Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This study, which is the first to evaluate cariprazine in pediatric patients with autism spectrum disorder (ASD) (including children 5-9 years of age) using an oral solution formulation, evaluated the safety, tolerability, pharmacokinetics (PK), and exploratory efficacy of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Methods: This clinical pharmacology, open-label, multiple-dose study enrolled 25 pediatric patients from 5 to 17 years of age, who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for ASD. All patients began treatment with cariprazine 0.5 mg once daily (QD) and underwent a titration over 7 days to maintenance doses of 1.5 or 3 mg QD for patients 13-17 years of age at Screening, 0.75 or 1.5 mg QD for patients 10-12 years of age at Screening, and 0.5 or 1.5 mg QD for patients 5-9 years of age at Screening. After 6 weeks total of dosing, there was a 6-week follow-up period. Study assessments included adverse events (AEs), safety parameters, noncompartmental PK parameters, and exploratory efficacy assessments, including the Aberrant Behavior Checklist-Irritability Subscale (ABC-I), Clinical Global Impressions (CGI-S), Caregiver Global Impressions (CgGI-S), Children's Yale-Brown Obsessive Compulsiveness Scale Modified for ASD (CYBOCS-ASD), Social Responsiveness Scale (SRS), and Vineland Adaptive Behavior Scale (VABS-III). Results: All AEs were mild or moderate in severity. Most frequent treatment-emergent adverse events (TEAEs) were increased weight, increased alanine aminotransferase, increased appetite, dizziness, agitation, and nasal congestion. Increases in weight were not considered clinically meaningful. Two subjects reported extrapyramidal symptom-related TEAEs that resolved without leading to discontinuation. Dose-normalized exposures of all analytes were modestly higher in pediatric patients from 5 to 9 years of age when compared to older patients. Consistent with previous studies, at steady state, the rank of exposure in plasma was DDCAR > cariprazine > DCAR. There was numerical improvement on all exploratory endpoints (ABC-I, CGI-S, CgGI-S, CYBOCS-ASD, SRS, and VABS-III). Conclusions: PK of cariprazine and its metabolites were characterized in pediatric patients with ASD at doses up to 3 mg QD (13-17 years) and 1.5 mg QD (5-12 years). Caripazine treatment was generally well tolerated and results from this study will inform the selection of appropriate pediatric doses for subsequent studies.

中文翻译：

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卡利拉嗪治疗自闭症谱系障碍儿科患者：药代动力学、安全性和耐受性研究的结果。

目的：卡利拉嗪是一种多巴胺 D3 优先的 D3/D2 和血清素 5-HT1A 受体部分激动剂，被批准用于治疗成人精神分裂症和与 I 型双相情感障碍相关的躁狂/混合或抑郁发作。这项研究是第一个使用口服溶液制剂评估卡利拉嗪用于自闭症谱系障碍 (ASD) 儿科患者（包括 5-9 岁儿童）的研究，评估了卡利拉嗪的安全性、耐受性、药代动力学 (PK) 和探索性疗效卡利拉嗪及其两种主要活性代谢物去甲基卡利拉嗪 (DCAR) 和双去甲基卡利拉嗪 (DDCAR)。方法：这项临床药理学、开放标签、多剂量研究招募了 25 名 5 至 17 岁的儿科患者，这些患者符合《精神疾病诊断和统计手册》第五版 ASD 标准。所有患者均开始使用卡利拉嗪 0.5 mg 每日一次 (QD) 治疗，并在 7 天内滴定至维持剂量（筛选时 13-17 岁的患者为 1.5 或 3 mg QD），10-12 岁的患者为 0.75 或 1.5 mg QD。筛查时年龄为 5-9 岁的患者每日一次 0.5 或 1.5 mg。总共给药 6 周后，有 6 周的随访期。研究评估包括不良事件 (AE)、安全性参数、非房室 PK 参数和探索性疗效评估，包括异常行为检查表-易激惹分量表 (ABC-I)、临床总体印象 (CGI-S)、护理人员总体印象 (CgGI- S)、儿童耶鲁布朗自闭症谱系障碍强迫量表 (CYBOCS-ASD)、社会反应量表 (SRS) 和瓦恩兰适应行为量表 (VABS-III)。结果：所有 AE 的严重程度均为轻度或中度。最常见的治疗中出现的不良事件（TEAE）是体重增加、丙氨酸转氨酶升高、食欲增加、头晕、烦躁和鼻塞。体重增加不被认为具有临床意义。两名受试者报告了与锥体外系症状相关的 TEAE，这些症状在未导致停药的情况下得到了缓解。与老年患者相比，5 至 9 岁儿童患者中所有分析物的剂量标准化暴露量略高。与之前的研究一致，在稳态时，血浆中暴露的顺序为DDCAR>卡利拉嗪>DCAR。所有探索性终点（ABC-I、CGI-S、CgGI-S、CYBOCS-ASD、SRS 和 VABS-III）均有数值改善。结论：卡利拉嗪及其代谢物在 ASD 儿童患者中的 PK 剂量高达 3 mg QD（13-17 岁）和 1.5 mg QD（5-12 岁）。卡帕嗪治疗通常具有良好的耐受性，本研究的结果将为后续研究选择适当的儿科剂量提供信息。