Pharmacokinetic Comparison of Orally Disintegrating and Conventional Donepezil Formulations in Healthy Korean Male Subjects: A Single-Dose, Randomized, Open-Label, 2-Sequence, 2-Period Crossover Study

Background: Donepezil is a potent inhibitor of acetylcholinesterase, an enzyme that is targeted in the treatment of Alzheimer's disease. Objective: The purpose of this study was to compare the pharmacokinetic characteristics of orally disintegrating (test) and conventional (reference) donepezil formulations to satisfy the regulatory requirement for marketing. Methods: A single-center randomized, single-dose, open-label, 2-way crossover study with a 21-day washout period was conducted in 22 healthy volunteers. Plasma samples for the analysis of donepezil were collected up to 240 hours after drug administration. Participants received either reference or test drug formulation of 10 mg donepezil in the first period and the alternative formulation in the second period. Plasma concentrations of donepezil were determined by validated high-performance liquid chromatography coupled to tandem mass spectrometry detection. Pharmacokinetic parameters, including C-max and AUC, were determined by noncompartmental analysis. ANOVA was carried out using log-transformed C-max and AUC, and the mean ratios and their 90% CIs were calculated. The safety profiles and tolerabilities of the 2 formulations were also assessed based on laboratory tests, 12-lead ECGs, vital signs, and physical examinations. Results: Of the 22 participants initially enrolled, 18 healthy Korean participants completed both treatment periods. Four subjects did not complete both treatments: 3 subjects withdrew consent for personal reasons, and 1 subject experienced adverse events. No significant differences in pharmacokinetic parameters between the 2 formulations were observed. The mean (SD) age, height, and weight of the participants were 25.8 (4.1) years, 173.6 (5.7) cm, and 68.9 (7.8) kg, respectively. The mean (SD) C-max, AUC(last), and AUC(inf) for the reference formulation were 33.26 (6.58) ng/mL, 1521.69 (344.04) ng x h/mL, and 1691.46 (443.05) ng x h/mL, respectively. Corresponding values for the test formulation were 34.23 (6.79) ng/mL, 1554.33 (390.23) ng x h/mL, and 1718.27 (447.03) ng x h/mL, respectively. The median T-max was 2 hours (range, 1-3 hours) for the reference and test formulations. The geometric mean ratios (90% CI) between the 2 formulations of donepezil were 102.9 (96.8-109.5) for C-max, 102.3 (96.1-108.9) for AUC(last), and 101.6 (95.4-108.2) for AUC(0-infinity), respectively. During the study, 15 and 14 adverse events were reported for the reference and test formulations, respectively, and all were transient, mild, and resolved during the treatment period. These adverse events included 7 cases of nausea, 3 cases of headache, and 1 case each of dizziness, vomiting, chills, and sweating. All adverse events were considered related to the study drugs. Conclusion: This study found that the test and reference formulations met the regulatory criteria for pharmacokinetic equivalence in these fasting healthy Korean male subjects. Both donepezil formulations appeared to be generally well tolerated. ClinicalTrials.gov indentifier: NCT01297036. (Clin Ther. 2011;33: 965-972) (C) 2011 Elsevier HS Journals, Inc. All rights reserved.