Drug–Drug Interactions and Individualized Clozapine Therapy in Patients with Depression: Insights from Real-World Data

Lei Jiang,1 Yue Zhang,2 Jie Wang,2 Cun Zhang,3 Dongdong Wang2 1Department of Pharmacy, Taixing Clinical College of Xuzhou Medical University, Taixing, Jiangsu, 225400, People’s Republic of China; 2Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 3Department of Pharmacy, Xuzhou Oriental Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of ChinaCorrespondence: Lei Jiang, Department of Pharmacy, Taixing Clinical College of Xuzhou Medical University, Taixing, Jiangsu, 225400, People’s Republic of China, Email [email protected]: 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.Methods: 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.Results: 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.Conclusion: 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. Keywords: drug–drug interactions, individualized therapy, clozapine, depression, real-world