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

Abstract

BackgroundDonepezil 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.MethodsEach healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm2, 87.5 mg/25 cm2, or 175 mg/50 cm2. 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.ResultsThe 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.ConclusionThe donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics.

Formulation, Preparation, Characterization, and Evaluation of Dicarboxylic Ionic Liquid Donepezil Transdermal Patches

“…These symptoms are dose-related and largely depend on the plasma fluctuations. When donepezil is orally administered, it is well absorbed and reaches peak plasma concentrations within 4 h then decreases until the next dose [ 21 ]. In this study, a single patch containing a donepezil dose of 400 mg was maintained for 24 h and the amount of donepezil moving through or into the tissue/membrane was continuously increased.…”

<p>Pharmacokinetic Evaluation by Modeling and Simulation Analysis of a Donepezil Patch Formulation in Healthy Male Volunteers</p>

“…Tolerability and Pharmacokinetics of Donepezil Patch were already published in "Drug Design, Development and Therapy". 13 In this study, problems with skin irritation were expected. However, the skin irritations to this study drug were mild.…”

“…Inter-day accuracy ranged from 96.27% to 105.98%, and inter-day precision (%CV) ranged from 0.7% to 4.3%. 13 There was no statistically significant difference in the demographic characteristics of the subjects included in this analysis among dose groups with 26.4 ± 4.4 years in age [mean ± standard deviation], 174.4 ± 6.1 cm in height, and 70.4 ± 7.8 kg in weight (Table 1).…”

“…PK analysis was conducted using the pooled data from the following two phase I studies in Korean male subjects: Study I. "A phase I clinical, Dose Escalation Study of the Safety, Tolerability and Pharmacokinetics of Donepezil Patch in Healthy Male Subjects (NCT01860625)", 13 where subjects were given a placebo transdermal patch (n=3 for each dose group) or a single patch containing a donepezil dose of 43.75, 87.5, or 175 mg (n=9 in each of the three dose groups; 36 subjects in total). Tolerability and Pharmacokinetics of Donepezil Patch were already published in "Drug Design, Development and Therapy".…”

“…Except for one subject, adhesiveness was over 50% for 72 hours. 13 Bloods for PK analysis were drawn at 0 h (pre- " in 24 healthy subjects, where each subject was initially administered a single dose of donepezil oral formulation (except in the cohort dosing group 1), followed by multiple doses of donepezil transdermal patches. In this study, subjects in dose group 1 received either continuous application of a 87.5 mg donepezil patch (n=9) or a placebo patch (n=3) over 15 d with patch renewal every 3 d. Subjects in dose group 2 either received a single oral dose of 10 mg of donepezil (n=9) or a placebo (n=3) in period 1, followed by a continuous application of a 175 mg donepezil patch over 15 d (patch renewal every Plasma donepezil concentrations were measured by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS).…”