Population modeling integrating pharmacokinetics, pharmacodynamics, pharmacogenetics, and clinical outcome in patients with sunitinib-treated cancer

The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRC given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug expos may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodyna (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, a the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mR within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-ev (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active d PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for individualization of anti-angiogenic therapies.