Population Pharmacokinetic Modeling and Exposure-Response Analysis for Aripiprazole Once Monthly in Subjects With Schizophrenia

Abstract

An intramuscular formulation of aripiprazole monohydrate dosed once monthly (AOM) was developed to address nonadherence with the approved oral tablets. A 3-compartment linear population pharmacokinetic model for oral and AOM doses was developed; relative bioavailability was estimated for AOM relative to oral dosing and body mass index and sex were significant predictors of AOM absorption rate constant (longer absorption half-life for women and absorption half-life increases with increasing body mass index). Aripiprazole apparent oral clearance for subjects with cytochrome P450 (CYP) 2D6 poor metabolizer status and in the presence of strong CYP2D6 inhibitors was approximately half that of subjects with CYP2D6 extensive metabolizer status and 24% lower in the presence of strong CYP3A4 inhibitors. Simulations of the population pharmacokinetics were conducted to evaluate the effect of different dose initiation strategies for AOM, the effects of CYP2D6 metabolizer status, coadministration of CYP2D6 and CYP3A4 inhibitors, and missed doses. An exposure-response model with an exponential hazard function of the model-predicted minimum concentration (C_min ) described the time to relapse. The hazard ratio (95% confidence interval) was 4.41 (2.89-6.75). Thus, a subject with a diagnosis of schizophrenia and C_min ≥ 95 ng/mL is 4.41 times less likely to relapse relative to a subject with C_min < 95 ng/mL.

Keywords: Abilify Maintena®; aripiprazole; population pharmacokinetics; schizophrenia.

Figure 1

Mean ± standard error aripiprazole concentration‐time plots, stratified by AOM dose. Note: Panels in the left column display concentrations following the first injection for the full time scale (top) and truncated to the first 72 hours (bottom) (study CN138020). Panels in the right column display concentrations following the fifth injection for the full time scale (top) and truncated to the first 72 hours (bottom) (study 31‐05‐244). AOM, aripiprazole once monthly.

Figure 2

Goodness‐of‐fit plots for final model of phase 1 and phase 3 oral plus AOM data. The observed concentrations >500 ng/mL represent <1% of the data. Panels in the right column display a line of identity (solid black). All panels have loess smooth lines of the data for the extensive metabolizers (dashed blue) and for the poor metabolizers (dashed red). AOM, aripiprazole once monthly; CYP, cytochrome P450; Conc, concentration.

Figure 3

Visual predictive check of the final model, stratified by administration route. Top panel, oral. Bottom panel, AOM. AOM, aripiprazole once monthly; CI, confidence interval.

Figure 4

Simulated median concentration vs day. The dashed horizontal lines represent the therapeutic window. Unless specified otherwise, all groups were administered the specified amount of oral aripiprazole to steady state followed by 400‐mg AOM with or without 14 days of concomitant administration of the specified amount of oral aripiprazole. Panel 1: First 2 doses, stratified by dosing initiation scheme. Panel 2: Following steady‐state administration of specified AOM dose, concentration versus days since previous active dose for CYP2D6 poor and extensive metabolizers. Panel 3: Simulated median steady‐state concentration vs days since previous active dose. All groups were administered the specified dose of AOM to steady state with or without the presence of chronic concomitant administration of CYP2D6 or CYP3A4 inhibitors. Panels 4 and 5: Second or third dose delayed by 7 or 8 days, stratified by reinitiation of dosing without and with supplemental oral therapy, respectively. Panels 6 and 7: Fourth or 10th dose delayed by 14 or 15 days, stratified by reinitiation of dosing without and with supplemental oral therapy, respectively. AOM, aripiprazole once monthly; CYP, cytochrome P450; EM, extensive metabolizers, PM, poor metabolizers, SS, steady state.

Figure 5

Kaplan‐Meier plot of survival (no relapse) vs time for placebo and 400‐/300‐mg aripiprazole AOM treatment groups, grouped by quartiles of predicted aripiprazole C_min. Quartile 1 is C_min ≤95 ng/mL; Quartile 2 is 95 < C_min ≤146 ng/mL; Quartile 3 is 146 <C_min ≤200 ng/mL; and Quartile 4 is 200 <C_min. Note: The minimum model‐predicted C_min was not 0 for the placebo treatment arm because of incomplete washout of prior oral dosing. The minimum model‐predicted C_min was 0.000329 ng/mL. AOM, aripiprazole once monthly; C_min, minimum predicted drug concentration.

Figure 6

Observed (red line) and model‐predicted (blue dashed line) probability of survival vs time for groups of predicted aripiprazole 0 < C_min ≤95 ng/mL and 95 < C_min ≤580 ng/mL. The shaded regions show the 90% prediction interval of the model‐predicted probability of survival vs time. C_min, minimum predicted drug concentration; PI, prediction interval.