Abstract

Purpose: To develop a population pharmacokinetic (PPK) model for paliperidone extended-release (ER) and to evaluate the influence of selected covariates.

Methods: Paliperidone was administered once daily as paliperidone ER 3 – 15 mg (n=1368) or 1-mg intravenous dose (n=20). PPK analysis was based on nine Phase 1 and four Phase 3 trials. Model development included five Phase 1 studies (n=206), model refinement and covariate analysis included three additional Phase 1 studies and two Phase 3 studies (n=692), and validation included one Phase 1 and two Phase 3 studies (n=470).

Results: Data were described with a linear, two-compartment model with zero-order input (estimated duration 23.9h) and first-order absorption (estimated lag time 0.668h). Apparent total paliperidone clearance and steady-state volume of distribution were estimated to be 13.8L/h and 487L, respectively. Lean body mass (LBM) and CrCL were significant predictors of paliperidone clearance. In subjects with normal renal function, predicted paliperidone AUC (paliperidone ER 6 mg) decreased from 482 to 410 (ng•hr/mL) as LBM increased from 42.8 to 67.5kg. For any given LBM, however, a change from normal renal function to mild impairment was predicted to increase paliperidone exposure by approximately 20%.

Conclusions: A two-compartment model with zero-order input, first-order absorption, and first-order elimination best described the PPK for paliperidone ER.

American Society for Clinical Pharmacology and Therapeutics (ASCPT); Anaheim, California; March 2007

By B. Cirincione, M. Redman, Jill Fiedler-Kelly, E. Ludwig, A. Vermeulen