Alkermes, Inc., Waltham, MA, USA.
Karuna Therapeutics, 33 Arch Street, Suite 3110, Boston, MA, 02110, USA.
CNS Drugs. 2020 Sep;34(9):961-972. doi: 10.1007/s40263-020-00745-1.
Aripiprazole lauroxil (AL) is a long-acting injectable antipsychotic approved for treatment of schizophrenia in adults. Approved AL doses and dosing regimens include 441 mg monthly, 662 mg monthly, and 882 mg monthly or every 6 weeks (q6wk), as well as the most recently approved dose, 1064 mg, administered every 2 months.
Pharmacokinetics, safety, and tolerability of an AL regimen with a dose interval of every 2 months (1064 mg) were compared with two other regimens available as monthly and q6wk options.
This study evaluated pharmacokinetics of AL given at a higher dosage strength (1064 mg) and at a longer dose interval (every 8 weeks [q8wk]) than previously studied. Patients with schizophrenia or schizoaffective disorder entering this 44-week, phase I, open-label, multicenter study had no recent exposure to aripiprazole and were maintained on other oral antipsychotics throughout the study. Patients were randomized to one of three AL dose regimens for 24 weeks (four 1064-mg injections [q8wk], five 882-mg injections [q6wk], or seven 441-mg injections [q4wk], with the last AL exposure at week 24). Oral aripiprazole was prohibited. Patients were followed for an additional 20 weeks to assess terminal aripiprazole plasma concentrations and ongoing safety. Plasma concentration samples were obtained at regular intervals to provide pharmacokinetic data for the duration of AL exposure and to measure persistence of plasma aripiprazole concentrations after AL discontinuation.
Eligible patients received AL 1064 mg q8wk (n = 35), 882 mg q6wk (n = 34), or 441 mg q4wk (n = 35). Overall, 103/104 (99.0%) patients were taking concomitant non-aripiprazole oral antipsychotic medications during the study. All three AL dose regimens provided continuous exposure to aripiprazole. Mean aripiprazole concentrations from the 1064-mg q8wk regimen were comparable to the 882-mg q6wk regimen and higher than the 441-mg q4wk regimen. Overall incidence by group of any adverse events (AEs) throughout the study was 68.6% (1064 mg q8wk), 50.0% (882 mg q6wk), and 65.7% (441 mg q4wk). The most common AE across regimens was injection-site pain (range 8.6%-11.4%). Serious AEs were reported by eight patients (all but one [increased psychosis in one patient, 441-mg q4wk group] considered unrelated to study drug). Discontinuations due to AEs were reported for 2.9%, 11.8%, and 5.7% of patients receiving the 8-, 6-, and 4-week regimens, respectively. AEs of akathisia, dyskinesia, and dystonia occurred in 2.9%, 8.6%, and 5.7% of patients in the 1064-mg q8wk group, 8.8%, 0%, and 2.9% in the 882-mg q6wk group, and 8.6%, 0%, and 0% in the 441-mg q4wk group, respectively.
AL 1064 mg q8wk provided continuous exposure to aripiprazole throughout the 8-week dosing interval and had a safety profile consistent with the 4- and 6-week regimens. These findings were used to support FDA approval of the 1064-mg dose administered every 2 months.
Clinicaltrials.gov: NCT02320032.
阿立哌唑月桂酸酯（AL）是一种长效注射用抗精神病药，适用于成人精神分裂症的治疗。已批准的 AL 剂量和给药方案包括每月 441mg、662mg 和 882mg，或每 6 周（q6wk）一次，以及最近批准的每 2 个月（q2mo）一次的 1064mg 剂量。
比较每月和每 6 周（q6wk）的两种方案，评估每 2 个月（1064mg）一次的 AL 方案的药代动力学、安全性和耐受性。
本研究评估了 AL 的药代动力学，AL 的剂量强度较高（1064mg），剂量间隔较长（每 8 周[q8wk]），与之前研究的结果不同。进入这项 44 周、1 期、开放性、多中心研究的精神分裂症或分裂情感障碍患者最近没有接触过阿立哌唑，整个研究期间都在服用其他口服抗精神病药物。患者被随机分配到三种 AL 剂量方案中的一种，持续 24 周（四次 1064mg 注射[q8wk]，五次 882mg 注射[q6wk]，或七次 441mg 注射[q4wk]，最后一次 AL 暴露在第 24 周）。禁止口服阿立哌唑。患者在额外的 20 周内接受随访，以评估终末阿立哌唑血浆浓度和持续安全性。定期采集血样以提供 AL 暴露期间的药代动力学数据，并测量 AL 停药后阿立哌唑血浆浓度的持续时间。
符合条件的患者接受 AL 1064mg q8wk（n=35）、882mg q6wk（n=34）或 441mg q4wk（n=35）。总体而言，103/104（99.0%）名患者在研究期间同时服用非阿立哌唑的口服抗精神病药物。所有三种 AL 剂量方案均提供了阿立哌唑的持续暴露。1064mg q8wk 方案的平均阿立哌唑浓度与 882mg q6wk 方案相当，高于 441mg q4wk 方案。整个研究期间，各组的任何不良事件（AE）的总发生率为 68.6%（1064mg q8wk）、50.0%（882mg q6wk）和 65.7%（441mg q4wk）。最常见的 AE 是注射部位疼痛（8.6%-11.4%）。8 名患者报告了严重不良事件（除了 1 名患者（441mg q4wk 组，1 名患者的精神病恶化）外，均认为与研究药物无关）。因 AE 而停药的分别占 2.9%、11.8%和 5.7%的患者。接受 8 周、6 周和 4 周方案的患者中，分别有 2.9%、8.6%和 5.7%的患者出现静坐不能、运动障碍和肌张力障碍的 AE，882mg q6wk 组分别有 8.6%、0%和 2.9%的患者出现运动障碍、肌张力障碍和运动障碍的 AE，441mg q4wk 组分别有 8.6%、0%和 0%的患者出现运动障碍、肌张力障碍和运动障碍的 AE。
AL 1064mg q8wk 整个 8 周给药间隔持续暴露于阿立哌唑，安全性与 4 周和 6 周方案一致。这些发现被用于支持 FDA 批准每 2 个月 1064mg 的剂量。
Clinicaltrials.gov：NCT02320032。
