TY - JOUR
TI - Pharmacogenetics in model-based optimization of bevacizumab therapy for metastatic colorectal cancer
AU - Papachristos, A.
AU - Karatza, E.
AU - Kalofonos, H.
AU - Sivolapenko, G.
JO - International Journal of Molecular Sciences
PY - 2020
VL - 21
TODO - 11
SP - null
PB - MDPI AG
SN - 1422-0067
TODO - 10.3390/ijms21113753
TODO - bevacizumab;  capecitabine;  fluoropyrimidine derivative;  fluorouracil;  intercellular adhesion molecule 1;  irinotecan;  levoleucovorin;  oxaliplatin;  vasculotropin A;  angiogenesis inhibitor;  bevacizumab;  intercellular adhesion molecule 1;  vasculotropin A, aged;  Article;  cancer combination chemotherapy;  clinical article;  cohort analysis;  controlled study;  dissociation constant;  drug clearance;  drug distribution;  drug elimination;  elimination rate constant;  female;  human;  limit of quantitation;  male;  metastatic colorectal cancer;  observational study;  pharmacogenetics;  rate constant;  steady state;  volume of distribution;  colorectal tumor;  genetics;  metabolic clearance rate;  metastasis;  middle aged;  pathology;  pharmacogenetic variant;  single nucleotide polymorphism, Aged;  Angiogenesis Inhibitors;  Bevacizumab;  Colorectal Neoplasms;  Female;  Humans;  Intercellular Adhesion Molecule-1;  Male;  Metabolic Clearance Rate;  Middle Aged;  Neoplasm Metastasis;  Pharmacogenomic Variants;  Polymorphism, Single Nucleotide;  Vascular Endothelial Growth Factor A
TODO - 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. VEGF-A (rs2010963, rs1570360, rs699947) and ICAM-1 (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 ICAM-1 rs1799969 (p < 0.0001), inter-compartmental clearance (Q) was significantly higher with mutant VEGF-A rs1570360 (p < 0.0001), and lower in patients with mutant VEGF-A rs699947 (p < 0.0001). The binding QSS model also showed that mutant ICAM-1 rs1799969 was associated with a lower CL (p = 0.0177). Mutant VEGF-A rs699947 was associated with a lower free VEGF-A levels, prior to the next dose (p = 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. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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