Clinical Pharmacology, BeiGene (USA), Inc., San Mateo, California, USA.
Pharmacometrics, Shanghai Qiangshi Information Technology Co., Ltd., Shanghai, China.
CPT Pharmacometrics Syst Pharmacol. 2023 Jan;12(1):95-109. doi: 10.1002/psp4.12880. Epub 2022 Nov 23.
Tislelizumab, a humanized immunoglobulin G4 monoclonal antibody, is a programmed cell death protein 1 (PD-1) inhibitor designed to minimize Fc gamma receptor binding on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The pharmacokinetic (PK) profile of tislelizumab was analyzed with population PK modeling using 14,473 observed serum concentration data points from 2596 cancer patients who received intravenous (i.v.) tislelizumab at 0.5-10 mg/kg every 2 weeks or every 3 weeks (q3w), or a 200 mg i.v. flat dose q3w in 12 clinical studies. Tislelizumab exhibited linear PK across the dose range tested. Baseline body weight, albumin, tumor size, tumor type, and presence of antidrug antibodies were identified as significant covariates on central clearance, whereas baseline body weight, sex, and age significantly affected central volume of distribution. Sensitivity analysis showed that these covariates did not have clinically relevant effects on tislelizumab PK. Other covariates evaluated, including race (Asian vs. White), lactate dehydrogenase, estimated glomerular filtration rate, renal function categories, hepatic function measures and categories, Eastern Cooperative Oncology Group performance status, therapy (monotherapy vs. combination therapy), and line of therapy did not show a statistically significant impact on tislelizumab PK. These results support the use of tislelizumab 200 mg i.v. q3w without dose adjustment in a variety of patient subpopulations.
替雷利珠单抗是一种人源化 IgG4 单克隆抗体，为程序性死亡受体 1（PD-1）抑制剂，旨在最大限度地减少巨噬细胞上 Fcγ 受体的结合，从而限制抗体依赖的吞噬作用，这是抗 PD-1 治疗产生耐药的潜在机制。采用群体药代动力学模型分析替雷利珠单抗的药代动力学（PK）特征，共纳入 2596 例接受替雷利珠单抗静脉输注（iv）治疗的癌症患者的 14473 个观察到的血清浓度数据点，剂量范围为 0.5-10 mg/kg，每 2 周或每 3 周（q3w）1 次，或在 12 项临床研究中每 3 周给予 200 mg 静脉推注固定剂量。结果显示，替雷利珠单抗在研究剂量范围内呈线性 PK 特征。基线体重、白蛋白、肿瘤大小、肿瘤类型和是否存在抗药物抗体被确定为中央清除率的显著协变量，而基线体重、性别和年龄则显著影响中央分布容积。敏感性分析表明，这些协变量对替雷利珠单抗 PK 无临床相关影响。评估的其他协变量包括种族（亚洲人 vs. 白人）、乳酸脱氢酶、估计肾小球滤过率、肾功能分类、肝功能测量和分类、东部肿瘤协作组体能状态、治疗方法（单药治疗 vs. 联合治疗）和治疗线数，对替雷利珠单抗 PK 无统计学显著影响。这些结果支持在各种患者亚群中使用替雷利珠单抗 200 mg 静脉推注，无需剂量调整。
