Effects of ketoconazole or rifampin on the pharmacokinetics of tivozanib hydrochloride, a vascular endothelial growth factor receptor tyrosine kinase inhibitor

The vascular endothelial growth factor (VEGF) pathway is associated with the promotion of endothelial cell proliferation, migration, and survival necessary for angiogenesis. VEGF and its three receptor isoforms are often overexpressed in many human solid tumors. Tivozanib is a potent, selective inhi...

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Published in:	Clinical pharmacology in drug development Vol. 4; no. 2; pp. 137 - 142
Main Authors:	Cotreau, Monette M., Siebers, Nicholas M., Miller, James, Strahs, Andrew L., Slichenmyer, William
Format:	Journal Article
Language:	English
Published:	United States Blackwell Publishing Ltd 01-03-2015 Wiley Subscription Services, Inc
Subjects:	Administration, Oral Adolescent Adult Angiogenesis Inhibitors - administration & dosage Angiogenesis Inhibitors - adverse effects Angiogenesis Inhibitors - blood Angiogenesis Inhibitors - pharmacokinetics Area Under Curve Biotransformation Cytochrome P-450 CYP3A - metabolism Cytochrome P-450 CYP3A Inducers - administration & dosage Cytochrome P-450 CYP3A Inducers - adverse effects Cytochrome P-450 CYP3A Inhibitors - administration & dosage Cytochrome P-450 CYP3A Inhibitors - adverse effects cytochrome P450 drug interaction Female Half-Life Humans Ketoconazole - administration & dosage Ketoconazole - adverse effects Male Metabolic Clearance Rate Middle Aged Models, Biological pharmacokinetics Phenylurea Compounds - administration & dosage Phenylurea Compounds - adverse effects Phenylurea Compounds - blood Phenylurea Compounds - pharmacokinetics Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - adverse effects Protein Kinase Inhibitors - blood Protein Kinase Inhibitors - pharmacokinetics Quinolines - administration & dosage Quinolines - adverse effects Quinolines - blood Quinolines - pharmacokinetics Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors Receptors, Vascular Endothelial Growth Factor - metabolism Rifampin - administration & dosage Rifampin - adverse effects tyrosine kinase inhibitor United States Vascular endothelial growth factor VEGF receptor Young Adult pharmacokinetics VEGF receptor cytochrome P450 tyrosine kinase inhibitor drug interaction
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Summary:	The vascular endothelial growth factor (VEGF) pathway is associated with the promotion of endothelial cell proliferation, migration, and survival necessary for angiogenesis. VEGF and its three receptor isoforms are often overexpressed in many human solid tumors. Tivozanib is a potent, selective inhibitor of VEGF receptors 1, 2, and 3, with a long half‐life. The purpose of these studies was to evaluate the effect of ketoconazole, a potent inhibitor of CYP3A4, and rifampin, a potent inducer of CYP3A4, on the pharmacokinetics of tivozanib. Two phase I, open‐label, 2‐period, single‐sequence studies evaluated the effect of steady‐state ketoconazole (NCT01363778) or rifampin (NCT01363804) on the pharmacokinetic profile, safety, and tolerability of a single oral 1.5‐mg dose of tivozanib. Tivozanib was well tolerated in both studies. Steady‐state ketoconazole did not cause a clinically significant change in the pharmacokinetics of a single dose of tivozanib; therefore, dosing of tivozanib with a CYP3A4 pathway inhibitor should not cause a clinically significant change in serum tivozanib levels. However, coadministration of tivozanib with rifampin caused a significant decrease in the area under the curve from 0 to infinity and half‐life and an increase in clearance of tivozanib, which suggest increased clearance via the enhanced CYP3A4‐mediated metabolism of tivozanib.
Bibliography:	istex:40B0DDDD3E6ADD1ADE4A37F460EB6A79364CA7BA ArticleID:CPDD145 AVEO Oncology and Astellas ark:/67375/WNG-LH2T7RB1-Z ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2160-763X 2160-7648
DOI:	10.1002/cpdd.145