Pharmacokinetic modeling of Donepezil after transdermal administration in rat
Jihyun Jeon(1), Nayoung Han(1), Hyun-moon Back(1), Seong-woo Goo(1), Junyoung Kim(1), Hwi-yeol Yun(1), Kwang-il Kwon(1)*
(1) College of Pharmacy, Chungnam National University, Korea
Purpose: Donepezil (DPZ) is a widely used for treatment of Alzheimer’s disease. But, most of patients were suffered from gastrointestinal symptoms such as nausea, vomiting, and diarrhea at a high start dose. Thus, transdermal administration is proposed to provide continuous drug delivery, leading to reducing side effects. The aim of this study was to develop a population pharmacokinetic (PK) model of transdermal DPZ patch in hairless rats.
Methods: The plasma concentration data was collected from the hairless rats during 0 to 168 hour, after administering transdermal patch at 6 dose-groups. Population PK analysis was performed using non-linear mixed effect modeling (NONMEM) software ver. 7.3 One- or two-compartment PK models were compared as structural model. A combination of zero- or first-order absorption with or without lag time was tested to consider the drug disposition from skin to blood. The inter-individual variability was estimated using additive, proportional, and exponential model. The residual error model was evaluated to be additive, proportional, or combined. All NONMEM analyses were carried out using the first-order conditional estimation method with the interaction option (FOCE + I). Final model was selected considering the goodness-of-fit and evaluated with visual predictive check (VPC, n=1,000) method.
Results: From 332 plasma concentrations (n=34), the final model was developed using one-compartment model with sequential zero- and first-order absorption. The estimated population mean values of clearance (CL) and volume of distribution (V) were 2.41 L/h and 17.3 L, respectively. The first order absorption rate constant (Ka) was 0.0213 h-1 (11 %) and duration of zero order absorption (D1) was 12.2 h (22 %). These estimated parameters of absorption phase were reasonable to reflect the physiologic feature of transdermal administration.
Conclusion: A transdermal absorption PK model was successfully developed using donepezil data and acceptable parameters were estimated. With our final model, absorption of donepezil amount through skin can be predicted and the basal form of our final model with zero-order absorption from skin compartment, can be extrapolated to other transdermal patch drug.
