Development of a Population Pharmacokinetic Model to Describe the Pharmacokinetics of Aripiprazole 2-Month Ready-to-Use, a New Long-Acting Injectable Formulation for Administration Once Every 2 Months

This work was sponsored by Otsuka Pharmaceutical Development & Commercialization Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark). Aripiprazole 2-month ready-to-use (Ari 2MRTU) is a novel long-acting injectable formulation of aripiprazole monohydrate for gluteal intramuscular administration once every 2 months. Population pharmacokinetic (popPK) modelling was undertaken to characterize the pharmacokinetics (PK) of Ari 2MRTU. A previously developed and validated popPK model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) formulations was expanded to include Ari 2MRTU. Overall, 8,899 aripiprazole PK samples from 1,191 adults were included in the dataset; of these, 240 patients had received Ari 2MRTU. All fixed-effects parameters from the prior model remained fixed, as did random-effects parameters for the first-order absorption rate constant of the oral and AOM routes, apart from CL/F and Vc/F, which were re-estimated. Covariate effects from the original model were retained; additional potential effects related to the absorption and relative bioavailability of Ari 2MRTU were tested. A 3-compartment model with linear elimination and different absorption models for each formulation best described the data. Ari 2MRTU absorption was modeled by a parallel zero-order and lagged first-order process that accounted for a double peak in aripiprazole plasma concentrations post-administration. Sex was a significant covariate on the absorption of Ari 2MRTU; however, simulated Cavg,ss values were identical in both sexes, indicating no clinically relevant effect. As expected, simulated aripiprazole concentrations were higher in poor metabolizers of CYP2D6. In conclusion, the final popPK model adequately described aripiprazole PK following Ari 2MRTU administration. The model can be used to perform simulations to support dosing of Ari 2MRTU across clinical scenarios.