Pharmacogenetics in Model-Based Optimization of Bevacizumab Therapy for Metastatic Colorectal Cancer Article Swipe
Apostolos Papachristos
,
Eleni Karatza
,
Haralabos P. Kalofonos
,
Gregory Sivolapenko
·
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.3390/ijms21113753
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/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. 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.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3390/ijms21113753
- https://www.mdpi.com/1422-0067/21/11/3753/pdf
- OA Status
- gold
- Cited By
- 10
- References
- 50
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3029588165
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W3029588165Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.3390/ijms21113753Digital Object Identifier
- Title
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Pharmacogenetics in Model-Based Optimization of Bevacizumab Therapy for Metastatic Colorectal CancerWork title
- Type
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articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2020Year of publication
- Publication date
-
2020-05-26Full publication date if available
- Authors
-
Apostolos Papachristos, Eleni Karatza, Haralabos P. Kalofonos, Gregory SivolapenkoList of authors in order
- Landing page
-
https://doi.org/10.3390/ijms21113753Publisher landing page
- PDF URL
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https://www.mdpi.com/1422-0067/21/11/3753/pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
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https://www.mdpi.com/1422-0067/21/11/3753/pdfDirect OA link when available
- Concepts
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Bevacizumab, Colorectal cancer, Pharmacokinetics, Medicine, Angiogenesis, Pharmacology, Vascular endothelial growth factor, Pharmacodynamics, Internal medicine, Chemotherapy, Cancer research, Cancer, VEGF receptorsTop concepts (fields/topics) attached by OpenAlex
- Cited by
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10Total citation count in OpenAlex
- Citations by year (recent)
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2024: 1, 2023: 2, 2022: 5, 2021: 1, 2020: 1Per-year citation counts (last 5 years)
- References (count)
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50Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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