Aripiprazole Lauroxil Pharmacokinetics: Modeling and Simulation to Support Dosing Considerations in Patients With Schizophrenia

Aripiprazole lauroxil (AL) is a novel, long-acting injectable atypical antipsychotic shown to be effective in treating acute schizophrenia. AL is a prodrug of aripiprazole that undergoes enzyme-mediated hydrolysis to form aripiprazole. Aripiprazole is subsequently metabolized by CYP3A4 and CYP2D6. A population pharmacokinetic (PK) model of AL was used to evaluate the impact of delayed dose scenarios and reinitiation of treatment with monthly AL administration of 441, 662 or 882 mg. A physiologically-based PK (PBPK) model was constructed to evaluate the effect of drug-drug and drug-gene interactions on aripiprazole exposure. The extended PK profile of AL results in sustained therapeutic coverage following a missed AL dose. Therefore, no oral aripiprazole supplementation is required when the time from the last injection is ≤6 weeks for 441 mg, or ≤8 weeks for 662 mg and 882 mg. Evaluation of the impact of strong CYP2D6 or CYP3A4 inhibitors, or CYP3A4 inducers on the PK of aripiprazole showed moderate changes in the systemic exposure of aripiprazole, irrespective of CYP2D6 genotype, and that AL dose adjustments are warranted when the CYP450 modulator is co-administered for >2 weeks. AL demonstrates unique PK characteristics, minimizing the potential impact of poor adherence to treatment when a dose is missed. The availability of 3 dose strengths allows for individual patient dose adjustment for drug-drug interactions or metabolic status, thus providing flexibility in treating patients with schizophrenia.