Real-World Pharmacokinetic and ExposureResponse Characterization of Venetoclax in Chinese Patients with Hematological Malignancies

Zhirui Liu,1, Xin Liu,2, Qiang Gong,3, Shiwei Qin,1 Xiao Zhu,2,4 Isabelle Hui-San Kuan,5 Wen Yao Mak,2 Xiaoqiang Xiang,2 Changsheng Jia,1 Qian Wang,1 Lin Cheng,1 Ling Li6,7 1Department of Pharmacy, the First Affiliated Hospital of Army Medical University, Chongqing, People’s Republic of China; 2Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Science, Fudan University, Shanghai, People’s Republic of China; 3Department of Hematology, the First Affiliated Hospital of Army Medical University, Chongqing, People’s Republic of China; 4State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers, Fudan University, Shanghai, People’s Republic of China; 5Momentum Metrix, San Francisco, CA, USA; 6Institute of Hepatobiliary Diseases of Zhongnan Hospital, Transplant Center of Wuhan University, Wuhan, People’s Republic of China; 7National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, People’s Republic of ChinaThese authors contributed equally to this workCorrespondence: Ling Li, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Wuhan, People’s Republic of China, Email zn000426@whu.edu.cn Lin Cheng, Department of Pharmacy, the First Affiliated Hospital of Army Medical University, Gaotanyan Street, Shapingba, Chongqing, People’s Republic of China, Email chenglin@tmmu.edu.cnIntroduction: Post-marketing evaluation of lower-dose regimens is critical for optimizing individualized oncology therapy. Venetoclax (VNX) is approved for the treatment of hematological malignancies at doses of ≥ 400 mg once daily following a ramp-up schedule. However, favorable clinical responses have been observed in Chinese patients receiving lower doses (≤ 200 mg/day), prompting further investigation.Methods: A prospective, non-interventional, real-world study was conducted in 76 Chinese patients, yielding 121 plasma samples. Published population pharmacokinetic (PopPK) models, primarily developed in Caucasian populations, were applied for external model-based comparisons of VNX exposure between Chinese patients and previously reported Caucasian populations. A new PopPK model was developed for the Chinese population, followed by exposure-response analysis to assess the relationship between VNX dose and therapeutic efficacy.Results: External model evaluation demonstrated higher VNX exposure in Chinese patients compared with Caucasian populations. The newly developed Chinese PopPK model estimated apparent clearance at 7.33 L/h, substantially lower than previously reported values in Caucasian patients (15– 19.54 L/h). Exposure–response analysis indicated that VNX at 200 mg/day achieved optimal therapeutic efficacy in combination therapy, with minimal incremental benefit observed at higher doses.Conclusion: Significant ethnic differences in VNX pharmacokinetics were identified. These findings support the clinical effectiveness of lower-dose (200 mg/day) VNX-based regimens in Chinese patients and highlight the importance of population-specific dose optimization. Keywords: venetoclax, hematological malignancy, exposure-response, therapeutic drug monitoring