Han Kelong, Peyret Thomas, Marchand Mathilde, Quartino Angelica, Gosselin Nathalie H, Girish Sandhya, Allison David E, Jin Jin
Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA, 19406, USA.
Cancer Chemother Pharmacol. 2016 Aug;78(2):341-51. doi: 10.1007/s00280-016-3079-6. Epub 2016 Jun 21.
Bevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics.
Rich and sparse bevacizumab serum concentrations were collected from Phase I through IV studies in early and metastatic cancers. Bevacizumab was given intravenously as single agent or in combination with chemotherapy for single- and multiple-dose schedules.
Model-building used 8943 bevacizumab concentrations from 1792 patients with colon/colorectal, non-small cell lung, kidney, pancreatic, breast, prostate and brain cancer. Bevacizumab doses ranged from 1 to 20 mg/kg given once every 1, 2 or 3 weeks. A two-compartment model best described the data. The population estimates of clearance (CL), central volume of distribution (V1) and half-life for a typical 70-kg patient were 9.01 mL/h, 2.88 L and 19.6 days. CL and V1 increased with body weight and were higher in males than females by 14 and 18 %, respectively. CL decreased with increasing albumin and decreasing alkaline phosphatase. The final model was externally validated using 1670 concentrations from 146 Japanese patients that were not used for model-building. Mean prediction errors were -2.1, 3.1 and 1.0 % for concentrations, CL and V1, respectively, confirming adequate predictive performance.
A robust bevacizumab pharmacokinetic model was developed and externally validated, which may be used to simulate bevacizumab exposure to optimize dosing strategies. Asian and non-Asian patients exhibited similar bevacizumab pharmacokinetics. Given the similarity in pharmacokinetics among monoclonal antibodies, this may inform pharmacokinetic studies in different ethnic groups for other therapeutic antibodies.
贝伐单抗已被批准用于多种癌症。本分析旨在全面评估贝伐单抗的药代动力学以及患者变量对贝伐单抗药代动力学的影响。
从I期至IV期研究中收集了早期和转移性癌症患者丰富和稀疏的贝伐单抗血清浓度数据。贝伐单抗作为单一药物静脉给药，或与化疗联合用于单剂量和多剂量方案。
模型构建使用了来自1792例结肠癌/结直肠癌、非小细胞肺癌、肾癌、胰腺癌、乳腺癌、前列腺癌和脑癌患者的8943个贝伐单抗浓度数据。贝伐单抗剂量范围为1至20mg/kg，每1、2或3周给药一次。二室模型最能描述这些数据。对于一名典型的70kg患者，清除率（CL）、中央分布容积（V1）和半衰期的群体估计值分别为9.01mL/h、2.88L和19.6天。CL和V1随体重增加而增加，男性比女性分别高14%和18%。CL随白蛋白增加和碱性磷酸酶降低而降低。最终模型使用146例日本患者的1670个未用于模型构建的浓度数据进行了外部验证。浓度、CL和V1的平均预测误差分别为-2.1%、3.1%和1.0%，证实了充分的预测性能。
建立了一个可靠的贝伐单抗药代动力学模型并进行了外部验证，该模型可用于模拟贝伐单抗暴露情况以优化给药策略。亚洲和非亚洲患者的贝伐单抗药代动力学相似。鉴于单克隆抗体药代动力学的相似性，这可能为其他治疗性抗体在不同种族群体中的药代动力学研究提供参考。
