Jiang Lei, Zhang Yue, Wang Jie, Zhang Cun, Wang Dongdong
Department of Pharmacy, Taixing Clinical College of Xuzhou Medical University, Taixing, Jiangsu, 225400, People's Republic of China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China.
Drug Des Devel Ther. 2025 Nov 4;19:9809-9823. doi: 10.2147/DDDT.S547878. eCollection 2025.
Clozapine is widely used in patients with depression but its metabolism via multiple hepatic enzymes raises concerns about drug-drug interactions (DDIs). The extent of these interactions in real-world clinical settings remains unclear.
This research involved 29 patients with depression from the real world, utilizing their clozapine concentration data, physiological and biochemical data, and drug combination data to construct a DDI evaluation model using the population pharmacokinetics (PPK) method and NONMEM software.
The results of our research reveal that fluvoxamine maleate has a noteworthy DDI with clozapine, and fluvoxamine reduced clozapine clearance by 56.5%, necessitating substantial dose reductions. Furthermore, clozapine doses of 9 mg/kg, 8 mg/kg, 7 mg/kg and 6 mg/kg are recommended for 40-47 kg, 47-70 kg, 70-100 kg and 100-120 kg patients with depression not takingw fluvoxamine maleate, respectively. Clozapine doses of 3 mg/kg and 2 mg/kg are recommended for 40-70 kg and 70-120 kg patients with depression taking fluvoxamine maleate, respectively.
This study provides the first real-world evidence to guide safe and individualized clozapine dosing in patients with depression, particularly in the context of fluvoxamine co-administration. When patients with depression patient are treated with fluvoxamine maleate, the dosage of clozapine needs to be reduced.
氯氮平广泛用于抑郁症患者，但它通过多种肝脏酶进行代谢，这引发了人们对药物相互作用（DDIs）的担忧。在现实临床环境中，这些相互作用的程度仍不清楚。
本研究纳入了29名来自现实世界的抑郁症患者，利用他们的氯氮平浓度数据、生理和生化数据以及药物联合使用数据，采用群体药代动力学（PPK）方法和NONMEM软件构建药物相互作用评估模型。
我们的研究结果显示，马来酸氟伏沙明与氯氮平存在显著的药物相互作用，马来酸氟伏沙明使氯氮平清除率降低了56.5%，因此需要大幅降低剂量。此外，对于体重40 - 47千克、47 - 70千克、70 - 100千克和100 - 120千克且未服用马来酸氟伏沙明的抑郁症患者，建议的氯氮平剂量分别为9毫克/千克、8毫克/千克、7毫克/千克和6毫克/千克。对于体重40 - 70千克和70 - 120千克且服用马来酸氟伏沙明的抑郁症患者，建议的氯氮平剂量分别为3毫克/千克和2毫克/千克。
本研究提供了首个现实世界证据，以指导抑郁症患者安全、个体化地使用氯氮平，尤其是在联合使用氟伏沙明的情况下。当抑郁症患者接受马来酸氟伏沙明治疗时，需要降低氯氮平的剂量。
