Research and Development Directorate, Gedeon Richter Plc, Budapest, Hungary.
Clin Pharmacokinet. 2024 Oct;63(10):1501-1510. doi: 10.1007/s40262-024-01431-x. Epub 2024 Oct 20.
Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6.
This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism.
Forty-two patients received oral doses of 1.5 mg cariprazine alone for 28 days (to reach steady state), followed by a co-administration of cariprazine 1.5 mg daily with erythromycin 500 mg twice daily (BID) and Enterol 250 mg BID for 21 days, followed by a 14-day post-treatment period. Blood samples were collected at predefined time points and analysed for cariprazine, its two active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and erythromycin using validated high performance liquid chromatography-tandem mass spectrometry methods. CYP2D6 phenotypes were determined by genotyping. The pharmacokinetic parameters were calculated using non-compartmental analysis.
Erythromycin increased the area under the curve (AUC) and peak concentration (C) of Total cariprazine (cariprazine + DCAR + DDCAR) by about 40-50% but did not affect the time to peak concentration (T). The CYP2D6 phenotypes had no substantial effect on the pharmacokinetics of cariprazine and its metabolites, either alone or in combination with erythromycin. Cariprazine was well tolerated and safe.
The findings suggest that co-administration of cariprazine with moderate CYP3A4 inhibitors may require dose adjustment or monitoring; however, pharmacogenetic testing for CYP2D6 is not necessary for optimising cariprazine therapy.
Trial registration number (EudraCT Number): 2018-003721-28. Date of registration: 21-SEP-2018.
卡利培嗪主要通过 CYP3A4 代谢，其次是 CYP2D6。
本研究旨在评估红霉素（一种中度细胞色素 P450（CYP）3A4 抑制剂）对男性精神分裂症患者卡利培嗪药代动力学的影响，并评估 CYP2D6 表型对卡利培嗪代谢的影响。
42 例患者连续 28 天单独口服 1.5 mg 卡利培嗪（达到稳态），然后每天口服 1.5 mg 卡利培嗪，同时每日口服红霉素 500 mg 两次（BID）和 Enterol 250 mg BID 共 21 天，然后进行 14 天的治疗后随访。在预设时间点采集血样，采用经验证的高效液相色谱-串联质谱法分析卡利培嗪及其两种活性代谢物：去甲卡利培嗪（DCAR）和二去甲卡利培嗪（DDCAR）以及红霉素的浓度。采用基因分型法确定 CYP2D6 表型。采用非房室模型分析法计算药代动力学参数。
红霉素使总卡利培嗪（卡利培嗪+DCAR+DDCAR）的 AUC 和 C 增加了约 40-50%，但不影响达峰时间（T）。CYP2D6 表型对卡利培嗪及其代谢物的药代动力学单独或与红霉素联合使用均无显著影响。卡利培嗪具有良好的耐受性和安全性。
这些发现表明，卡利培嗪与中度 CYP3A4 抑制剂联合使用可能需要调整剂量或监测；然而，对于优化卡利培嗪治疗，CYP2D6 的药物遗传学检测并非必要。
试验注册号（EudraCT 编号）：2018-003721-28。注册日期：2018 年 9 月 21 日。
