2010 - Berlin - Germany

PAGE 2010: Applications- CNS
Yu-Yuan Chiu

Population Pharmacokinetics of Lurasidone in Healthy Subjects and Subjects with Schizophrenia

Y. Chiu(1), J. Nielsen(2), D. Sarrubi(1), K. Kowalski(2)

(1) Dainippon Sumitomo Pharma America, Inc., Fort Lee, NJ, USA(2) Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA

Objectives: Population pharmacokinetic (PK) analysis was performed to characterize lurasidone concentration-time profiles in healthy subjects and subjects with schizophrenia. Effects of covariates on lurasidone PK parameters were investigated to derive a final predictive PK model.

Methods: Nonlinear mixed effects modeling methodology was implemented in this analysis using NONMEM® (version 6). The first-order conditional estimation (FOCE) method with interaction was used to fit the lurasidone serum concentration data. A two stage, stepwise forward selection and backward elimination procedure was used to identify relationships between population PK parameters and selected covariates including baseline body weight, age, race, gender, and meal status. Standard goodness-of-fit diagnostics and posterior predictive checks were used to evaluate the adequacy of the PK model fit and predictions.

Results: A three compartment model with first-order absorption, absorption lag time, and first-order elimination characterized the lurasidone PK in 11735 lurasidone concentrations from 1353 healthy subjects and subjects with schizophrenia.  Seven covariate effects out of 19 covariate effects investigated were included in the final parsimonious model following forward selection and backward elimination procedures. Parameter estimates were generally estimated with good precision (less than 30% SEM). Diagnostic plots and posterior predictive check results stratified by dose suggest that total lurasidone exposure increases in a linear fashion within the dose range tested (10 to 600 mg/day). Similarly, peak serum concentrations suggest a dose-proportional increase within the range of 10 to 160 mg/day.  There was insufficient evidence of an age effect on the PK of lurasidone as assessed by the population PK analysis.  Race, gender, and weight were individually associated with less than two-fold changes in typical predicted AUC(0-24) or Cmax values.  Food increased lurasidone exposure which is consistent with clinical findings.

Conclusions: The population PK model adequately characterized lurasidone PK in healthy subjects and subjects with schizophrenia. Changes in exposure from age, race, gender, and weight are not regarded as clinically relevant.

Reference: PAGE 19 (2010) Abstr 1729 [www.page-meeting.org/?abstract=1729]
Poster: Applications- CNS