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Effects of ketoconazole or rifampin on the pharmacokinetics of tivozanib hydrochloride, a vascular endothelial growth factor receptor tyrosine kinase inhibitor
Author(s) -
Cotreau Monette M.,
Siebers Nicholas M.,
Miller James,
Strahs Andrew L.,
Slichenmyer William
Publication year - 2014
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.145
Subject(s) - pharmacokinetics , ketoconazole , pharmacology , medicine , vascular endothelial growth factor , tolerability , cancer research , vegf receptors , adverse effect , antifungal , dermatology
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.