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

Abstract

Introduction

This study characterized the pharmacokinetics (PKs) of a donepezil patch formulation currently under development, using mixed effect modeling analysis, and explored optimal patch dosing regimens in comparison with the donepezil oral formulation.

Methods

PK data used in this analysis were from 60 healthy Korean male subjects participating in two Phase I studies, where subjects received single or multiple doses of donepezil of 43.75, 87.5, and 175 mg via patches, and 12 of them received a single oral dose of 10 mg of donepezil, followed by a single dose of donepezil via a patch. Donepezil PKs were analyzed by nonlinear mixed effect modeling using NONMEM software.

Results

A well-stirred model with two-compartment distribution and delayed absorption was chosen as the best model for the oral formulation. The PKs of donepezil after the patch applications were best described by a two-compartment linear model with zero-order absorption (D2) and absorption delay. The relative bioavailability (BA) of donepezil after the patch application compared with oral dosing was described to be affected by the duration of patch application.

Conclusion

PK simulations based on the chosen PK models suggested that, overall, donepezil exposure in plasma is similar whether with 10 mg of oral donepezil every 24 h or a 175 mg patch every 72 h, and likewise with 5 mg of oral donepezil every 24 h or an 87.5 mg patch every 72 h.

Keywords:

• clinical trial(s)
• clinical trial simulation(s)
• pharmacokinetics
• pharmacometrics
• analysis

Acknowledgments

This work was supported by iCure Pharmaceutical Incorporated (Seoul, Republic of Korea), the manufacturer of the donepezil patch. The authors have had no financial relationships in the past 3 years with any organization that might have an interest in the submitted work, and there are no other relationships or activities that could have influenced the results and interpretation of the submitted work. The abstract of this paper was presented at the Alzheimer’s Association International Conference as a poster presentation. The poster’s abstract was published in “Poster Abstracts” in Alzheimer’s & Dementia. The URL is as follows:https://www.clinicaltherapeutics.com/article/S0149-2918(17)30468-X/fulltext. This paper was checked and edited by Bioedit^® LTD on the 15th December 2017.

Abbreviations

ALAG, absorption delay; ALAG2, absorption lag for central compartment; ADUR, actual duration of patch application; BA, relative bioavailability; CI, confidence interval; CLFO, apparent total clearance of the drug from plasma after oral administration; CV, coefficient of variation; DV, dependent variable; D2, duration of zero-order absorption; ϵ, residual error; F2, bioavailability for peripheral compartment; FOCE, first-order conditional estimation method; IFF, baseline relative bioavailability; IIV, inter-individual variation; IPRED, individual predictions; Ka, absorption rate constant; Km, concentration at half maximum velocity; LC-MS/MS, liquid chromatography-tandem mass spectrometry; PDUR, planned duration of patch application; PRED, population predictions; MM, michaelis-menten; PK, pharmacokinetic; Q, intercompartmental clearance; Vc, central volume of distribution; Vd, volume of distribution; Vmax, maximum velocity; Vp, peripheral volume of distribution.

Data Sharing Statement

We are sorry that we cannot share the data. The data are intellectual properties of the sponsor.

Disclosure

HD, SK, YS, and YC were employees of iCure Pharmaceutical Incorporated at the time of the study. Ms Seok Kyu Yoon reports grants and non-financial support from iCure Pharmaceutical Incorporated, during the conduct of the study. Ms Dong Hyun Hong reports a patent 1017967710000 issued. Seong Su Kim reports a patent KR 10-1454362 issued. Dr Young Kweon Choi reports a patent 1017967710000 issued. The authors report no other conflicts of interest in this study.