Biperiden Challenge Model in Healthy Elderly as Proof-of-Pharmacology Tool: A Randomized, Placebo-Controlled Trial

Selective M₁ 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 M₁ mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M₁ 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 M₁ 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.