A 3‐month toxicity study of GB‐5001, a donepezil one‐month depot injection formulation, by intramuscular injection in dogs

Abstract

AbstractBackgroundDonepezil, an acetylcholinesterase inhibitor for treatment of Alzheimer’s disease (AD), is administered as daily tablets. The treatment compliance, however, is particularly challenging in AD patients for various reasons such as difficulty in swallowing medication, tolerating side effects, and/or complying with the appropriate dosage. GB‐5001 is a novel once monthly intramuscular (IM) depot injection of donepezil to improve treatment compliance developed using G2GBIO’s InnoLAMP® technology. The objective of this study was to evaluate the toxicity of GB‐5001 in beagle dogs for further development.MethodGB‐5001 was administered once every 4 weeks via bolus IM injection to 16 male and 16 female beagle dogs (7.4∼13.3 kg) for 3 months, and 4 male dogs and 4 female dogs in the vehicle group and the highest dose level group were evaluated for the reversibility or long‐term effects following a 2‐month non‐dosing recovery period. The dose levels were 0 (vehicle), 280, 560, and 1120 mg/dose. The following parameters and endpoints were evaluated in this study: standard toxicology parameters, ophthalmoscopic, electrocardiographic examination, gross, histopathologic examinations, and toxicokinetic parameters.ResultNo fatality occurred during this study and there were no toxicologically significant clinical changes or pathological findings related to GB‐5001 in all groups. Systemic exposure to Donepezil was independent of sex. Following IM injection once every 4‐weeks of GB‐5001, mean Cmax and AUC0‐last values of Donepezil increased dose dependently on Days 1 and 57. And systemic exposure (AUC0‐last) to Donepezil increased slightly (<2 fold) on Day 57 compared to Day 1.ConclusionGB‐5001 was tolerated at all dose levels when administered once every 4 weeks via IM injection to male and female beagle dogs for 3 months at doses of 0, 280, 560 and 1120 mg/dose. The clinical observations of swelling and nodules at the dose sites are considered to be vehicle‐related as evidenced by the similar incidence in control. Consequently, the no‐observed‐adverse‐effect‐level (NOAEL) is considered to be 1120 mg/dose.