Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer
| Autor: | B. Moritz, Meta H M Diekstra, Fritz Sörgel, Ulrich Jaehde, Henk-Jan Guchelaar, K. Mross, Danny Houtsma, Christoph Stelzer, Achim Fritsch, Thomas Gauler, Egbert Oosterwijk, Lambertus A. Kiemeney, D J A R Moes, L. Bergmann, F. Kanefendt, Max Roessler, Stephen L. Hauser, Jesse J. Swen, Martina Kinzig, D. Schindele |
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| Rok vydání: | 2017 |
| Předmět: |
education.field_of_study
medicine.drug_class Sunitinib business.industry Population Cancer Pharmacology urologic and male genital diseases medicine.disease 030226 pharmacology & pharmacy Tyrosine-kinase inhibitor 3. Good health 03 medical and health sciences 0302 clinical medicine Pharmacokinetics 030220 oncology & carcinogenesis Modeling and Simulation Pharmacodynamics medicine Pharmacology (medical) education business Pharmacogenetics Active metabolite medicine.drug |
| Zdroj: | CPT: Pharmacometrics & Systems Pharmacology. 6:604-613 |
| ISSN: | 2163-8306 |
| Popis: | The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies. |
| Databáze: | OpenAIRE |
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