Bridging Sunitinib Exposure to Time-to-Tumor Progression in Hepatocellular Carcinoma Patients With Mathematical Modeling of an Angiogenic Biomarker.
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 (sVEGFR2 ). 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 sVEGFR2 dynamics. The results suggest that 1) active drug concentration (i.e., sunitinib and its metabolite) inhibits the release of sVEGFR2 and that such inhibition is associated with TGI, and 2) daily sVEGFR2 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.
Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.
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Ait-Oudhia
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
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Mager
Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
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Pokuri
Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
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Tomaszewski
Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
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Groman
Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
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Zagst
Clinical Pharmacology and Regulatory Affairs, Buffalo, New York, USA.
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Fetterly
Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
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Iyer
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008962:Models, Theoretical; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010865:Pilot Projects; D011758:Pyrroles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077210:Sunitinib; D015996:Survival Rate; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib