Background

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.

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

Registration

Clinicaltrials.gov: NCT02320032

中文翻译：

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长效可注射抗精神病药阿立哌唑月桂醇的 2 个月剂量间隔方案的药代动力学、安全性和耐受性：44 周 I 期研究的结果。

背景

阿立哌唑月桂醇 (AL) 是一种长效注射用抗精神病药，被批准用于治疗成人精神分裂症。批准的 AL 剂量和给药方案包括每月 441 毫克、每月 662 毫克和每月 882 毫克或每 6 周（q6wk），以及最近批准的剂量 1064 毫克，每 2 个月给药一次。

客观的

将剂量间隔为每 2 个月 (1064 mg) 的 AL 方案的药代动力学、安全性和耐受性与其他两种可作为每月和每 6 周选项的方案进行比较。

方法

本研究评估了以比先前研究更高的剂量强度 (1064 mg) 和更长的剂量间隔（每 8 周 [q8wk]）给药的 AL 的药代动力学。进入这项为期 44 周、I 期、开放标签、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，并在整个研究过程中一直服用其他口服抗精神病药。患者被随机分配至 3 种 AL 剂量方案之一，持续 24 周（4 次 1064 毫克注射 [q8wk]、5 次 882 毫克注射 [q6wk] 或 7 次 441 毫克注射 [q4wk]，最后一次 AL 暴露在第 24 周） ）。禁止口服阿立哌唑。对患者进行了另外 20 周的随访，以评估阿立哌唑的终末血浆浓度和持续的安全性。

结果

符合条件的患者接受 AL 1064 mg q8wk ( n  = 35)、882 mg q6wk ( n  = 34) 或 441 mg q4wk ( n = 35）。总体而言，103/104 (99.0%) 患者在研究期间同时服用非阿立哌唑口服抗精神病药物。所有三种 AL 剂量方案均提供持续暴露于阿立哌唑。1064 mg q8wk 方案的平均阿立哌唑浓度与 882 mg q6wk 方案相当，高于 441 mg q4wk 方案。整个研究期间任何不良事件 (AE) 的组的总体发生率为 68.6%（1064 毫克每 8 周）、50.0%（882 毫克每 6 周）和 65.7%（441 毫克每 4 周）。各种方案中最常见的 AE 是注射部位疼痛（范围 8.6%–11.4%）。8 名患者报告了严重的 AE（除 1 名外 [1 名患者的精神病增加，441 毫克 q4wk 组] 被认为与研究药物无关）。接受 8 周、6 周和 4 周治疗方案的患者中，报告因 AE 停药的比例分别为 2.9%、11.8% 和 5.7%，分别。静坐不能、运动障碍和肌张力障碍 AE 分别发生在 1064 毫克 q8wk 组的 2.9%、8.6% 和 5.7%，882mg q6wk 组的 8.8%、0% 和 2.9% 和 8.6%， 441 毫克 q4wk 组分别为 0% 和 0%。

结论

AL 1064 mg q8wk 在整个 8 周给药间隔期间持续暴露于阿立哌唑，其安全性与 4 周和 6 周方案一致。这些发现用于支持 FDA 批准每 2 个月给药 1064 毫克的剂量。

登记

Clinicaltrials.gov：NCT02320032