晚期非鳞状非小细胞肺癌患者中 PF-06439535（贝伐珠单抗生物类似药）和参照贝伐珠单抗（安维汀）的群体药代动力学建模。
Population pharmacokinetic modeling of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin) in patients with advanced non-squamous non-small cell lung cancer.
机构信息
Clinical Pharmacology/Pharmacometrics, Pfizer Global Product Development, Pfizer Inc., 300 Technology Square, Cambridge, MA, 02140, USA.
Clinical Pharmacology/Pharmacometrics, Pfizer Global Product Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA.
出版信息
Cancer Chemother Pharmacol. 2020 Mar;85(3):487-499. doi: 10.1007/s00280-019-03946-8. Epub 2019 Nov 26.
PURPOSE
The objectives of this analysis were to characterize the population pharmacokinetics (PK) of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin) sourced from the European Union (bevacizumab-EU) in patients with advanced non-squamous non-small cell lung cancer (NSCLC), and to quantify the difference in PK parameters between the two drug products via covariate analysis.
METHODS
Pooled PF-06439535 and bevacizumab-EU serum concentration data from a comparative clinical efficacy and safety study (NCT02364999) in patients with NSCLC (N = 719) were analyzed using a non-linear mixed-effects modeling approach. Patients received PF-06439535 plus chemotherapy or bevacizumab-EU plus chemotherapy every 21 days for 4-6 cycles, followed by monotherapy with PF-06439535 or bevacizumab-EU. PF-06439535 or bevacizumab-EU was administered intravenously at a dose of 15 mg/kg. Effects of patient and disease covariates, as well as the drug product (PF-06439535 versus bevacizumab-EU), on PK were investigated.
RESULTS
Overall, 8632 serum bevacizumab concentrations from 351 patients in the PF-06439535 group and 354 patients in the bevacizumab-EU group were included in the analysis. A two-compartment model adequately described the combined data. Clearance (CL) and central volume of distribution (V) estimates were 0.0113 L/h and 2.99 L for a typical 71-kg female patient with NSCLC administered bevacizumab-EU. CL and V increased with body weight and were higher in males than females even after accounting for differences in body weight. The 95% confidence intervals for the effect of drug product on CL and V encompassed unity.
CONCLUSIONS
The population PK of PF-06439535 and bevacizumab-EU were well characterized by a two-compartment model. Covariate analysis did not reveal any appreciable differences between PK parameters for PF-06439535 and bevacizumab-EU in patients with NSCLC.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT02364999.
目的
本分析的目的是描述 PF-06439535（贝伐珠单抗生物类似药）和源自欧盟的参照贝伐珠单抗（Avastin）在晚期非鳞状非小细胞肺癌（NSCLC）患者中的群体药代动力学（PK）特征，并通过协变量分析量化两种药物产品之间 PK 参数的差异。
方法
对一项 NSCLC 患者比较临床疗效和安全性的研究（NCT02364999）中 PF-06439535 和贝伐珠单抗-EU 的血清浓度合并数据（N=719）进行分析，采用非线性混合效应建模方法。患者每 21 天接受 PF-06439535 联合化疗或贝伐珠单抗-EU 联合化疗 4-6 个周期，随后分别接受 PF-06439535 或贝伐珠单抗-EU 的单药治疗。PF-06439535 或贝伐珠单抗-EU 静脉给药剂量为 15mg/kg。考察了患者和疾病协变量以及药物产品（PF-06439535 与贝伐珠单抗-EU）对 PK 的影响。
结果
总体而言，纳入 PF-06439535 组 351 例和贝伐珠单抗-EU 组 354 例患者的 8632 个血清贝伐珠单抗浓度数据纳入分析。合并数据采用两室模型进行了充分描述。典型的 71kg 女性 NSCLC 患者给予贝伐珠单抗-EU 的清除率（CL）和中央分布容积（V）估计值分别为 0.0113L/h 和 2.99L。CL 和 V 随体重增加而增加，且男性高于女性，即使考虑到体重差异也是如此。药物产品对 CL 和 V 的影响的 95%置信区间包含 1。
结论
PF-06439535 和贝伐珠单抗-EU 的群体 PK 由两室模型很好地描述。协变量分析未显示 NSCLC 患者中 PF-06439535 和贝伐珠单抗-EU 的 PK 参数存在任何明显差异。
临床试验注册
ClinicalTrials.gov，NCT02364999。
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