Anastasia Tsyplakova (1), Vangelis Karalis (1)
(1) Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Greece
Objectives: Donepezil is a widely used drug for symptomatic relief of Alzheimer’s disease. Clinical trial data indicate high variability among patients, and individualization of the dosing regimen is necessary to achieve an optimal therapeutic outcome. A useful tool in this direction is the application of population pharmacokinetics. The aim of this study was to develop a population pharmacokinetic model of donepezil by also evaluating the potential influence of important demographic characteristics of the population. In addition, simulations for individualization of donepezil dosing regimens were performed based on the developed model. Internal and external validation was also applied to the final model, as well as to a relevant literature model [1].
Methods: Data from 28 volunteers, enrolled in a two-sequence, two-period, crossover (2 × 2) bio-equivalence study, were utilized in the pharmacokinetic modelling. The analysis was implemented in MonolixTM 2019R2. The selection of the best pharmacokinetic model was based both on its descriptive ability of the experimental data, as well as with a series of statistical and graphical diagnostic tools. Based on the finally developed model, simulations were performed in Mlxplore (MonolixTM) for the three doses of 5, 10, 23 mg in healthy, renal insufficient, and subjects of different weight categories.
Results: The kinetics of donepezil were best described by a two-compartment model, with first-order absorption (with lag time) and elimination kinetics. A combined error model was used to estimate residual variability. The average estimate of the first-order absorption rate constant was equal to 1.61h-1, while lag time was found to be equal to 0.848 h. The mean apparent clearance was 14.0 l/h, while the mean apparent inter-compartmental clearance was equal to 43.9 l/h. In addition, the mean apparent volume of distribution in the central compartment was 44.3 l and in the peripheral compartment was 552 l. Body mass index (BMI) positively influenced the volume of distribution in the central compartment. The simulations showed that only the daily dose of 23mg leads to therapeutic values. For patients with renal insufficiency, it was found that the dosing regimen had to be adjusted for all grades of renal insufficiency for the three doses. For patients of all weights, it showed that the dosing regimen needed to be adjusted for the 5 and 10 mg doses. For the 23 mg dose, the simulation showed that the dosing regimen should be changed only for underweight patients.
Conclusions: The final model shows the most similarities to the population pharmacokinetic model developed as part of the approval of the reference product (Aricept®). BMI as a covariate was found to affect the volume of the central compartment and consequently the range and level of plasma concentrations of donepezil, as shown by the simulations. Therefore, the maximum dose of 23 mg should be taken with caution in underweight patients and monitoring of these patients during treatment is very important due to an increased risk of side effects.
References:
[1] Noetzli M, Guidi M, Ebbing K, Eyer S, Wilhelm L, Michon A, Thomazic V, Stancu I, Alnawaqil AM, Bula C, Zumbach S, Gaillard M, Giannakopoulos P, von Gunten A, Csajka C, Eap CB. Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance. Br J Clin Pharmacol. 2014 Jul;78(1):135-44. doi: 10.1111/bcp.12325.
Reference: PAGE 29 (2021) Abstr 9752 [www.page-meeting.org/?abstract=9752]
Poster: Methodology - Other topics