Comparison of Steady-State Pharmacokinetics of Donepezil Transdermal Delivery System with Oral Donepezil

Abstract

Background: Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States.

Objective: To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil.

Methods: Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 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 steady state on Week 5.

Results: All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) 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 dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively).

Conclusion: Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.

Keywords: Alzheimer type dementia; Alzheimer’s disease; bioequivalence; donepezil; transdermal patch.

Fig. 1

Study design. QD, once daily; QW, once weekly; TDS, transdermal delivery system.

Fig. 2

Participant disposition and analyses populations. ^*These participants were randomized to receive 10 mg/d donepezil TDS followed by oral donepezil. ^†Two participants discontinued from the trial in Period 3 because of noncompliance with the protocol or in-house rules. d, day; TDS, transdermal delivery system.

Fig. 3

Mean steady-state (Week 5) plasma concentration-time curves for 5 mg/d donepezil TDS, 10 mg/d donepezil TDS, and 10 mg/d oral donepezil. Donepezil TDS was applied weekly for 5 weeks; oral donepezil was administered daily for 5 weeks. The replicated steady-state pharmacokinetic profile for oral donepezil on Days 1–6 is shown as a dashed line to represent that they are replicated from Day 7 (144–168 h). TDS, transdermal delivery system.

Fig. 4

Donepezil exposure for (A) 10 mg/d donepezil TDS and (B) 5 mg/d donepezil TDS (dose normalized) versus oral donepezil. Bars are the 90% CIs. AUC_0168,ss, area under the curve at steady state; CI, confidence interval; C_max,ss, maximum concentration at steady state; LSM, least-squares mean; TDS, transdermal delivery system.