Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-Acting Injectable Antipsychotic in Persons With Schizophrenia

Abstract

Background: Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice.

Methods: Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations.

Findings: The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing.

Conclusions: This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.

Figures

FIGURE 1

Conversion of aripiprazole lauroxil to aripiprazole. Aripiprazole lauroxil is a prodrug of aripiprazole. After intramuscular injection of aripiprazole lauroxil, there is a slow dissolution of the drug particles (A), which is followed by enzyme-mediated cleavage, generating N-hydroxymethyl aripiprazole and lauric acid (B). Water-mediated hydrolysis converts N-hydroxymethyl aripiprazole to aripiprazole and formaldehyde (C).

FIGURE 2

Structure of final PopPK model. ALAG indicates absorption lag time; CL/F, apparent clearance of aripiprazole; CLM/F/fm, apparent clearance of dehydro-aripiprazole; D1, input duration; IM, intramuscular; Ka, first-order rate of absorption; VC/F, apparent volume of aripiprazole central compartment; VCM/F/fm, apparent volume of dehydro-aripiprazole central compartment; VP/F, apparent volume of aripiprazole peripheral compartment; VPM/F/fm, apparent volume of dehydro-aripiprazole peripheral compartment; Q/F, intercompartmental clearance of aripiprazole; QM/F/fm, intercompartmental clearance of dehydro-aripiprazole.

FIGURE 3

Median-simulated aripiprazole plasma concentrations after administration of aripiprazole lauroxil 662 mg q4wk and 882 mg q6wk compared with the 441 mg and 882 mg q4wk dose regimens evaluated in the phase 3 efficacy and safety study of aripiprazole lauroxil. The shaded region represents the 21-day oral aripiprazole lead-in period.

FIGURE 4

Dose-normalized predose aripiprazole concentrations observed in the open-label, long-term, safety extension study of aripiprazole lauroxil in patients with stable schizophrenia who completed active treatment in the 12-week phase 3 trial and continued to participate in the safety extension trial on the same treatment regimen. Aripiprazole concentrations were normalized based on aripiprazole equivalents for the corresponding aripiprazole lauroxil dose of 441 mg (300 mg aripiprazole equivalents) or 882 mg (600 mg equivalents).

FIGURE 5

Median-simulated aripiprazole plasma concentrations after a missed aripiprazole lauroxil dose at steady state for (A) 441 mg q4wk, (B) 662 mg q4wk, and (C) 882 mg q4wk and q6wk doses, respectively. The asterisks represent the resumption of aripiprazole lauroxil after a missed dose.