Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors.
Abstract
Various biomarkers have been proposed for sunitinib therapy in gastrointestinal stromal tumor (GIST). However, the lack of "real-life" comparative studies hampers the selection of the most appropriate one. We, therefore, set up a pharmacometric simulation framework to compare each proposed biomarker. Models describing relations between sunitinib exposure, adverse events (hand-foot syndrome, fatigue, hypertension, and neutropenia), soluble VEGFR (sVEGFR)-3, and overall survival (OS) were connected to evaluate the differences in survival and adverse events under different dosing algorithms. Various fixed dosing regimens [4/2 (weeks on/weeks off) or 2/1 (50 mg), and continuous daily dosing (37.5 mg)] and individualization approaches [concentration-adjusted dosing (CAD), toxicity-adjusted dosing (TAD), and sVEGFR-3-adjusted dosing (VAD)] were explored following earlier suggested blood sampling schedules and dose-reduction criteria. Model-based forecasts of biomarker changes were evaluated for predictive accuracy and the advantage of a model-based dosing algorithm was evaluated for clinical implementation. The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) inc...Continue Reading
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