Single dose pharmacokinetics of the novel transdermal donepezil patch in healthy volunteers

Abstract

Background: Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer's disease. The aim of this randomized, single-blind, placebo-controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects.

Methods: Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), or 175 mg/50 cm(2). Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study.

Results: The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74-76 hours (~2-4 hours after patch removal), and mean t1/2β was ~63.77-93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%-86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period.

Conclusion: The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics.

Keywords: donepezil; healthy subjects; pharmacokinetics; transdermal patch.

Figure 1

Plasma concentration-time curves of donepezil 72 hour after patch application. Notes: Data points are expressed as mean ± standard deviation. Patch was applied at hour 0.

Figure 2

Box-Whisker plots of donepezil pharmacokinetics in subjects 72 hours after patch application. Notes: Box-Whisker plots of C_max/dose for donepezil (A) and of AUC_inf/dose for donepezil (B) 72 hours after application of the donepezil patch. The box edges indicate the minimum and the maximum values of each parameter. The whiskers extend from the 25th and 75th quartiles, and the line in the middle indicates the median value. Abbreviations: AUC_inf, area under the plasma concentration–time curve from time 0 to infinity; AUC_inf/dose, dose-normalized area under the plasma concentration–time curve from time 0 to infinity; C_max, measured maximum plasma concentration; C_max/dose, dose-normalized measured maximum plasma concentration.

Figure 3

Distribution of individual skin irritation scores after removal of the donepezil patch. Notes: Data are for irritation scores assessed at these times: the time of patch removal, which was 72 hours after patch application (A); 1 hour after patch removal, which was 73 hours after patch application (B) 12 hours after patch removal, which was 84 hours after patch application (C); 24 hours after patch removal, which was 96 hours after patch application (D). The scores are defined as follows: 0, no evidence of irritation; 1, minimal erythema; 2, definite erythema, readily visible; 3, erythema and papules.