Population Pharmacokinetic Modeling and Exposure-Response Analysis for Aripiprazole Once Monthly in Subjects With Schizophrenia
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 (Cmin) 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 Cmin ≥ 95 ng/mL is 4.41 times less likely to relapse relative to a subject with Cmin < 95 ng/mL.
By Xiaofeng Wang, Arash Raoufinia, Sébastien Bihorel, Julie Passarell, Suresh Mallikaarjun, Luann Phillips