Seon-jong Park, Woo-jin Jung, Tran Thi Quyen, Ngo Thi Lien, Jung-woo Chae, Hwi-yeol Yun
College of Pharmacy, Chung-nam National University, Republic of Korea
Objectives: Donepezil oral dosage form was widely used with Alzheimer’s disease in last decades. Since adverse drug reaction (ADR) related on fast absorption of donepezil per oral (PO) were reported by previous reports, donepezil patch is evolved as an alternative treatment. However, the large variability orginated from dermal absorption and change of dosage form from oral to patch would be generated by poor PK prediction of donepezil patch. Therefore, The main aim of this study is to develop donepezil pharmacokinetic modeling based on population approaches to convert equivalent systemic exposure prediction from oral to patch and its application to figure out optimal patch dosage in comparisons with therapeutic dose of donepezil oral form.
Methods: To develop donepezil PK model, in-vitro skin permeability test of patch, single dose phase I clinical trials for donepezil 10mg PO and three dosage of patch (80mg, 120mg and 160mg) were conducted. Model selection was driven by a significant decrease in the objective function value, and successful minimization and covariate estimation. After completion of model development, area under the plasma curve (AUCss) and maximum plasma concentration (Cmax,ss) at steady-state in dosing interval were calculated in simulation results to explore therapeutic equivalent dose between dosage forms. Simulation applied once weekly for 4 weeks with patch versus once daily for a week with oral, was performed based on 2 by 2 crossover designs. The therapeutic equivalent dose were decided using bioequivalence (BE) criteria (0.80 ~ 1.25 of ln transformed AUCss and Cmax,ss). The PK model were analyzed using NONMEM 7.4 assisted by PsN 4.9.0., and Pheonix® 8.1. were used for calculation of AUCss and Cmax,ss and judgement of therapeutic equivalent dose.
Results: Zero-order kinetics based on in-vitro skin permeability test from skin to depot compartment were applied to explain dermal absorption pattern of patch. In addition, first-order absorption was used for absorption of depot to central compartment for patch and it is also used for oral absorption of donepezil on each. Both of each absorption model were connected to central compartment for systemic merged into at one. According to simulation results using final model, AUCss and Cmax,ss were predicted 6452g∙hr/ml (95% confidence interval (CI) 6238~6951 ug∙hr/ml) and 67.08ug/ml (95% (CI) 62.55~ 69.89 ug/ml) after donepezil 10mg once daily dose during 7 days at steady-state. The AUCss and Cmax,ss of 170mg of donepezil patch are expected as equivalent to those of oral donepezil.
Conclusions: The oral and transdermal patch donepezil popPK model was well established and successfully converted by dose between patch and oral form of donepezil. Furthermore, we could suggest patch dose which has the same therapeutic equivalent dose to 10mg oral donepezil after multiple dosing administration using the developed model. Future studies, following our suggestion, are warranted for constructing population PK models with greater precision.
References:
[1]S Jackson (2004), The safety and tolerability of donepezil in patients with Alzheimer’s disease.
Br J Clin Pharmacol. 2004 Nov; 58(Suppl 1): 1–8. doi: 10.1111/j.1365-
2125.2004.01848.x
[2] S.L Rogers & L.T.Friedhoff (1998) , Pharmacokinetic and pharmacodynamic profile of donepezil HCL following single oral doses. Br J Clin Pharmacol. 1998 Nov; 46(Suppl 1): 1–6. doi: 10.1046/j.1365-2125.1998.0460
[3] H.Y Choi at al (2015). Therapeutic dosage assessment based on population pharmacokinetics of a novel single-dose transdermal donepezil patch in healthy volunteers. Eur J Clin Pharmacol. 2015 Aug;71(8):967-77. doi: 10.1007/s00228-015-1875-2.
[4] Y.H Kim at al (2015). Single dose pharmacokinetics of the novel transdermal donepezil patch in healthy volunteers. Drug Des Devel Ther. 2015; 9: 1419–1426,doi:10.2147/DDDT.S78555
[4] Y.W Choi at al (2015). Bioequivalence study of Donepezil hydrochloride in healthy Korean volunteers. Transl Clin Pharmacol. 2015 Jun;23(1):26-30.
Reference: PAGE () Abstr 9419 [www.page-meeting.org/?abstract=9419]
Poster: Drug/Disease Modelling - Other Topics