1. Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer
- Author
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Diekstra, M.H.M., Fritsch, A., Kanefendt, F., Swen, J.J., Moes, D., Sorgel, F., Kinzig, M., Stelzer, C., Schindele, D., Gauler, T., Hauser, S., Houtsma, D., Roessler, M., Moritz, B., Mross, K., Bergmann, L., Oosterwijk, E., Kiemeney, L.A.L.M., Guchelaar, H.J., Jaehde, U., Diekstra, M.H.M., Fritsch, A., Kanefendt, F., Swen, J.J., Moes, D., Sorgel, F., Kinzig, M., Stelzer, C., Schindele, D., Gauler, T., Hauser, S., Houtsma, D., Roessler, M., Moritz, B., Mross, K., Bergmann, L., Oosterwijk, E., Kiemeney, L.A.L.M., Guchelaar, H.J., and Jaehde, U.
- Abstract
Contains fulltext : 177889.pdf (publisher's version ) (Open Access), 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.
- Published
- 2017