Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health Sciences, University of Patras, 26504 Patra, Greece.
Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15771 Athens, Greece.
Int J Mol Sci. 2020 May 26;21(11):3753. doi: 10.3390/ijms21113753.
Vascular endothelial growth factor A (VEGF-A) and intercellular adhesion molecule 1 (ICAM-1) are significant regulators of angiogenesis, an important biological process involved in carcinogenesis. Bevacizumab, an anti-VEGF monoclonal antibody (MAB), is approved for the treatment of metastatic Colorectal cancer (mCRC), however clinical outcomes are highly variable. In the present study, we developed a pharmacokinetic (PK), a simplified quasi-steady state (QSS) and a pharmacokinetic/pharmacodynamic (PK/PD) model to identify potential sources of variability. A total of 46 mCRC patients, who received bevacizumab in combination with chemotherapy were studied. (rs2010963, rs1570360, rs699947) and (rs5498, rs1799969) genes' polymorphisms, age, gender, weight, and dosing scheme were investigated as possible co-variates of the model's parameters. Polymorphisms, trough, and peak levels of bevacizumab, and free VEGF-A were determined in whole blood and serum. Data were analyzed using nonlinear mixed-effects modeling. The two-compartment PK model showed that clearance (CL) was significantly lower in patients with mutant rs1799969 ( < 0.0001), inter-compartmental clearance (Q) was significantly higher with mutant rs1570360 ( < 0.0001), and lower in patients with mutant rs699947 ( < 0.0001). The binding QSS model also showed that mutant rs1799969 was associated with a lower CL ( = 0.0177). Mutant rs699947 was associated with a lower free VEGF-A levels, prior to the next dose ( = 0.000445). The above results were confirmed by the PK/PD model. Findings of the present study indicated that variants of the genes regulating angiogenesis might affect PK and PD characteristics of bevacizumab, possibly influencing the clinical outcomes.
血管内皮生长因子 A（VEGF-A）和细胞间黏附分子 1（ICAM-1）是血管生成的重要调节因子，血管生成是癌症发生过程中的一个重要生物学过程。贝伐单抗是一种抗 VEGF 单克隆抗体（MAB），已被批准用于转移性结直肠癌（mCRC）的治疗，但临床结果差异很大。在本研究中，我们开发了一种药代动力学（PK）、简化准稳态（QSS）和药代动力学/药效学（PK/PD）模型，以确定潜在的变异性来源。共研究了 46 名接受贝伐单抗联合化疗的 mCRC 患者。研究了（rs2010963、rs1570360、rs699947）和（rs5498、rs1799969）基因的多态性、年龄、性别、体重和剂量方案，作为模型参数的可能协变量。在全血和血清中测定了贝伐单抗的多态性、谷值和峰值水平以及游离 VEGF-A。使用非线性混合效应建模分析数据。两室 PK 模型显示，携带突变 rs1799969 的患者清除率（CL）明显降低（<0.0001），携带突变 rs1570360 的患者隔室间清除率（Q）明显升高（<0.0001），携带突变 rs699947 的患者 CL 降低（<0.0001）。结合 QSS 模型也表明，突变 rs1799969 与较低的 CL 相关（=0.0177）。突变 rs699947 与下一次给药前的游离 VEGF-A 水平降低相关（=0.000445）。PK/PD 模型也证实了上述结果。本研究结果表明，调节血管生成的基因变异可能影响贝伐单抗的 PK 和 PD 特征，可能影响临床结果。
