Development of a Population Pharmacokinetic Model to Describe the Pharmacokinetics of Aripiprazole 2-Month Ready-to-Use, a Novel Long-Acting Injectable Formulation of Aripiprazole for Administration Once Every 2 Months
Yanlin Wang (1), Matthew Harlin (1), Frank Larsen (2), Xiaofeng Wang (1), Wansu Park (3), Benjamin Rich (4), Jogarao V. Gobburu (5), Arash Raoufinia (1)
(1) Otsuka Pharmaceutical Development & Commercialization Inc., USA, (2) H. Lundbeck A/S, Denmark, (3) Alnylam Pharmaceuticals, USA, (4) InnoMx Inc., Canada, (5) University of Maryland, USA
Introduction: Compared with oral antipsychotics, long-acting injectable (LAI) antipsychotic formulations are associated with greater treatment adherence and a reduced risk of hospitalization or relapse[1]. Aripiprazole 2-month ready-to-use (Ari 2MRTU) 960 mg is a novel LAI formulation of aripiprazole monohydrate for gluteal intramuscular administration once every 2 months. Ari 2MRTU 960 will offer an extended dosing interval versus aripiprazole once-monthly 400 mg (AOM 400). As part of the development of Ari 2MRTU 960, population pharmacokinetic (popPK) modelling was undertaken to characterize the pharmacokinetics (PK) of this formulation. The final popPK model is described here.
Objectives:
- To develop a popPK model that characterize the absorption and disposition of aripiprazole when administered once every 2 months as a novel ready-to-use long-acting injectable formulation and evaluate clinically relevant sources of variability in drug exposure.
Methods: A previously developed and validated popPK model for characterizing aripiprazole plasma concentrations following administration of oral or AOM 400 (gluteal or deltoid intramuscular injection) formulations was expanded to include the novel Ari 2MRTU formulation [2]. Overall, 8,899 aripiprazole PK samples from 1,191 adults (schizophrenia, schizoaffective disorder, or bipolar I disorder [BP-I], n=1,139; healthy individuals, n=52) from ten Phase 1 and 3 trials were included in the final combined analysis dataset; of these, 240 patients with schizophrenia or BP-I received Ari 2MRTU across three trials. All fixed-effects parameters from the prior model remained fixed throughout the model development, 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, with additional potential effects related to the absorption and relative bioavailability of the Ari 2MRTU formulation formally tested using a modified stepwise approach. Data were analyzed using non-linear mixed effects modeling software (NONMEM v7.4.2).
Results: A 3-compartment model with linear elimination and different absorption models for each formulation best described the data. Absorption of the Ari 2MRTU formulation was modeled by a parallel zero-order and lagged first-order process that accounted for an identified double peak in plasma concentrations of aripiprazole post-administration of Ari 2MRTU. All disposition parameters were shared between the formulations except Vc/F (oral and AOM formulations, 93.4 L; Ari 2MRTU formulation, 2035 L); the different Vc/F value for the Ari 2MRTU formulation was attributed to the terminal half-life being absorption driven. Sex was a significant covariate on the absorption of the Ari 2MRTU formulation (90.7% higher absorption rate constant and 56.0% lower fraction of first-order absorption in males versus females); however, simulated Cavg,ss values were identical in both sexes, indicating no clinically relevant effect. As expected, simulated aripiprazole concentrations were higher in poor versus extensive metabolizers of CYP2D6; the effect of CYP2D6 metabolizer status was thus retained as a covariate from the prior model.
Conclusions: The final popPK model was considered fit for purpose, adequately describing aripiprazole PK following administration of Ari 2MRTU 960. The model also established estimates for key popPK parameters and identified sources of variability in drug exposure. The model can be used to perform simulations to support dosing of Ari 2MRTU 960 across multiple realistic clinical scenarios.
References:
[1] Kishimoto T, Hagi K, Kurokawa S, et al. Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre–post studies. Lancet Psychiatry 2021;8:387-404.
[2] Wang Y, Wang X, Harlin M, et al. An alternative start regimen with aripiprazole once-monthly in patients with schizophrenia: population pharmacokinetic analysis of a single-day, two-injection start with gluteal and/or deltoid intramuscular injection. Curr Med Res Opin 2021;37(11):1961-1972.