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A pharmacometric framework for axitinib exposure, efficacy and safety in metastatic renal cell carcinoma patients.

A pharmacometric framework for axitinib exposure, efficacy and safety in metastatic renal cell carcinoma patients.
Author Information (click to view)

Schindler E, Amantea MA, Karlsson MO, Friberg LE,


Schindler E, Amantea MA, Karlsson MO, Friberg LE, (click to view)

Schindler E, Amantea MA, Karlsson MO, Friberg LE,

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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.

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