Bioequivalence and Safety Comparison of Once-Weekly Donepezil Transdermal System With Oral Donepezil: Results of a Phase 1 Pharmacokinetic Study in Healthy Volunteers

Abstract: Oral donepezil is widely prescribed for dementia of the Alzheimer’s type. Donepezil transdermal system (TDS; Adlarity®) was also recently approved. Here, we report bioequivalence and safety results from the trial comparing once-weekly 10-mg/d and 5-mg/d donepezil TDSs with once-daily 10-mg oral donepezil. In this open-label, randomized, crossover trial (NCT04617782), healthy volunteers (aged 18-55 years) received 5-mg/d donepezil TDS during the 5-week Period 1, then 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at Week 5 of each treatment. Of 60 participants, all received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. The steady-state adjusted geometric mean ratios (% [90% CI]) of TDS to oral donepezil for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h), respectively, were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for 5-mg/d (dose normalized) TDSs. The 90% CIs for the geometric mean ratios were generally within the accepted 80%-125% range for establishing bioequivalence. Adverse events occurred in 54.5% of participants with 10-mg/d TDS, 53.3% with 5-mg/d TDS, and 57.1% with oral donepezil. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system adverse events (14.5% vs 53.6% and 14.5% vs 30.4%, respectively). Both donepezil TDS strengths were bioequivalent to oral donepezil on a milligram-per-day basis. The safety profile of donepezil TDS supports its use for dementia of the Alzheimer’s type.Short Description: The poster will present results of the pivotal pharmacokinetic study submitted to the US Food and Drug Administration. This open-label, randomized, phase 1 crossover study in healthy volunteers assessed bioequivalence of once-weekly donepezil transdermal system (TDS) with once-daily oral donepezil. Results show that once-weekly 10-mg/d and 5-mg donepezil TDSs are bioequivalent to once-daily 10-mg oral donepezil, and donepezil TDS was associated with lower incidences of gastrointestinal-related and central nervous system-related adverse events than oral donepezil.Name of Sponsoring Organization(s): Corium, Inc