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Long-acting injectable (LAI) antipsychotics are an important treatment option for patients with schizophrenia. Advances and variability in formulation technology have provided several LAI antipsychotic treatment options for schizophrenia, with a wide range of doses and dose intervals. However, clinical reviews of LAIs have not focused on formulation development despite its clinical relevance to injection safety and technique. This article reviews the relationship between formulation technology and clinical practices for LAIs, with a focus on aripiprazole lauroxil, a long-acting atypical antipsychotic indicated for the treatment of schizophrenia. The formulation developed for aripiprazole lauroxil is an aqueous-based suspension suitable for use as a prefilled syringe that, after injection, will release aripiprazole slowly into the plasma. The clinical relationship between the aripiprazole lauroxil formulation and proper injection techniques is explained, including why tapping and shaking the syringe to resuspend the drug particles and rapid injection speed are key steps for best injection practices for this formulation.

Background: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia in adults, can be started with either 21 days of daily oral aripiprazole supplementation or a 1-day initiation regimen consisting of a single injection of a NanoCrystal® Dispersion formulation of AL (ALNCD) and a single dose of 30 mg oral aripiprazole. This phase I study assessed the pharmacokinetics and safety of deltoid versus gluteal ALNCD injections. Methods: Patients with schizophrenia or schizoaffective disorder (N = 47) were randomized 1:1 to receive a single intramuscular dose of ALNCD in the deltoid or gluteal muscle. Plasma samples were collected over 85 days to measure ALNCD concentration by injection site. Relative aripiprazole bioavailability for deltoid versus gluteal injection was assessed based on area under the curve (AUC∞ and AUClast) and maximum concentration (Cmax) values. Adverse events were monitored throughout the study. Results: Plasma aripiprazole concentrations after a single ALNCD injection were comparable between deltoid and gluteal administration. Mean maximum plasma aripiprazole concentrations were 196.1 ng/ml (deltoid) and 175.0 ng/ml (gluteal). Exposure to aripiprazole was similar, with mean AUC∞ values of 6591 day × ng/ml for deltoid and 6437 day × ng/ml for gluteal. Aripiprazole bioavailability was not significantly different between injection sites. ALNCD administration in the deltoid or gluteal muscle was well tolerated, with similar safety profiles at both sites. Conclusion: ALNCD demonstrated similar exposure and safety profiles between the two administration sites, suggesting that ALNCD can be given in either the gluteal or the deltoid muscles as a component of the 1-day initiation regimen for AL.

Clinicians using long-acting injectable (LAI) antipsychotics may assume that there is uniformity in the injection technique for all LAIs. However, because LAIs have significant differences in their formulation, each requires a specific administration procedure. Here, we focus on how the formulation properties of the atypical LAI aripiprazole lauroxil impact its administration.The history of LAI formulations is presented as a background to recent advances in formulation technology. A shared challenge for new LAIs is to adapt the formulation of insoluble drugs to aqueous-based suspensions.The early LAIs kept the drug product dissolved as oil-based solutions, which were stable and did not require mixing prior to injection. However, oil-based solutions tend to be viscous and cause injection-site reactions (ISRs).New LAI formulations tend to be aqueous-based suspensions and need to be resuspended or reconstituted before injection. Beyond this common element, formulation properties lead to differences in administration for each of the available LAIs.We reviewed the formulations of LAIs indicated for the treatment of schizophrenia and how they impact instructions for use, with a focus on aripiprazole lauroxil.Aripiprazole monohydrate and olanzapine pamoate are lyophilized powders that require reconstitution before administration and should be injected slowly. Risperidone is formulated as microspheres in powder form that require reconstitution before injection, although the injection speed is not specified. Paliperidone palmitate is a ready-to-use aqueous suspension of crystalline particles and should be injected slowly. Aripiprazole lauroxil is an aqueous-based, ready-to-use suspension of crystalline particles. Unlike other LAIs, the formulation of aripiprazole lauroxil contains particles that are loosely associated to facilitate resuspension. Because loosely associated suspensions are shear-thinning, meaning the viscosity of the formulation decreases with higher injection force, the injection must be given rapidly. Vigorous shaking and rapid injection are key aspects of administration and have been accepted by patients and investigators in clinical trials. In a pivotal phase 3 study of aripiprazole lauroxil, the incidence of ISRs was low (3.9% and 5.8% for aripiprazole lauroxil 441mg and 882mg , respectively) and mostly associated with the first injection.Advances in formulation technology have increased LAI options for patients with schizophrenia. The aripiprazole lauroxil formulation differs from other LAIs in that the particles are loosely associated to support use as a ready-to-use pre-filled syringe. Because the suspension is shear-thinning, aripiprazole lauroxil requires rapid injection, which is not required when using other LAIs. An understanding of the differences in formulation design and how they impact the specific techniques associated with an LAI is essential for successful administration.Funding Acknowledgements: This study was funded by Alkermes, Inc.

Background: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia in adults, can be started with either 21 days of daily oral aripiprazole supplementation or a 1-day initiation regimen consisting of a single injection of a NanoCrystal® Dispersion formulation of AL (ALNCD) and a single dose of 30 mg oral aripiprazole. This phase I study assessed the pharmacokinetics and safety of deltoid versus gluteal ALNCD injections. Methods: Patients with schizophrenia or schizoaffective disorder ( N = 47) were randomized 1:1 to receive a single intramuscular dose of ALNCD in the deltoid or gluteal muscle. Plasma samples were collected over 85 days to measure ALNCD concentration by injection site. Relative aripiprazole bioavailability for deltoid versus gluteal injection was assessed based on area under the curve (AUC∞ and AUClast) and maximum concentration (Cmax) values. Adverse events were monitored throughout the study. Results: Plasma aripiprazole concentrations after a single ALNCD injection were comparable between deltoid and gluteal administration. Mean maximum plasma aripiprazole concentrations were 196.1 ng/ml (deltoid) and 175.0 ng/ml (gluteal). Exposure to aripiprazole was similar, with mean AUC∞ values of 6591 day × ng/ml for deltoid and 6437 day × ng/ml for gluteal. Aripiprazole bioavailability was not significantly different between injection sites. ALNCD administration in the deltoid or gluteal muscle was well tolerated, with similar safety profiles at both sites. Conclusion: ALNCD demonstrated similar exposure and safety profiles between the two administration sites, suggesting that ALNCD can be given in either the gluteal or the deltoid muscles as a component of the 1-day initiation regimen for AL.