Masuda Takashi, Funakoshi Taro, Horimatsu Takahiro, Masui Sho, Hira Daiki, Inoue Marin, Yajima Kodai, Nakagawa Shunsaku, Ikemi Yasuaki, Hamanishi Junzo, Takai Atsushi, Yamamoto Shinya, Matsubara Takeshi, Mandai Masaki, Seno Hiroshi, Yanagita Motoko, Muto Manabu, Terada Tomohiro, Yonezawa Atsushi
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Cancer Chemother Pharmacol. 2025 Mar 21;95(1):46. doi: 10.1007/s00280-025-04769-6.
Bevacizumab (BV) is an effective therapeutic antibody utilized in various cancers. Serum BV concentration can be a factor that potentially affects its therapeutic efficacy. Although proteinuria could affect BV pharmacokinetics, its influence was not evaluated in the previous population pharmacokinetic (PopPK) studies. Because BV can cause proteinuria as an adverse event, the present study aimed to develop a PopPK model in patients with proteinuria and to evaluate the influence of proteinuria on BV pharmacokinetics.
This prospective cohort study enrolled 70 Japanese cancer patients newly starting BV, and 368 concentration samples from these patients were analyzed. Serum BV concentrations were measured at several time points including at the onset of proteinuria. PopPK analysis was conducted using a non-linear mixed-effects modeling program. A two-compartment model was used to estimate total body clearance (CL).
Serum BV concentrations divided by the dose per body weight and dosing interval tended to be lower in patients with higher urinary protein to creatinine ratio (UPCR). The covariate analysis showed that increasing BV CL was associated with decreasing serum albumin concentration and increasing body weight and UPCR. The simulated median trough concentrations of BV in patients with Common Terminology Criteria for Adverse Events grades 1, 2, and 3 proteinuria were decreased by 12.0%, 20.6%, and 31.5%, respectively, compared to those in patients with grade 0.
We successfully established a PopPK model incorporating UPCR to predict serum BV concentrations in patients with proteinuria. Our study provides additional insights to better understand BV pharmacokinetics.
贝伐单抗（BV）是一种用于多种癌症的有效治疗性抗体。血清BV浓度可能是影响其治疗效果的一个因素。虽然蛋白尿可能影响BV的药代动力学，但在以往的群体药代动力学（PopPK）研究中并未评估其影响。由于BV可导致蛋白尿作为一种不良事件，本研究旨在建立蛋白尿患者的PopPK模型，并评估蛋白尿对BV药代动力学的影响。
这项前瞻性队列研究纳入了70名新开始使用BV的日本癌症患者，并分析了这些患者的368份血药浓度样本。在包括蛋白尿发作时的几个时间点测量血清BV浓度。使用非线性混合效应建模程序进行PopPK分析。采用二室模型估算总体清除率（CL）。
尿蛋白与肌酐比值（UPCR）较高的患者中，血清BV浓度除以体重和给药间隔后的数值往往较低。协变量分析表明，BV清除率增加与血清白蛋白浓度降低、体重增加和UPCR增加有关。与0级患者相比，不良事件通用术语标准1、2和3级蛋白尿患者的BV模拟中位谷浓度分别降低了12.0%、20.6%和31.5%。
我们成功建立了一个纳入UPCR的PopPK模型，以预测蛋白尿患者的血清BV浓度。我们的研究为更好地理解BV药代动力学提供了更多见解。
