Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration

Abstract

Background: Two open-label, randomized, parallel-arm studies compared pharmacokinetics, safety, and tolerability of aripiprazole once-monthly 400 mg following deltoid vs gluteal injection in patients with schizophrenia.

Methods: In the single-dose study, 1 injection of aripiprazole once-monthly 400 mg in the deltoid (n=17) or gluteal (n=18) muscle (NCT01646827) was administered. In the multiple-dose study, the first aripiprazole once-monthly 400 mg injection was administered in either the deltoid (n=71) or gluteal (n=67) muscle followed by 4 once-monthly deltoid injections (NCT01909466).

Results: After single-dose administration, aripiprazole exposure (area under the concentration-time curve) was similar between deltoid and gluteal administrations, whereas median time to maximum plasma concentration was shorter (7.1 [deltoid] vs 24.1 days [gluteal]) and maximum concentration was 31% higher after deltoid administration. In the multiple-dose study, median time to maximum plasma concentration for deltoid administration was shorter (3.95 vs 7.1 days), whereas aripiprazole mean trough concentrations, maximum concentration, and area under the concentration-time curve were comparable between deltoid and gluteal muscles (historical data comparison). Multiple-dose pharmacokinetic results for the major metabolite, dehydro-aripiprazole, followed a similar pattern to that of the parent drug for both deltoid and gluteal injection sites. Safety and tolerability profiles were similar after gluteal or deltoid injections. Based on observed data, minimum aripiprazole concentrations achieved by aripiprazole once-monthly 400 mg are comparable with those of oral aripiprazole 15 to 20 mg/d.

Conclusions: The deltoid muscle is a safe alternative injection site for aripiprazole once-monthly 400 mg in patients with schizophrenia.

Keywords: antipsychotic; aripiprazole once-monthly 400 mg; injection site; pharmacokinetics; safety/tolerability.

© The Author 2017. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.

Mean (SD) aripiprazole concentration-time profiles after deltoid or gluteal injection of aripiprazole once-monthly 400 as single- or multiple-dose administrations. Because data are from multiple trials, only time points that were common in all trials are displayed. In multiple-dose studies (injections given every 28 d), samples at days 28, 56, 84, and 112 are predosing concentrations (trough levels), and more frequent sampling was done at steady state from days 112 to 140. Historical gluteal multiple-dose data are from an open-label, parallel-arm, multiple-dose, 24-week study (Mallikaarjun et al., 2013).

Figure 2.

Aripiprazole Cmin,ss after monthly injections of aripiprazole 400 mg at the deltoid site and comparison with historical data from the gluteal site. Steady-state concentration data for the deltoid site are from the multiple-dose study following the fifth injection, with gluteal/deltoid and deltoid/deltoid administration groups combined. Historical data are from patients with schizophrenia in a phase 3 randomized, placebo-controlled, 52-week study (Kane et al., 2012); a phase 3, randomized, active-controlled 38-week study (Fleischhacker et al., 2014); and a phase 1, open-label, parallel-arm, multiple-dose, 24-week study (Mallikaarjun et al., 2013). Boxes span the 25th and 75th percentiles with a thick horizontal bar at the median. Error bars denote the 10th and 90th percentiles. Dashed horizontal lines represent the therapeutic window (i.e., the median simulated Cmin,ss for oral aripiprazole 10 mg/d [94.0 ng/mL] and the 75th percentile of the simulated Cmax,ss for oral aripiprazole 30 mg/d [534 ng/mL]) based on population pharmacokinetic (PK) simulations of once-daily oral aripiprazole (Raoufinia et al., 2015). Points represent individual outliers below the 10th and above the 90th percentiles. Cmax,ss=maximum plasma concentration at steady state; Cmin,ss=minimum plasma concentration at steady state.