Hee Yoon Jung (1), Woo Jin Jung (1), Jung-woo Chae (1)*, Hwi-yeol Yun (1)*
(1) College of Pharmacy, Chungnam National University, Republic of Korea
Objectives: Donepezil, a reversible inhibitor of the acetylcholinesterase enzyme, is used to treat mild-to-moderate and severe Alzheimer’s disease (AD). Despite that donepezil is widely used in oral tablet form, oral acetylcholinesterase inhibitors may cause elevation of peripheral acetylcholine and induce adverse effects (AE) [1]. Although, many of pharmaceutical industry has tried to develop a transdermal patch formulation to lessen dosing frequency to increase the patient’s treatment compliance and to prevent AE by reducing the rapid absorption of the drug, there are still limitations in exploring the equivalent patch dose in comparison to the oral dosage form. In this study, we aimed to develop a population pharmacokinetic (PK) oral and patch combination model to implement kinetics of donepezil and its application to predict compatible dose between formulations.
Methods: Pharmacokinetic (PK) data was collected from exploratory clinical trial, which enrolled 48 subjects. For the population PK development, a two-compartment model was developed to describe the PK distribution and elimination of oral and patch form, with first-order absorption model for oral dosage form and additional transit compartments applied for the explanation of the patch absorption. Analysis was conducted by using NONMEM 7.4 assisted by PsN 4.9.0. The residual error was estimated using the combined error model. NONMEM analyses were carried out by first-order conditional estimation method with the interaction option (FOCE + I). The final model describing both oral and patch pharmacokinetic was selected by comparing objective function value and was evaluated by diagnostic methods such as goodness-of-fit (GOF) and visual predictive check (VPC, n=200) for adequacy and prediction. The equivalent patch dose, referencing with daily administration of donepezil 10mg oral dose at the steady-state, were explored with simulation studies regarding the various patch doses and were decided using the bioequivalence (BE) criteria (90% confidence interval of the ln transformed AUC-ss and Cmax-ss falling between 0.80 ~ 1.25). The bioequivalence analysis was performed using Phoenix WinNolin 8.3.
Results: Population PK oral and patch combination model for donepezil successfully described the PK profiles, which we obtained from the clinical trial. The final parameters of the model were reasonable to reflect the feature of both oral and patch administration. As for the simulation and bioequivalence analysis results, the patch formulations of dose ranging between 170mg and 238mg for once a week administration were identified to be equivalent to the administration of daily 10mg oral dose.
Conclusions: In this study, we developed population PK oral and patch combination model for donepezil that characterizes the PK of donepezil oral and patch formulation simultaneously and acceptable parameters were estimated. Furthermore, we could suggest the patch dose which is equivalent to 10mg oral donepezil after multiple dosing administration, using the developed model.
* These authors contributed equally to this work as correspondence.
Acknowledgement: This study was supported by Institute of Information and Communications Technology Planning and Evaluation grant funded by the government of the Republic of Korea (MSIT; No. 2020-0-01441, Artificial Intelligence Convergence Research Center, Chungnam National University).
References:
[1] Rogers at al., A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology. 1998; 50(1), 136–145
Reference: PAGE 29 (2021) Abstr 9703 [www.page-meeting.org/?abstract=9703]
Poster: Drug/Disease Modelling - CNS