期刊
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
卷 6, 期 6, 页码 373-382出版社
WILEY
DOI: 10.1002/psp4.12193
关键词
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资金
- Swedish Cancer Society, Sweden
- DDMoRe, which is an Innovative Medicines Initiative Joint Undertaking under European Union [115156]
- Pfizer
The relationships between exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble VEGF receptors (sVEGFR)-1, -2, -3, and soluble stem cell factor receptor (sKIT)), tumor sum of longest diameters (SLD), diastolic blood pressure (dBP), and overall survival (OS) were investigated in a modeling framework. The dataset included 64 metastatic renal cell carcinoma patients (mRCC) treated with oral axitinib. Biomarker timecourses were described by indirect response (IDR) models where axitinib inhibits sVEGFR-1, -2, and -3 production, and VEGF degradation. No effect was identified on sKIT. A tumor model using sVEGFR-3 dynamics as driver predicted SLD data well. An IDR model, with axitinib exposure stimulating the response, characterized dBP increase. In a time-to-event model the SLD timecourse predicted OS better than exposure, biomarker-or dBP-related metrics. This type of framework can be used to relate pharmacokinetics, efficacy, and safety to long-term clinical outcome in mRCC patients treated with VEGFR inhibitors. ClinicalTrial.gov identifier NCT00569946.)
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