Population Pharmacokinetic and Exposure-Response Analysis of the Cognitive Effects of TAK-071 in Participants With Parkinson Disease and Cognitive Impairment.

TAK-071 is a novel muscarinic M₁ positive allosteric modulator under investigation for the treatment of cognitive impairment and falls associated with Parkinson disease (PD). This study evaluated population pharmacokinetics of TAK-071 following single (1-160 mg) and multiple (3-15 mg once daily) oral-dose TAK-071 in 112 healthy participants and 53 participants with PD from Phase 1 and Phase 2 studies. A 1-compartment model with a delayed absorption phase adequately described TAK-071 pharmacokinetics. Age, body weight, dose, and formulation were significant covariates. Model simulations indicated that age-adjusted dosing is unnecessary. An exposure-response relationship on cognitive function (attention, executive function, memory, global) was evaluated. Benefits were observed on attention, executive function, and global cognition, and these plateaued between 5 and 7.5 mg once daily, supporting a dose of 7.5 mg for future clinical studies, as 7.5 mg was well tolerated. As patients with PD can have an increased risk of falls, the relationship between cognitive function and risk of falls, as assessed by stride time variability, was explored. Cognition response for the attention domain score showed consistent and sustained improvement in stride time variability compared with when no response was observed, supporting further investigation of TAK-071 in PD for the risk of falls.