Clinical pharmacokinetics of bevacizumab in patients with solid tumors
Clinical pharmacokinetics of bevacizumab in patients with solid tumors
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DOI：
10.1007/s00280-007-0664-8
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发表时间：
2008-10-01
影响因子：
3
通讯作者：
Gaudreault, Jacques
中科院分区：
文献类型：
--
作者：
Lu, Jian-Feng;Bruno, Rene;Gaudreault, Jacques
目的研究贝伐单抗的群体药代动力学特征，探讨人口学因素、疾病严重程度和合并化疗药物对其药代动力学行为的影响。采用非线性混合效应模型法（NONMEM.Results）分析了491例实体瘤患者的4，629个贝伐珠单抗浓度，这些患者接受的贝伐珠单抗剂量范围为1 ~ 20 mg/kg，给药频率范围为每周1次~每3周1次。在最终模型中，典型女性的估计清除率（CL）和中央室分布容积（V-c）分别为0.207 L/天和2.39 L。男性和女性的终末半衰期估计值均为20天。体重和性别是解释CL和V-c患者间变异性的最显著协变量。男性的清除率比女性快26%。低血清白蛋白和高血清碱性磷酸酶患者的CL分别比典型患者快19%和23%。与长消除半衰期一致，模拟显示，当维持每周mg/kg剂量率时，可以维持类似的稳态暴露，因此允许贝伐单抗的给药与细胞毒性药物的给药频率一致。结论PK参数与其他IgG分子一致。结果支持贝伐珠单抗每2周一次或每3周一次给药方案（以mg/kg计）。
Objective To characterize the population pharmacokinetics of bevacizumab and the influence of demographic factors, disease severity, and concomitantly used chemotherapy agents on it's pharmacokinetic behavior.Patients and methods Data from eight clinical trials with bevacizumab administered by intravenous infusion were included. A total of 4,629 bevacizumab concentrations from 491 patients with solid tumors, who received bevacizumab doses ranging from 1 to 20 mg/kg at a dosing frequency ranging from weekly to every 3 weeks, were analyzed using a nonlinear mixed-effects modeling approach (NONMEM).Results The best structural model was a two-compartment model with first-order elimination. In the final model, estimated clearance (CL) and central compartment volume of distribution (V-c) were 0.207 L/day and 2.39 L for a typical female. The terminal half-life estimate was similar to 20 days for both men and women. Body weight and gender were the most significant covariates to explain interpatient variability for CL and V-c. Clearance was 26% faster in men than in women. Patients with low serum albumin and high serum alkaline phosphatase had 19 and 23% faster CL, respectively, than a typical patient. Consistent with the long elimination half life, simulations showed that similar steady-state exposures can be maintained when the weekly mg/kg dose rate is maintained, therefore allowing administration of bevacizumab to coincide with the frequency of administration of the cytotoxic agents.Conclusion The PK parameters were consistent with those of other IgG molecules. The results support dosing bevacizumab on a once every 2 weeks or once every 3 weeks dosing schedule on a mg/kg basis.