Open AccessBridging Sunitinib Exposure to Time‐to‐Tumor Progression in Hepatocellular Carcinoma Patients With Mathematical Modeling of an Angiogenic Biomarker
Author(s) -
AitOudhia S,
Mager DE,
Pokuri V,
Tomaszewski G,
Groman A,
Zagst P,
Fetterly G,
Iyer R
Publication year - 2016
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12084
Subject(s) - sunitinib , sorafenib , hepatocellular carcinoma , medicine , biomarker , oncology , pharmacodynamics , pharmacokinetics , angiogenesis , pazopanib , vascular endothelial growth factor , bevacizumab , cancer , pharmacology , vegf receptors , chemotherapy , biology , biochemistry
Hepatocellular carcinoma (HCC) is third in cancer‐related causes of death worldwide and its treatment is a significant unmet medical need. Sunitinib is a selective tyrosine kinase inhibitor of the angiogenic biomarker: soluble vascular endothelial growth factor receptor‐2 (sVEGFR 2 ). Sunitinib failed its primary overall survival endpoint in patients with advanced HCC in a phase III trial compared to sorafenib. In the present study, pharmacokinetic‐pharmacodynamic modeling was used to link drug‐exposure to tumor‐growth‐inhibition (TGI) and time‐to‐tumor progression (TTP) through sVEGFR 2 dynamics. The results suggest that 1) active drug concentration (i.e., sunitinib and its metabolite) inhibits the release of sVEGFR 2 and that such inhibition is associated with TGI, and 2) daily sVEGFR 2 exposure is likely a reliable predictor for the TTP in HCC patients. Moreover, the model quantitatively links the dynamics of an angiogenesis biomarker to TTP and accurately predicts observed literature‐reported results of placebo treatment.