Περίληψη:
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.
Συγγραφείς:
Papachristos, A.
Karatza, E.
Kalofonos, H.
Sivolapenko, G.
Λέξεις-κλειδιά:
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
