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Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure–response analysis

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Abstract

Purpose

Venetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QTc) interval and to evaluate the relationship between systemic venetoclax concentration and QTc interval.

Methods

The study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 105) or non-Hodgkin’s lymphoma (n = 71) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study. Electrocardiograms were collected in triplicate at time-matched points (2, 4, 6, and 8 h) prior to the first venetoclax administration and after repeated venetoclax administration to achieve steady state conditions. Venetoclax doses ranged from 100 to 1200 mg daily. Plasma venetoclax samples were collected after steady state electrocardiogram measurements.

Results

The mean and upper bound of the 2-sided 90 % confidence interval (CI) QTc change from baseline were <5 and <10 ms, respectively, at all time points and doses (<400, 400, and >400 mg). Three subjects had single QTc values >500 ms and/or ΔQTc > 60 ms. The effect of venetoclax concentration on both ΔQTc and QTc was not statistically significant (P > 0.05). At the mean maximum concentrations achieved with therapeutic (400 mg) and supra-therapeutic (1200 mg) venetoclax doses, the estimated drug effects on QTc were 0.137 (90 % CI [−1.01 to 1.28]) and 0.263 (90 % CI [–1.92 to 2.45]) ms, respectively.

Conclusion

Venetoclax does not prolong QTc interval even at supra-therapeutic doses, and there is no relationship between venetoclax concentrations and QTc interval.

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Acknowledgments

We thank the patients who participated in this trial and their families; the study coordinators and the support staff at the clinical sites; and AbbVie and Genentech venetoclax team members.

Funding

This study was supported by AbbVie in collaboration with Genentech/Roche. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data as well as the writing, review, and approval of the manuscript. Venetoclax (ABT-199/GDC-0199) is being developed in collaboration between AbbVie and Genentech.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, Abbvie, 1 North Waukegan Road, North Chicago, IL, 60064, USA

    Kevin J. Freise, Martin Dunbar, Aksana K. Jones, David Hoffman, Shekman Wong & Ahmed Hamed Salem

  2. Medical Affairs, Abbvie, 1 North Waukegan Road, North Chicago, 60064, IL, USA

    Sari L. Heitner Enschede

  3. Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

    Ahmed Hamed Salem

Authors
  1. Kevin J. Freise
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  2. Martin Dunbar
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  3. Aksana K. Jones
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  4. David Hoffman
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  5. Sari L. Heitner Enschede
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  6. Shekman Wong
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  7. Ahmed Hamed Salem
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Corresponding author

Correspondence to Ahmed Hamed Salem.

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Conflict of interest

All authors are employees of AbbVie and may hold AbbVie stock or stock options.

Ethical approval

The study was conducted in accordance with the principles described in the Declaration of Helsinki (1946) up to and including the Seoul revision (2008). A common clinical protocol was approved for each site by the appropriate Institutional Review Board, and all subjects provided written informed consent prior to participation.

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Freise, K.J., Dunbar, M., Jones, A.K. et al. Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure–response analysis. Cancer Chemother Pharmacol 78, 847–853 (2016). https://doi.org/10.1007/s00280-016-3144-1

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  • DOI: https://doi.org/10.1007/s00280-016-3144-1

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