Clozapine Drug–Drug Interactions and Individualized Dosing in Bipolar Disorder: A Model-Informed Precision Dosing Approach

Yue Zhang,1,* Jie Wang,1,* Xue Tian,1,* Yi-Jia Zhang,1,* Ye Li,1,* Su-Mei He,2 Cun Zhang,3 Xiao Chen,4 Dong-Dong Wang1 1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy and School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 2Department of Pharmacy, Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu, 215153, People’s Republic of China; 3Department of Pharmacy, Xuzhou Oriental Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 4School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Su-Mei He, Department of Pharmacy, Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu, 215153, People’s Republic of China, Email [email protected] Dong-Dong Wang, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy and School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China, Email [email protected]: Clozapine is an effective treatment for bipolar disorder (BD), but its clinical use is complicated by drug–drug interactions (DDI), which may reduce efficacy or increase toxicity. This study aims to explore clozapine DDI and its individualized administration regimens for patients with BD based on model-informed precision dosing (MIPD) technology, and achieve clinical precision medication.Methods: Data are collected from 51 patients with BD treated with clozapine, including all concomitant medications used in clinical practice. The MIPD technique is used to explore the potential DDI, and the Monte Carlo simulation is adopted to recommend the optimal administration regimen.Results: It is ultimately found that zopiclone, zolpidem tartrate with clozapine have DDI. When patients with BD have no combined medication of zopiclone or zolpidem tartrate, the recommended doses of clozapine for patients at 40– 45 kg, 45– 60 kg, 60– 78 kg, 78– 106 kg, and 106– 120 kg are 10 mg/kg/day, 9 mg/kg/day, 8 mg/kg/day, 7 mg/kg/day, and 6 mg/kg/day, respectively. When patients with BD are combined with zopiclone, the recommended doses of clozapine for patients at 40– 60 kg and 60– 120 kg are 4 mg/kg/day and 3 mg/kg/day, respectively. When patients with BD are combined with zolpidem tartrate, the recommended doses of clozapine for patients at 40– 52 kg and 52– 120 kg are 5 mg/kg/day and 4 mg/kg/day, respectively.Conclusion: This study explores the DDI of clozapine in patients with BD based on MIPD, and recommends the individualized dosing regimen of clozapine in patients with BD according to concomitant medication. These findings provide weight- and drug-specific dosing recommendations that may improve the safety and efficacy of clozapine in BD patients. Keywords: clozapine, bipolar disorder, drug–drug interactions, zopiclone, zolpidem tartrate