Schindler E, Amantea MA, Karlsson MO, Friberg LE, (click to view)
CPT: pharmacometrics & systems pharmacology 2017 04 05() doi 10.1002/psp4.12193
Abstract
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 time-courses 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 time-course 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. (http://ClinicalTrial.gov identifier NCT00569946) This article is protected by copyright. All rights reserved.