperiden showed significant impairment of sustained attention (-2.1 percentage point in adaptive tracking [95%CI, -3.043 to -1.148], verbal memory (2-3 fewer words recalled [95%CI, -5.9 to -0.2]) and working memory (up to a 50-millisecond increase in the n-back task reaction time [95%CI, 21.854-77.882]) compared with placebo. The PK data were best fitted by a 2-compartment model and showed high interoccasion and intersubject variability. Population PK-PD analysis quantified significant concentration-effect relationships for the n-back reaction time, n-back accuracy, and adaptive tracking. In conclusion, biperiden caused M mAChR-related dose- and concentration-dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof-of-pharmacology studies and to demonstrate cognition-enhancing effects of new cholinergic compounds that are being developed.
选择性 M 毒蕈碱乙酰胆碱受体（mAChR）激动剂正在被开发为治疗导致认知功能障碍的神经退行性和神经精神疾病的对症治疗药物。在健康受试者的早期临床开发中证明认知增强作用具有挑战性。M mAChR 拮抗剂比哌啶的挑战可以用于证明选择性 M mAChR 激动剂的促认知和药理学作用。本研究的目的是开发这样的模型。为此，12 名健康老年受试者参加了一项随机、安慰剂对照、三向交叉研究，以研究 2 和 4mg 比哌啶的耐受性、药代动力学（PK）和药效学（PD）效应。使用神经认知任务和电生理测量进行了多次 PD 评估。开发了一个群体 PK-PD 模型。与安慰剂相比，4mg 比哌啶显著损害了持续注意力（适应性跟踪中减少 2.1 个百分点[-3.043 至-1.148]）、言语记忆（少回忆 2-3 个单词[-5.9 至-0.2]）和工作记忆（n-back 任务反应时间最多增加 50 毫秒[95%CI，21.854-77.882]）。PK 数据通过 2 室模型拟合最佳，表现出高个体间和个体内变异性。群体 PK-PD 分析定量了 n-back 反应时间、n-back 准确性和适应性跟踪的显著浓度-效应关系。总之，比哌啶引起了与 M mAChR 相关的剂量和浓度依赖性的认知功能暂时下降。因此，比哌啶药理学挑战模型可用于药理学研究，并证明正在开发的新胆碱能化合物的认知增强作用。
