Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of A Novel Donepezil Patch Formulation

Aims: Donepezil is a well-known reversible noncompetitive acetylcholinesterase inhibitor for the symptomatic treatment of Alzheimer's disease (AD). The purpose of this study was to explore the pharmacokinetics (PK) of donezezil patch under clinical development using mixed effect modeling analysis, and to expore optimal dosing regimens of the donepezil patch in comparison with donepezil oral formulation.

Methods: PK data used in this analysis were from 44 Korean, healthy, male subjects in two phase 1 studies, where all the subjects received single or multiple doses of donepezil patch of 43.75, 87.5, and 175 mg, and 12 of them received single oral dose of donepezil, 10 mg followed by single dose of donepezil patch. Plasma concentrations of donepezil were measured using validated LC/MS-MS. Donepezil PK were analyzed by nonlinear mixed effect modeling implemented in NONMEM (version 7.3).

Results: The PK modeling analysis were conducted seqentially for oral formulation and patch, which describes the data of oral formulation compared to simultaneous analysis of both oral and patch formulations. PK for oral formulation was modeled first, then the PK of patch was modeled after fixing the oral absorption related parameters of absorption rate constant (ka) and absorption delay (ALAG1) as the estimates of the previous fitting, since the predose concentrations of patch was not 0. A well-stirred model with two-compartment distribution and delayed absorption was chosen as the final model for the oral formulation, where the Michaelis-Menten equation describes both first-pass effect during absorption and systemic clearance. The relative bioavailability of donepezil after patch application compared to oral dosing was described to be affected by the duration of patch application, and the study. In the basic goodness of plots, no significant trend in the model fitting was shown in PK models of both oral and patch formulations described the PK data. The final model predicted the real, observed concentration data reasonably well. The Monte-Carlo simulation for plasma donepezil concentration predicted that overall, exposure to plasma donepezil is similar between donepezil 10 mg oral dosing every 24 hours and donepezil patch 175 mg every 72 hours, and between donepezil 5 mg oral dosing every 24 hours and donepezil patch 87.5 mg every 72 hours.

Conclusion: We developed a population PK model describing the plasma PK of donepezil patch formulation and compared it with that of donepzeil oral formulation in healthy Korean adult males. PK simulation based on the final PK model suggested that donepezil 175 mg patch every 72 hours shows similar concentration profile with oral dosing of donepezil 10 mg every 24 hours, and 87.5 mg patch every 72 hours with oral dosing of 5 mg every 24 hours.