Pharmacogenetics in Model-Based Optimization of Bevacizumab Therapy for Metastatic Colorectal Cancer.

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.