045: Population Pharmacokinetics of GB-5001, a Long-acting Intramuscular Injection of Donepezil, in Healthy Participants

Statement of Purpose, Innovation or Hypothesis: GB-5001 is a sustained-release intramuscular (IM) injectable of donepezil for a monthly treatment interval under development for the treatment of Alzheimer’s disease. The aim of this study was to develop a population pharmacokinetic (PK) model for donepezil in both IM and oral formulations, and to optimize the dose of the IM formulation to achieve systemic exposure comparable to that of the oral formulation following multiple administration.

Description of Methods & Materials: A Phase 1, randomized, double-blind, placebo-controlled, dose-escalation study was conducted. Among a total of 48 participants, 36 participants were assigned into 3 cohorts and randomized to receive a single dose of the IM formulation (GB-5001 70 mg, 140 mg, and 280 mg) or a matching placebo in a 3:1 ratio. 12 participants were assigned to a separate cohort to receive a single dose of the oral formulation (Aricept tablet 10 mg). Serial blood samples were collected for PK analysis. Based on the concentration data, a population PK model of donepezil for the IM and oral formulation was developed using NONMEM. The model was evaluated based on goodness-of-fit plots, conditional weighted residuals, and visual predictive check (VPC). Furthermore, based on the final PK model, bootstrapping with 1000 replications was conducted for the validation of the parameter estimates. The final PK model was used for Monte Carlo simulations (N=200) of plasma donepezil concentrations. The simulation scenario included three administrations of a 210 mg IM formulation at four-week intervals and daily administrations of a 10 mg oral formulation for 84 days.

Data & Results: A total of 39 subjects with 853 concentration data of donepezil were used for population PK modeling. The PKs of donepezil were best described by a two-compartment model, which incorporated distinct absorption compartments for the IM and oral formulation. Considering the different distribution and elimination profiles between the oral and IM formulations, the volume of distribution, clearance, inter-compartmental clearance, and residual errors of donepezil concentration were separately modeled for each formulation. The IM formulation was described by a dual first-order absorption with lag time and a simultaneous zero-order absorption. The oral formulation was described by a first-order absorption with lag time. The diagnostic plots, VPC results, and bootstrapping analysis indicated that the PK model adequately described the observed data. The steady state systemic exposure obtained from the simulated data was comparable between the IM and oral formulations. The mean ± standard deviation (SD) of the simulated steady state C_max of the IM and oral formulation were 49.00 ± 16.02 and 45.34 ± 10.83 ug/L, respectively. The mean ± SD of the simulated steady state AUC of the IM formulation (observed AUC throughout 28 days after the third administration) and oral formulation (observed AUC of day 84 multiplied by 28) were 21834.57 ± 7288.64 and 20265.28 ± 5759.60 h·μg/L, respectively.

Interpretation, Conclusion or Significance: Our population PK model of donepezil well explained the PKs of both the IM and oral formulation. This model could be further utilized for multiple-dose bioequivalence simulations, which will aid in designing future clinical trials and selecting doses that demonstrate bioequivalence with the current oral dosing regimen.

Disclosures: Eunyoung Seol and Heeyong Lee are employees of G2GBIO, Inc. The other authors do not have any conflicts of interest in this study.

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