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

Song Mu, Borje Darpo, Zhiyu Tang, William Novotny, Manal Tawashi, Hongqi Xue, Michael Willett, Leo Lin, Sri Sahasranaman, Ying C Ou, Song Mu, Borje Darpo, Zhiyu Tang, William Novotny, Manal Tawashi, Hongqi Xue, Michael Willett, Leo Lin, Sri Sahasranaman, Ying C Ou

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.

Conflict of interest statement

B.D. owns stock and is eligible for stock options in E.R.T., Rochester, NY. S.M., Z.T., W.N., M.T., L.L., Y.O., and S.S. own stock and are eligible for stock options in BeiGene, Inc., San Mateo, CA. All other authors declared no competing interests for this work.

© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Mean (SD) zanubrutinib plasma concentrations (ng/mL) vs. time. Blue line, zanubrutinib 160 mg (n = 28); red line, zanubrutinib 480 mg (n = 30).
Figure 2
Figure 2
Effects of zanubrutinib on ECG parameters. (a) Change‐from‐baseline heart rate (ΔHR) across time points and (b) mean change from baseline in QTcF interval over time using Fridericia’s formula (ΔQTcF). Study participants received zanubrutinib 160 mg (open squares), zanubrutinib 480 mg (open triangles), moxifloxacin (open diamonds), or placebo (open circles).
Figure 3
Figure 3
Zanubrutinib C‐QTc analysis. (a) Scatter plot of observed zanubrutinib plasma concentrations and mean change from baseline in QTcF interval over time using Fridericia’s formula (ΔΔQTcF) and (b) mean (90% confidence interval (CI)) model‐predicted and observed ΔΔQTcF across deciles of zanubrutinib plasma concentrations. (a) The solid red line with dashed red curves above and below denotes the model‐predicted mean (90% CI) ΔΔQTcF. The blue squares and red triangles denote the pairs of observed zanubrutinib plasma concentrations and ΔΔQTcF by participants for the 160‐mg and 480‐mg doses of zanubrutinib, respectively. (b) The red dots with vertical bars denote the observed mean (90% CI) ΔΔQTcF at the median zanubrutinib plasma concentration within each decile. The solid black line within the gray shaded area denotes the model‐predicted mean (90% CI) ΔΔQTcF. The horizontal red line with notches shows the range of concentrations divided into deciles for zanubrutinib. The area between each decile represents the point at which 10% of the data are present; the first notch to second notch denotes the first 10% of the data, the second notch to third notch denotes the second 10%, and so on.

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