No QTc Prolongation With Zanubrutinib: Results of Concentration-QTc Analysis From a Thorough QT Study in Healthy Subjects

Clin Transl Sci. 2020 Sep;13(5):923-931. doi: 10.1111/cts.12779. Epub 2020 Apr 8.

Abstract

This thorough QT (TQT) study evaluated the effect of zanubrutinib on electrocardiogram (ECG) parameters by using concentration-QTc (C-QTc) analysis as the primary analysis for this study. Part A of the study determined the safety and tolerability of a single supratherapeutic dose of zanubrutinib (480 mg) in healthy volunteers. Part B was a randomized, blinded, placebo-controlled and positive-controlled, four-way crossover, TQT study of single therapeutic (160 mg) and supratherapeutic (480 mg) doses of zanubrutinib, placebo, and open-label moxifloxacin 400 mg. Thirty-two participants received at least 1 dose of zanubrutinib, and 26 participants completed all 4 periods. Zanubrutinib did not have any effect on heart rate or cardiac conduction (pulse rate, QRS interval, or T-wave morphology) and was generally well-tolerated. Using C-QTc analysis, the predicted placebo-corrected change-from-baseline QT interval using Fridericia's formula (ΔΔQTcF) was -3.4 msec (90% confidence interval: -4.9 to -1.9 msec) at peak concentrations of the 480 mg dose. A QT effect (ΔΔQTcF) exceeding 10 msec could be excluded within the observed concentration range at 160 and 480 mg doses. Assay sensitivity was established by moxifloxacin with 90% lower bound exceeding 5 msec. Implementing a C-QTc analysis prospectively in this TQT study resulted in a substantially smaller sample size to maintain a similar study power as shown in the traditional time-point analysis. A single 160-mg or 480-mg zanubrutinib dose did not prolong the QTc interval or have any other clinically relevant effects on ECG parameters.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Electrocardiography
  • Female
  • Healthy Volunteers
  • Heart Rate / drug effects
  • Humans
  • Long QT Syndrome / chemically induced
  • Long QT Syndrome / diagnosis*
  • Male
  • Middle Aged
  • Piperidines / administration & dosage
  • Piperidines / adverse effects*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects*
  • Pyrazoles / administration & dosage
  • Pyrazoles / adverse effects*
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects*
  • Young Adult

Substances

  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • zanubrutinib
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human