Out Of The Pipeline

Aripiprazole lauroxil nanocrystal suspension

Current Psychiatry. 2018 November;17(11):34-36,38-40

References

1. Meyer JM. Converting oral to long acting injectable antipsychotics: a guide for the perplexed. CNS Spectrums. 2017;22(S1):14-28.
2. Kishimoto T, Hagi K, Nitta M, et al. Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies. Schizophr Bull. 2018;44(3):603-619.
3. Hard ML, Wehr AY, Sadler BM, et al. Population pharmacokinetic analysis and model-based simulations of aripiprazole for a 1-day initiation regimen for the long-acting antipsychotic aripiprazole lauroxil. Eur J Drug Metab Pharmacokinet. 2018;43(4):461-469.
4. Hard ML, Wehr AY, Du Y, et al. Pharmacokinetic evaluation of a 1-day treatment initiation option for starting long-acting aripiprazole lauroxil for schizophrenia. J Clin Psychopharmacol. 2018;38(5):435-441.
5. Byerly MJ, Thompson A, Carmody T, et al. Validity of electronically monitored medication adherence and conventional adherence measures in schizophrenia. Psychiatric Services. 2007;58(6):844-847.
6. Remington G, Teo C, Mann S, et al. Examining levels of antipsychotic adherence to better understand nonadherence. J Clin Psychopharmacol. 2013;33(2):261-263.
7. Aristada Initio [package insert]. Waltham, MA: Alkermes Inc; 2018.
8. Hard ML, Mills RJ, Sadler BM, et al. Aripiprazole lauroxil: pharmacokinetic profile of this long-acting injectable antipsychotic in persons with schizophrenia. J Clin Psychopharmacol. 2017;37(3):289-295.
9. Aristada Initio [package insert]. Waltham, MA: Alkermes Inc; 2018.
10. Meltzer HY, Risinger R, Nasrallah HA, et al. A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia. J Clin Psychiatry. 2015;76(8):1085-1090.
11. Aristada [package insert]. Waltham, MA: Alkermes Inc; 2018.
12. Fleischhacker WW, Eerdekens M, Karcher K, et al. Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. J Clin Psychiatry. 2003;64(10):1250-1257.
13. Hard ML, Mills RJ, Sadler BM, et al. Pharmacokinetic profile of a 2-month dose regimen of aripiprazole lauroxil: a phase I study and a population pharmacokinetic model. CNS Drugs. 2017;31(7):617-624.

Long-acting injectable (LAI) antipsychotics were developed due to the pervasive problem of oral medication nonadherence among patients with severe mental illnesses. While use of LAI antipsychotics reduces hospitalization rates, one issue in transitioning patients to certain LAI preparations is the need for prolonged oral coverage when beginning treatment with agents that cannot be loaded.^1,2 Nonadherence with this bridging oral therapy places the patient at risk for symptom exacerbation until effective antipsychotic plasma levels are achieved from the LAI.¹ To obviate the need for 3 weeks of oral medication coverage when commencing treatment with aripiprazole lauroxil (AL; Aristada), a new LAI form of AL was developed utilizing smaller nanomolecular-sized particles. The nanocrystal suspension has a shorter T_max and much shorter half-life than AL, provides effective plasma levels within 1 week of the injection when combined with a single 30 mg oral dose, and is administered at the same time the maintenance AL injection is given. Aristada lauroxil nanocrystal suspension (Aristada Initio) was approved on June 29, 2018 for the treatment of adults with schizophrenia (Table 1). The approval of this initiation regimen was based on pharmacokinetic studies demonstrating comparable plasma aripiprazole levels to that which would be achieved when using 21 days of oral aripiprazole coverage.^3,4

Clinical implications

Nonadherence with oral antipsychotics is a common problem for patients with schizophrenia, one that is often underappreciated by clinicians.⁵ Whether one uses 70% or 80% as the measure of oral medication adherence, at least 50% of schizophrenia patients are nonadherent, with resultant increased risks for symptom exacerbation and hospitalization.^5,6 Although 2 LAI forms of aripiprazole have been introduced over the past few years, neither was designed to be loaded, resulting in the need for 2 or 3 weeks of oral antipsychotic coverage following the first injectable dose.¹ The primary reason for LAI antipsychotic therapy is oral medication nonadherence, and thus the need for 14 to 21 days of oral coverage at the outset of treatment creates a risk for symptom exacerbation if the patient is nonadherent with this oral bridging therapy which is needed to achieve the necessary serum concentrations until the long-acting formulation takes over.

One approach was to create a new form of AL using smaller nanomolecular particles rather than the micron-sized particles used for maintenance AL injections.^3,4 This nanocrystal suspension is called Aristada Initio (ALncd) and has a median T_max that ranges from 16 to 35 days, compared with 41 days for single-dose injections of AL. ALncd also has a much shorter median half-life of 15 to 18 days, compared with 53.9 to 57.2 days for AL (Table 2^7,8). Utilizing these kinetic differences, a 1-day initiation regimen was developed to dispense with the need for 3 weeks of oral medication coverage when commencing AL treatment.^3,4 In lieu of 3 weeks of oral coverage starting at the time of the first AL injection, patients instead will receive an injection of ALncd 675 mg, and a single oral 30 mg aripiprazole dose. The combination of ALncd and the single 30 mg oral dose when added to the initial AL injection provides aripiprazole levels in the first weeks of therapy that are comparable to those seen in the previous paradigm, when patients took 21 days of oral aripiprazole after the first AL injection.³

Use in adults with schizophrenia. After establishing tolerability with oral aripiprazole, ALncd675 mg is administered as an IM injection by a health care professional, and the patient is concomitantly given a single 30 mg oral dose of aripiprazole. Only one dosage form of ALncd is available: 675 mg. The maintenance AL dose chosen by the clinician (441, 662, 882, or 1,064 mg) is also administered at the same time, but must be injected in the other deltoid or gluteal muscle. The injection volume for ALncd is 2.4 mL and can be administered in the deltoid or gluteus muscle.⁹ If the patient prefers not to have 2 injections on the same day, the AL dose can be administered up to 10 days thereafter.⁹ This 10-day window for administering AL relates to the long time to maximum plasma levels from single AL injections. The relevant drug levels during the first weeks are provided predominantly from the initiation regimen of ALncd injection plus the single 30 mg oral dose.³ In instances when a patient agrees to receive both ALncd and AL injections but refuses the 30 mg oral dose, effective plasma levels will be seen in the middle of the second week of therapy.

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Aripiprazole lauroxil nanocrystal suspension

References

Clinical implications

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