Donepezil is an acetylcholinesterase inhibitor widely used in Alzheimer’s disease, but its clinical effectiveness can be limited by the need for daily oral administration and associated adherence issues. To address this limitation, long-acting injectable (LAI) formulations such as GB-5001 have been developed to enable less frequent dosing. This Phase 1, open-label, active-controlled, dose-escalation study was designed to characterize the safety profile, tolerability, pharmacokinetics, and pharmacodynamics of GB-5001 in healthy adult men. Participants were assigned to receive either GB-5001A or GB-5001D via intramuscular or subcutaneous injection, or oral donepezil (Aricept®). Safety assessments were conducted alongside pharmacokinetic sampling and pharmacodynamic evaluation based on acetylcholinesterase inhibition. The potential influence of CYP2D6 metabolic phenotype on drug exposure was also explored, supported by pharmacokinetic modeling and simulation approaches. Fifty healthy male volunteers completed the study. After intramuscular administration, GB-5001A (70, 140, and 280 mg) showed a clear dose-dependent increase in systemic exposure (AUCinf and Cmax), with substantially prolonged drug exposure compared with oral donepezil 10 mg. No serious safety concerns were identified. The most frequently reported adverse events were mild injection-site reactions, observed in all groups except the GB-5001A 70 mg intramuscular cohort and the oral donepezil group. Sustained inhibition of acetylcholinesterase activity was also observed with GB-5001A. Overall, GB-5001A demonstrated acceptable tolerability, predictable dose-exposure relationships, and extended pharmacokinetic persistence, with an estimated 3–4 times longer half-life than oral donepezil. These findings, together with modeling results, support its potential as a long-acting once-monthly intramuscular therapeutic option for Alzheimer’s disease.
