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Methods for ECG Evaluation of Indicators of Cardiac Risk, and Susceptibility to Aconitine-induced Arrhythmias in Rats Following Status Epilepticus
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Effect of axitinib on the QT interval in healthy volunteers

Ana Ruiz-Garcia1, Brett E Houk, Yazdi K Pithavala

  • 1Clinical Pharmacology, Pfizer Inc, San Diego, CA, USA.

Cancer Chemotherapy and Pharmacology
|January 16, 2015
PubMed
Abstract

Insights

Axitinib, used for advanced renal cell carcinoma, did not cause significant QTc prolongation in healthy volunteers, even at high doses. This finding supports its safety profile in patients.

Area of Science:

  • Pharmacology
  • Cardiology
  • Oncology

Background:

  • Axitinib is a targeted therapy for advanced renal cell carcinoma (RCC).
  • Preclinical data suggested axitinib does not prolong the corrected QT interval (QTc).

Purpose of the Study:

  • To assess the effect of axitinib on QTc prolongation in healthy volunteers.
  • To evaluate QTc changes using concentration-QTc response modeling.

Main Methods:

  • A single 5-mg dose of axitinib was administered to healthy volunteers.
  • QTc prolongation was assessed alone and with ketoconazole (a CYP3A4/5 inhibitor).
  • One-stage concentration-QTc response modeling was employed.

Main Results:

  • Axitinib alone showed a flat QTc-concentration relationship, with a mean highest placebo-matched QTc change of -3.0 ms.
  • Ketoconazole increased heart rate, while axitinib decreased it.
  • At supratherapeutic axitinib exposure (with ketoconazole), the model predicted a mean QTc change of 6.5 ms.

Conclusions:

  • Axitinib was not associated with clinically significant QTc prolongation.
  • Observed axitinib concentrations exceeded those in RCC patients at the highest approved dose.
  • The study supports the cardiac safety of axitinib in its therapeutic use.

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