Safety, pharmacokinetics and quantitative EEG modulation of TAK‐071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects

• Published in: British journal of clinical pharmacology Vol. 88; no. 2; pp. 600 - 612
• Main Authors: Yin, Wei, Mamashli, Fahimeh, Buhl, Derek L., Khudyakov, Polyna, Volfson, Dmitri, Martenyi, Ferenc, Gevorkyan, Hakop, Rosen, Laura, Simen, Arthur A.
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.02.2022
• Subjects: Alzheimer's disease; Donepezil - adverse effects; Dose-Response Relationship, Drug; Double-Blind Method; Electroencephalography; electrophysiology; Healthy Volunteers; Humans; Original; Parkinson's disease; pharmacokinetic‐pharmacodynamic; phase I; Receptor, Muscarinic M1 - agonists; phase I; Parkinson's disease; pharmacokinetic-pharmacodynamic; electrophysiology; Alzheimer's disease
• DOI: 10.1111/bcp.14975
• ISSN: 0306-5251

Aims TAK‐071 is a muscarinic M1 receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first‐in‐human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK‐071. Methods TAK‐071 was administered as single and multiple doses in a randomized, double‐blind, placebo‐controlled, parallel‐group design in healthy volunteers alone and in combination with donepezil. Laboratory, electrocardiogram (ECG) and electroencephalogram (EEG) evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate the pharmacokinetics (PK), relative bioavailability and food effect. Results TAK‐071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK‐071 demonstrated a long mean (% coefficient of variation) half‐life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Coadministration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK‐071 40‐80 mg increased power in the 7‐9 Hz range in the posterior electrode group with eyes open and 120‐160 mg doses increased power in the 16‐18 Hz range and reduced power in the 2‐4 Hz range in central‐posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK‐071 at high doses and was enhanced with coadministration of donepezil under the eyes‐closed condition. Conclusions PK and safety profiles of TAK‐071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK‐071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK‐071 is warranted.