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Integrated nonclinical and clinical risk assessment of the investigational proteasome inhibitor ixazomib on the QTc interval in cancer patients

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Abstract

Background

Ixazomib is the first oral, proteasome inhibitor to reach phase III trials. Here, we present an integrated nonclinical and clinical assessment of ixazomib’s effect on QTc intervals.

Methods

Nonclinical studies assessed (1) the in vitro binding of ixazomib to the hERG channel and (2) its effect on QT/QTc in dogs (N = 4) via telemetry. Pharmacokinetic-matched triplicate electrocardiograms were collected in four clinical phase I studies of intravenous (0.125–3.11 mg/m2, N = 125, solid tumors/lymphoma) or oral (0.24–3.95 mg/m2, N = 120, multiple myeloma) ixazomib. The relationship between ixazomib plasma concentration and heart rate (HR)-corrected QT using Fridericia (QTcF) or population (QTcP) methods was analyzed using linear mixed-effects models with fixed effects for day and time.

Results

In vitro binding potency for ixazomib to the hERG channel was weak (K i 24.9 μM; IC50 59.6 μM), and nonclinical telemetry studies showed no QT/QTc prolongation at doses up to 4.2 mg/m2. In cancer patients, ixazomib, when evaluated at doses yielding various plasma concentrations (with 26 % of data greater than mean C max for the 4 mg phase 3 dose), had no meaningful effect on QTc based on model-predicted mean change in QTcF/QTcP from baseline. There was no relationship between ixazomib concentration and RR, suggesting no effect on HR.

Conclusions

Ixazomib has no clinically meaningful effects on QTc or HR. Integrating preclinical data and concentration–QTc modeling of phase 1 data may obviate the need for a dedicated QTc study in oncology. A framework for QT assessment in oncology drug development is proposed.

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Acknowledgments

The authors would like to thank the patients, their families and caregivers, and the healthcare professionals who participated in the C16001, C16002, C16003, and C16004 studies. The authors would also like to acknowledge Jane Saunders, a medical writer with FireKite, part of KnowledgePoint360, an Ashfield company, for writing support during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc.

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Authors and Affiliations

  1. Millennium Pharmaceuticals, Inc., a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA

    Neeraj Gupta, Sean Ottinger, Ai-Min Hui & Karthik Venkatakrishnan

  2. Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA

    Yeamin Huh & Matthew M. Hutmacher

Authors
  1. Neeraj Gupta
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  2. Yeamin Huh
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  3. Matthew M. Hutmacher
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  4. Sean Ottinger
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  5. Ai-Min Hui
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  6. Karthik Venkatakrishnan
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Corresponding author

Correspondence to Neeraj Gupta.

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Financial support

This work was funded by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Conflict of interest

NG, SO, A-MH, and KV are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. YM and MMH have received research funding from Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Informed consent

Informed consent was obtained from all individual participants enrolled in the studies included in the analysis.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Gupta, N., Huh, Y., Hutmacher, M.M. et al. Integrated nonclinical and clinical risk assessment of the investigational proteasome inhibitor ixazomib on the QTc interval in cancer patients. Cancer Chemother Pharmacol 76, 507–516 (2015). https://doi.org/10.1007/s00280-015-2815-7

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  • DOI: https://doi.org/10.1007/s00280-015-2815-7

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