title: Effects of ketoconazole or rifampin on the pharmacokinetics of tivozanib hydrochloride, a vascular endothelial growth factor receptor tyrosine kinase inhibitor.
abstract: 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.
authors.affiliation: AVEO Oncology, Cambridge, MA, USA.
authors.forename: Monette M
authors.initials: MM
authors.lastname: Cotreau
authors.affiliation: Covance, Madison, WI, USA.|Covance, Daytona, FL, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Siebers
authors.affiliation: AVEO Oncology, Cambridge, MA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Miller
authors.affiliation: AVEO Oncology, Cambridge, MA, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Strahs
authors.affiliation: AVEO Oncology, Cambridge, MA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Slichenmyer
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage* / Q000009:adverse effects; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012293:Rifampin / Q000008:administration & dosage* / Q000009:adverse effects; D014481:United States; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C553176:tivozanib; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D007654:Ketoconazole; D012293:Rifampin
keywords: VEGF receptor; cytochrome P450; drug interaction; pharmacokinetics; tyrosine kinase inhibitor