학술논문
Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors.
Document Type
Academic Journal
Author
Centanni M; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.; Krishnan SM; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.; Friberg LE; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. lena.friberg@farmbio.uu.se.
Source
Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE
Subject
Language
English
Abstract
Purpose: 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.
Experimental Design: 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.
Results: The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) increased median OS as compared with a fixed dose schedule (19.9 and 21.5 months, respectively) and CAD (19.7 and 21.3 months, respectively), without markedly raising the risk of intolerable toxicities. Changes in neutrophil count and sVEGFR-3 were accurately forecasted in the majority of subjects (>65%), based on biweekly blood sampling.
Conclusions: Dose adjustments based on the pharmacodynamic biomarkers neutrophil count and sVEGFR-3 can increase OS while retaining drug safety. Future efforts could explore the possibility of incorporating a model-based dose approach in clinical practice to increase dosing accuracy for these biomarkers.
(©2020 American Association for Cancer Research.)
Experimental Design: 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.
Results: The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) increased median OS as compared with a fixed dose schedule (19.9 and 21.5 months, respectively) and CAD (19.7 and 21.3 months, respectively), without markedly raising the risk of intolerable toxicities. Changes in neutrophil count and sVEGFR-3 were accurately forecasted in the majority of subjects (>65%), based on biweekly blood sampling.
Conclusions: Dose adjustments based on the pharmacodynamic biomarkers neutrophil count and sVEGFR-3 can increase OS while retaining drug safety. Future efforts could explore the possibility of incorporating a model-based dose approach in clinical practice to increase dosing accuracy for these biomarkers.
(©2020 American Association for Cancer Research.)