title: Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers.
abstract: OBJECTIVE
  Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by cytochrome P450 (CYP) 3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. Co-administration with CYP inhibitors may increase systemic exposure to axitinib and alter its safety profile. This study evaluated changes in axitinib plasma pharmacokinetic parameters and assessed safety and tolerability in healthy subjects, following axitinib co-administration with the potent CYP3A inhibitor ketoconazole.
  
  
  METHODS
  In this randomized, single-blind, two-way crossover study, 32 healthy volunteers received placebo, followed by a single 5-mg oral dose of axitinib, administered either alone or on the fourth day of dosing with oral ketoconazole (400 mg/day for 7 days).
  
  
  RESULTS
  Axitinib exposure was significantly increased in the presence of ketoconazole, with a geometric mean ratio for area under the plasma concentration-time curve from time zero to infinity of 2.06 (90% confidence interval [CI]: 1.84-2.30) and a geometric mean ratio for maximum plasma concentration (C(max)) of 1.50 (90% CI: 1.33-1.70). For axitinib alone or with ketoconazole, C(max) occurred 1.5 and 2.0 h after dosing, respectively. Adverse events were predominantly mild; the most commonly reported treatment-related adverse events were headache and nausea.
  
  
  CONCLUSIONS
  Axitinib plasma exposures and peak concentrations were increased following concurrent administration of axitinib and ketoconazole in healthy volunteers. Axitinib alone and in combination with ketoconazole was well tolerated. These findings provide an upper exposure for expected axitinib plasma concentrations in the presence of potent metabolic inhibition.
authors.affiliation: Pfizer Oncology, 10555 Science Center Drive, San Diego, CA 92121, USA. yazdi.pithavala@pfizer.com
authors.forename: Yazdi K
authors.initials: YK
authors.lastname: Pithavala
authors.forename: Warren
authors.initials: W
authors.lastname: Tong
authors.forename: Janessa
authors.initials: J
authors.lastname: Mount
authors.forename: Sadayappan V
authors.initials: SV
authors.lastname: Rahavendran
authors.forename: May
authors.initials: M
authors.lastname: Garrett
authors.forename: Brian
authors.initials: B
authors.lastname: Hee
authors.forename: Paulina
authors.initials: P
authors.lastname: Selaru
authors.forename: Nenad
authors.initials: N
authors.lastname: Sarapa
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Klamerus
mesh_terms: D000284:Administration, Oral; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077784:Axitinib; D001711:Biotransformation / Q000235:genetics; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016037:Single-Blind Method
chemical_list: D020533:Angiogenesis Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007191:Indazoles; D000077784:Axitinib; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole