PHARMACOKINETICS OF MEMANTINE AND DONEPEZIL AFTER A SINGLE DOSE OF A ONCE-DAILY FIXED-DOSE COMBINATION CAPSULE OF MEMANTINE EXTENDED RELEASE AND DONEPEZIL IN TWO PHASE I TRIALS

Abstract

Combining two standard-of-care therapeutics into a single dosage unit may increase compliance and adherence to treatment, leading to an improved therapeutic outcome. A fixed-dose combination (FDC) capsule containing 28-mg memantine extended release (ER) and 10-mg donepezil was developed and tested for (1) bioequivalence with co-administered commercially available memantine ER (Namenda XR, 28 mg) and donepezil (Aricept, 10 mg), (2) bioavailability following food intake, and (3) bioavailability following sprinkling of the capsule contents on applesauce. Both studies were single-dose, randomized, open-label, and crossover (with 21-day washout periods between treatments), conducted in 18-45-year-old healthy individuals. In Study 1, fasting participants (N=38) received Treatment A (co-administration of Namenda XR and Aricept) or Treatment B (FDC). In Study 2, participants (N=36) received three treatments: Treatment A (intact FDC capsule, while fasting), Treatment B (intact FDC capsule, following a high-fat meal), and Treatment C (FDC contents sprinkled on applesauce, while fasting). In both studies, C max and AUC 0- ˇž for memantine and donepezil were compared using a linear mixed-effects model. Bioequivalence or no effect in the comparison of treatments was declared if the 90% confidence intervals (CI) of the least-squares geometric mean ratios of C max and AUC 0- ˇž were within the range of 80.00%-125.00%. T max values were compared using a Wilcoxon signed-rank test. Safety parameters were also evaluated. CIs of all the comparisons were within 80.00%-125.00% window. The FDC capsule containing memantine ER and donepezil was bioequivalent to co-administered Namenda XR and Aricept. There was no significant food effect on the bioavailability of the FDC capsule. The intact FDC capsule and capsule contents sprinkled on applesauce were bioequivalent. There were no clinically relevant differences in T max across treatments. Safety profiles were also similar across treatments. A FDC capsule containing 28-mg memantine ER and 10-mg donepezil is bioequivalent to co-administered commercially available memantine ER and donepezil. In addition to ingestion by swallowing with or without food, the formulation allows for sprinkling of the capsule contents on applesauce, making ingestion and administration easier for patients and caregivers, respectively. Sponsorship: Forest Research Institute.