title: Effect of axitinib on the QT interval in healthy volunteers.
abstract: OBJECTIVE
  Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization.
  
  
  METHODS
  The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily).
  
  
  RESULTS
  Axitinib and ketoconazole had opposite effects on heart rate: Axitinib lowered it, ketoconazole raised it. The final analysis showed a flat relationship between QTc and axitinib concentration (slope -0.0314 ms·mL/ng) for axitinib alone. Mean highest placebo-matched change from baseline in QTc was -3.0 [90 % confidence interval (CI) -5.4, -0.6] ms. At supratherapeutic axitinib exposures achieved with potent cytochrome P450 3A4/5 inhibition by ketoconazole, the model predicted mean QTc change of 6.5 (90 % CI 4.4-8.5) ms. The slope population mean estimate was -0.331 (95 % CI -0.860, 0.198) ms·mL/µg for ketoconazole alone and 0.0725 (0.0445-0.1005) ms·mL/ng for axitinib in the presence of ketoconazole. The results were then compared with those obtained based on more widely used Fridericia's, Bazett's, and study-specific correction methods.
  
  
  CONCLUSIONS
  Since axitinib plasma concentrations observed in this study exceeded the range of concentrations observed in patients with RCC at the highest approved clinical dose (10 mg twice daily), axitinib was not associated with clinically significant QTc prolongation in target populations.
authors.affiliation: Clinical Pharmacology, Pfizer Inc, San Diego, CA, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Garcia
authors.forename: Brett E
authors.initials: BE
authors.lastname: Houk
authors.forename: Yazdi K
authors.initials: YK
authors.lastname: Pithavala
authors.forename: Melvin
authors.initials: M
authors.lastname: Toh
authors.forename: Nenad
authors.initials: N
authors.lastname: Sarapa
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tortorici
mesh_terms: D000328:Adult; D000077784:Axitinib; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D007191:Indazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D016037:Single-Blind Method
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib; D007654:Ketoconazole