Out of the Pipeline Aripiprazole lauroxil nanocrystal suspension Jonathan M. Meyer, MD New long- ong-acting injectable (LAI) antipsychot- Table 1 acting injectable ics were developed due to the pervasive Fast facts about aripiprazole formulation Lproblem of oral medication nonad- lauroxil nanocrystal suspension herence among patients with severe mental simplifies the Brand name: Aristada Initio illnesses. While use of LAI antipsychotics initiation regimen reduces hospitalization rates, one issue in Class: Long-acting injectable atypical antipsychotic (aripiprazole) transitioning patients to certain LAI prepa- Indication: Adults with schizophrenia rations is the need for prolonged oral cover- Approval date: June 29, 2018 age when beginning treatment with agents that cannot be loaded.1,2 Nonadherence with Availability date: August 1, 2018 this bridging oral therapy places the patient Manufacturer: Alkermes, Inc., Waltham, MA at risk for symptom exacerbation until effec- Dosing forms: 675 mg IM injection tive antipsychotic plasma levels are achieved Recommended dosage for schizophrenia: 1 After establishing oral aripiprazole tolerability, from the LAI. To obviate the need for 3 weeks administer 675 mg IM along with a single of oral medication coverage when commenc- 30 mg oral aripiprazole dose at the time of ing treatment with aripiprazole lauroxil (AL; initiating aripiprazole lauroxil maintenance treatment. The maintenance dose of Aristada), a new LAI form of AL was devel- aripiprazole lauroxil should be given at the oped utilizing smaller nanomolecular-sized same time as aripiprazole lauroxil nanocrystal, particles. The nanocrystal suspension has a but can be given up to 10 days thereafter. Aripiprazole lauroxil nanocrystal also can be shorter Tmax and much shorter half-life than administered with the maintenance aripiprazole AL, provides effective plasma levels within lauroxil injection when resuming treatment in patients who meet the missed dose guidelines 1 week of the injection when combined with for supplemental medication coverage a single 30 mg oral dose, and is administered at the same time the maintenance AL injec- tion is given. Aristada lauroxil nanocrystal suspension (Aristada Initio) was approved by clinicians.5 Whether one uses 70% or on June 29, 2018 for the treatment of adults 80% as the measure of oral medication with schizophrenia (Table 1). The approval adherence, at least 50% of schizophrenia of this initiation regimen was based on phar- patients are nonadherent, with resultant macokinetic studies demonstrating com- increased risks for symptom exacerbation Discuss this article at parable plasma aripiprazole levels to that Dr. Meyer is a Psychopharmacology Consultant, California Department www.facebook.com/ which would be achieved when using 21 of State Hospitals, Sacramento, California; Clinical Professor of MDedgePsychiatry days of oral aripiprazole coverage.3,4 Psychiatry, University of California, San Diego, La Jolla, California; and Deputy Editor of CURRENT PSYCHIATRY. Disclosure Clinical implications Dr. Meyer is a consultant to Acadia Pharmaceuticals, Alkermes, Nonadherence with oral antipsychotics is a Allergan, Neurocrine, and Teva Pharmaceutical Industries, and a speaker for Acadia Pharmaceuticals, Alkermes, Allergan, Merck, common problem for patients with schizo- Current Psychiatry Neurocrine, Otsuka America, Inc., Sunovion Pharmaceuticals, and Teva 34 November 2018 phrenia, one that is often underappreciated Pharmaceutical Industries. Out of the Pipeline Table 2 Aripiprazole lauroxil nanocrystal suspension: Basic kinetic information Factor Description Bioavailability 100% Half-life 15 to 18 days Administration Once Dosage None. As only one dosage form is available, the package insert contains cautionary adjustments language regarding situations with less-than-expected drug exposure (use of CYP3A4 inducers), more-than-expected drug exposure (strong CYP3A4 or 2D6 inhibitors or known 2D6 poor metabolizers), or increased pharmacodynamic effects (concurrent use of antihypertensives or benzodiazepines) Source: References 7,8 Clinical Point This 1-day initiation regimen dispenses and hospitalization.5,6 Although 2 LAI AL injection, patients instead will receive with the need for forms of aripiprazole have been intro- an injection of ALncd 675 mg, and a single 3 weeks of oral duced over the past few years, neither oral 30 mg aripiprazole dose. The combi- coverage when was designed to be loaded, resulting in nation of ALncd and the single 30 mg oral starting aripiprazole the need for 2 or 3 weeks of oral antipsy- dose when added to the initial AL injection chotic coverage following the first inject- provides aripiprazole levels in the first lauroxil able dose.1 The primary reason for LAI weeks of therapy that are comparable to antipsychotic therapy is oral medication those seen in the previous paradigm, when nonadherence, and thus the need for 14 patients took 21 days of oral aripiprazole to 21 days of oral coverage at the outset of after the first AL injection.3 treatment creates a risk for symptom exac- erbation if the patient is nonadherent with Use in adults with schizophrenia. After this oral bridging therapy which is needed establishing tolerability with oral aripip- to achieve the necessary serum concen- razole, ALncd 675 mg is administered as trations until the long-acting formulation an IM injection by a health care profes- takes over. sional, and the patient is concomitantly One approach was to create a new form given a single 30 mg oral dose of aripip- of AL using smaller nanomolecular parti- razole. Only one dosage form of ALncd cles rather than the micron-sized particles is available: 675 mg. The maintenance used for maintenance AL injections.3,4 This AL dose chosen by the clinician (441, 662, nanocrystal suspension is called Aristada 882, or 1,064 mg) is also administered at Initio (ALncd) and has a median Tmax that the same time, but must be injected in the ranges from 16 to 35 days, compared with other deltoid or gluteal muscle. The injec- 41 days for single-dose injections of AL. tion volume for ALncd is 2.4 mL and can ALncd also has a much shorter median be administered in the deltoid or gluteus half-life of 15 to 18 days, compared muscle.9 If the patient prefers not to have with 53.9 to 57.2 days for AL (Table 27,8). 2 injections on the same day, the AL dose Utilizing these kinetic differences, a 1-day can be administered up to 10 days thereaf- initiation regimen was developed to dis- ter.9 This 10-day window for administering pense with the need for 3 weeks of oral AL relates to the long time to maximum medication coverage when commencing plasma levels from single AL injections. AL treatment.3,4 In lieu of 3 weeks of oral The relevant drug levels during the first Current Psychiatry coverage starting at the time of the first weeks are provided predominantly from Vol. 17, No. 11 35 Out of the Pipeline Figure 1 Comparison of mean plasma aripiprazole levels when 441 mg IM aripiprazole lauroxil is initiated with 21 days of oral aripiprazole coverage (15 mg/d) or 675 mg IM aripiprazole lauroxil nanocrystal suspension plus a single 30 mg oral aripiprazole dose 300 AL 441 mg/1-day initiation (N = 39) AL 441 mg/21-day initiation (N = 40) 200 Clinical Point The maintenance 100 AL dose is given at Concentration (ng/mL) the same time as the new nanocrystal 0 suspension 0246810121416182022242628 Sampling time (days) formulation, plus a Single 30 mg oral aripiprazole dose (Day 1) Last dose of 15 mg oral aripiprazole dose 1-day initiation regimen group 21-day initiation regimen group 30 mg oral dose Source: Adapted from reference 4 the initiation regimen of ALncd injec- mg: 11%; 882 mg: 11%; placebo: 4%).10 Only tion plus the single 30 mg oral dose.3 In 2 of 415 AL-treated patients discontinued instances when a patient agrees to receive the study due to akathisia. Injection-site both ALncd and AL injections but refuses reactions were reported by 4%, 5%, and the 30 mg oral dose, effective plasma lev- 2% of patients treated with AL 441 mg, AL els will be seen in the middle of the second 882 mg, and placebo, respectively. Most of week of therapy. these were injection-site pain associated with the first injection, and decreased with Pharmacologic profile, adverse each subsequent injection. Other injection- reactions site reactions (induration, swelling, and Aripiprazole is a dopamine partial agonist redness) occurred at rates <1%.11 atypical antipsychotic that has been com- Having established that the range of mercially available in the United States plasma aripiprazole levels consistent with since November 15, 2002, and its adverse effective treatment is bounded by levels effect profile is well characterized. The LAI seen with AL 441 mg or 882 mg monthly, formulation AL was approved on October the FDA did not require additional effi- 5, 2015. In the pivotal, 12-week, fixed-dose, cacy studies for new AL doses provided placebo-controlled clinical trial of AL 441 that pharmacokinetic (PK) studies could mg or 882 mg monthly for adults with an demonstrate levels within the effec- acute exacerbation of schizophrenia, the tive range. This is consistent with how only adverse effect that occurred in ≥5% new doses of other LAI antipsychotic of AL-treated patients and a rate at least preparations have been addressed in the Current Psychiatry 36 November 2018 twice that of placebo was akathisia (441 past. For example, the 37.5 mg dose of continued on page 38 Out of the Pipeline continued from page 36 Figure