Aripiprazole lauroxil nanocrystal suspension
Current Psychiatry. 2018 November;17(11):34-36,38-40
Author and Disclosure Information
Dr. Meyer is a Psychopharmacology Consultant, California Department of State Hospitals, Sacramento, California; Clinical Professor of Psychiatry, University of California, San Diego, La Jolla, California; and Deputy Editor of Current Psychiatry.
Dr. Meyer is a consultant to Acadia Pharmaceuticals, Alkermes, Allergan, Neurocrine, and Teva Pharmaceutical Industries, and a speaker for Acadia Pharmaceuticals, Alkermes, Allergan, Merck, Neurocrine, Otsuka America, Inc., Sunovion Pharmaceuticals, and Teva Pharmaceutical Industries.
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.
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.
Pharmacologic profile, adverse reactions
Aripiprazole is a dopamine partial agonist atypical antipsychotic that has been commercially available in the United States since November 15, 2002, and its adverse effect profile is well characterized. The LAI formulation AL was approved on October 5, 2015. In the pivotal, 12-week, fixed-dose, placebo-controlled clinical trial of AL 441 mg or 882 mg monthly for adults with an acute exacerbation of schizophrenia, the only adverse effect that occurred in ≥5% of AL-treated patients and a rate at least twice that of placebo was akathisia (441 mg: 11%; 882 mg: 11%; placebo: 4%).10 Only 2 of 415 AL-treated patients discontinued the study due to akathisia. Injection-site reactions were reported by 4%, 5%, and 2% of patients treated with AL 441 mg, AL 882 mg, and placebo, respectively. Most of these were injection-site pain associated with the first injection, and decreased with each subsequent injection. Other injection-site reactions (induration, swelling, and redness) occurred at rates <1%.11
Having established that the range of plasma aripiprazole levels consistent with effective treatment is bounded by levels seen with AL 441 mg or 882 mg monthly, the FDA did not require additional efficacy studies for new AL doses provided that pharmacokinetic (PK) studies could demonstrate levels within the effective range. This is consistent with how new doses of other LAI antipsychotic preparations have been addressed in the past. For example, the 37.5 mg dose of risperidone microspheres was approved based on PK data, although the pivotal efficacy trials included doses of 25 mg, 50 mg, and 75 mg.12 Based on PK studies, AL doses of 662 mg monthly, 882 mg every 6 weeks, and 1,064 mg every 8 weeks were previously approved.13 The approval process for ALncd followed a similar pathway, and is based on PK results combined with tolerability data amassed during the PK studies. The package insert thus notes that in PK studies the safety profile of ALncd was generally consistent with that observed for AL (see Tolerability).
Pharmacokinetic outcomes. A comparative phase 1 PK study was performed to evaluate initiation regimens: either 21 days of oral aripiprazole (15 mg/d) and one AL dose (n = 81) or one injection of ALncd plus a single dose of 30 mg oral aripiprazole and one AL dose (n = 80). Patients were randomized 1:1:1:1 to receive an AL dose of either 441 mg or 882 mg combined with the oral or the new ALncdinitiation regimen. As shown in Figure 1 and Figure 2, the mean plasma levels seen with 675 mg IM ALncd plus a single dose of 30 mg oral aripiprazole were comparable with levels achieved using 21 days of oral aripiprazole coverage, regardless of whether the regimen was paired with a maintenance AL dose of 441 mg or 882 mg.4
Tolerability. In PK studies, the safety profile and incidences of injection site reactions of ALncd were generally consistent with those observed for aripiprazole lauroxil.9 In the phase I PK study comparing oral initiation with ALncd plus a single 30 mg oral aripiprazole dose, there were 2 mild cases of akathisia in the 21-day oral aripiprazole groups (n = 81) and 4 cases in the ALncd groups (n = 80) (3 mild cases, 1 moderate case). None of the adverse events related to akathisia were deemed serious, and no patients discontinued participation in the trial due to akathisia.9
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