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Effect of Tucatinib on Cardiac Repolarization in Healthy Volunteers

Ariel R Topletz-Erickson1, JoAl G Mayor2, Hsu-Tai Liu3

  • 1Clinical Pharmacology and Pharmacometrics, Seagen Inc., 21823 30th Drive SE, Bothell, WA, 98021, USA.

Drugs in R&D
|September 26, 2023
PubMed
Abstract

Insights

Tucatinib, a HER2 inhibitor, showed no clinically relevant effects on cardiac repolarization in healthy volunteers. This negative QT/corrected QT (TQT) study supports its safety profile for treating HER2-positive cancers.

Area of Science:

  • Pharmacology and Toxicology
  • Cardiology
  • Oncology

Background:

  • Tucatinib is a selective HER2 tyrosine kinase inhibitor used for metastatic HER2-positive breast and colorectal cancers.
  • The International Council for Harmonisation (ICH) E14 guideline requires QT/corrected QT (TQT) studies to assess drug-induced cardiac repolarization effects.
  • Assessing cardiac safety is crucial for drug approval and patient well-being.

Purpose of the Study:

  • To evaluate the effect of tucatinib on cardiac repolarization in healthy volunteers.
  • To determine if tucatinib prolongs the QT interval, a measure of cardiac repolarization.
  • To comply with ICH E14 guidelines for drug safety assessment.

Main Methods:

  • A phase I, randomized, partially double-blind, placebo- and positive-controlled, three-period crossover study.
  • Healthy volunteers received tucatinib (300 mg twice daily) or placebo.
  • The primary endpoint was the placebo-corrected change from baseline in QT interval corrected for heart rate using Fridericia's method (ΔΔQTcF).

Main Results:

  • Tucatinib did not significantly affect the QTcF interval, with ΔΔQTcF ranging from -2.9 to 0 msec.
  • The upper bound of the 90% confidence interval for ΔΔQTcF was consistently below 5 ms.
  • Tucatinib showed no clinically relevant impact on heart rate or cardiac conduction, with a manageable safety profile.

Conclusions:

  • Tucatinib demonstrated no clinically relevant effects on electrocardiogram (ECG) parameters, including cardiac repolarization.
  • This study is a clearly negative TQT study according to ICH E14 guidance.
  • The findings support the cardiac safety profile of tucatinib for its approved indications.

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