Julia Korell (1), Bruce Green (1), An Vermeulen (2)
(1) Model Answers Pty Ltd, Brisbane, Australia; (2) Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium
Objectives: The aim of this work was to develop a population pharmacokinetic (PK) model for aripiprazole and its metabolite, dehydro-aripiprazole.
Methods: Steady-state plasma concentration–time data for aripiprazole and dehydro-aripiprazole were available from an open-label PK study in 86 subjects. Model development was performed in two steps: 1) a population PK model for the parent drug was developed on the aripiprazole data alone, then 2) sequential modeling using the PPP+D method [1] was applied to obtain a parent-metabolite PK model using the combined aripiprazole and dehydro-aripiprazole data. Covariates tested for the parent and parent-metabolite model included weight, lean body weight (LBW), age, sex, race, and CYP2D6 phenotype. Model development was performed in NONMEM v7.2, using FOCE with interaction. The final parent-metabolite model was evaluated using visual predictive checks (VPCs).
Results: A one-compartment model with first-order absorption and elimination together with a proportional error best described the aripiprazole data. Between-subject variability (BSV) was included on all structural parameters. LBW and CYP2D6 phenotype were found to be significant covariates on aripiprazole plasma clearance. The typical clearance (CL/F) of aripiprazole in extensive metabolizers was found to be 3.44 L/hr (BSV = 32.6%). Ultra-rapid metabolizers showed an increase in CL/F of 49%, while CL/F decreased by 53% in poor and intermediate metabolizers. Typical estimates for the volume of distribution (V/F) and absorption rate constant of aripiprazole were 243 L (BSV = 38.3%) and 1.54 hr-1 (BSV = 73.1%), respectively.
The PK of dehydro-aripiprazole in the final parent-metabolite model was also best described by a one-compartment model with first-order elimination. The typical clearance of dehydro-aripiprazole (CLm/fm) was 10.9 L/hr (BSV = 42.7%). The fraction of aripiprazole metabolized (fm) to dehydro-aripiprazole was fixed at 1, while the volume of distribution of the metabolite was fixed to the estimate of the parent drug. LBW was also a significant covariate on CLm/fm.
VPCs for the final parent-metabolite model showed adequate predictive performance of the model to describe both aripiprazole and dehydro-aripiprazole data.
Conclusions: A sequential parent-metabolite PK model for aripiprazole and dehydro- aripiprazole with adequate predictive performance was developed.
References:
[1] Zhang L, Beal S, Sheiner L. Simultaneous vs. Sequential Analysis for Population PK/PD Data I: Best-Case Performance. Journal of Pharmacokinetics and Pharmacodynamics 2003;30(6):387–404.
Reference: PAGE 24 (2015) Abstr 3488 [www.page-meeting.org/?abstract=3488]
Poster: Drug/Disease modeling - CNS