Size matters: the importance of particle size in a newly developed injectable formulation for the treatment of schizophrenia

Abstract

One of the challenges with initiating long-acting injectable (LAI) antipsychotic regimens is achieving relevant drug levels quickly. After first injection of the LAI antipsychotic aripiprazole lauroxil (AL), the lag to reaching relevant plasma aripiprazole levels was initially addressed using supplemental oral aripiprazole for 21 days. A 1-day AL initiation regimen using a NanoCrystal® Dispersion formulation of AL (ALNCD; Aristada Initio®) combined with a single 30 mg dose of oral aripiprazole has been developed as an alternative approach. We compared the 1-day AL initiation regimen (ALNCD + 30 mg oral aripiprazole for 1 day) with the 21-day AL initiation regimen (AL + 15 mg/day of oral aripiprazole for 21 days) using kinetic modeling. Observed and modeled data demonstrate that the 1-day AL initiation regimen provides continuous aripiprazole exposure comparable to the 21-day AL initiation regimen. Each component of the 1-day AL initiation regimen (30 mg oral aripiprazole, ALNCD, and AL) contributes to aripiprazole plasma levels at different times, with oral aripiprazole predominating in the first week, then ALNCD and AL over time. In a double-blind, placebo-controlled, phase 1 study in patients with schizophrenia, the 1-day initiation regimen resulted in rapid achievement of relevant plasma aripiprazole levels comparable to those from the 21-day initiation regimen. Safety and tolerability of the 1-day regimen were consistent with the known profile of aripiprazole. Each part of the 1-day initiation regimen, together with AL, is necessary for continuous aripiprazole exposure from treatment initiation until the next regularly scheduled AL injection is administered.

Aripiprazole lauroxil 2-month formulation with 1-day initiation in patients hospitalized for an acute exacerbation of schizophrenia: exploratory efficacy and patient-reported outcomes in the randomized controlled ALPINE study

“…AL was initiated on study day 1 using a 1-day regimen that included a single gluteal injection of AL NanoCrystal® Dispersion (AL NCD ; ARISTADA INITIO®) plus a single 30 mg oral aripiprazole tablet. The AL NCD formulation has a faster dissolution time and results in a more rapid rise in plasma aripiprazole concentrations compared with AL [ 17 , 27 ]. However, because AL NCD is also an LAI, a single, one-time 30 mg dose of oral aripiprazole is administered on the same day as the AL NCD injection to eliminate any remaining delay in achieving aripiprazole plasma concentrations that are associated with a therapeutic effect [ 17 ].…”

“…The AL NCD formulation has a faster dissolution time and results in a more rapid rise in plasma aripiprazole concentrations compared with AL [ 17 , 27 ]. However, because AL NCD is also an LAI, a single, one-time 30 mg dose of oral aripiprazole is administered on the same day as the AL NCD injection to eliminate any remaining delay in achieving aripiprazole plasma concentrations that are associated with a therapeutic effect [ 17 ]. AL 1064 mg was administered in a gluteal injection on day 8 and every 8 weeks thereafter (for a total of 3 injections of AL 1064 mg); no oral aripiprazole was administered with AL 1064 injections.…”

“…Aripiprazole lauroxil (AL; ARISTADA®), a prodrug of aripiprazole, is a long-acting injectable (LAI) atypical antipsychotic indicated for the treatment of schizophrenia in adults [ 17 , 18 ]. The randomized, controlled, phase 3b Aripiprazole Lauroxil and Paliperidone palmitate: INitiation Effectiveness (ALPINE) study evaluated the efficacy and safety of a 2-month formulation of AL started with a 1-day initiation regimen during hospitalization for an acute exacerbation of schizophrenia [ 19 ].…”

Aripiprazole Lauroxil Dosing Regimens: Understanding Dosage Strengths and Injection Intervals

“…The selection of an AL regimen is based on plasma aripiprazole concentrations at steady state; therefore, to understand the characteristics that differentiate the available AL dosing regimens, it is important to examine the plasma aripiprazole concentrations at steady state, not considering the early concentrations during the LAI initiation period. For illustrative purposes, the steady-state plasma concentration profiles starting 6 months after AL regimen initiation (see Jain 14 for details) are shown in Figure 1B. Figure 1 also illustrates the relationship between steady-state plasma concentrations over time (Figure 1B) and the range of plasma concentrations averaged over injection interval at steady state ( C avg,ss ), shown as box plots in Figure 1C.…”

“…AL is a prodrug of aripiprazole that is formulated as a suspension of micrometersized drug particles of AL that are slowly released into the bloodstream and converted to aripiprazole, allowing for dose intervals of up to 2 months depending on the dose administered. 13,14 When prescribing an LAI antipsychotic for an individual patient, clinicians consider patient characteristics such as course of illness, past history of response to and tolerance of other antipsychotics, likelihood of adherence, and treatment preferences. 11,12,15,16 After selecting an LAI, the clinician must choose from among available dosing regimens, which vary according to dosage strength (ie, milligram of drug per injection given) and injection interval (recommended time between injections).…”