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Evaluation of the effects of an oral notch inhibitor, crenigacestat (LY3039478), on QT interval, and bioavailability studies conducted in healthy subjects

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Crenigacestat (LY3039478) is a Notch inhibitor currently being investigated in advanced cancer patients. Conducting clinical pharmacology studies in healthy subjects avoids nonbeneficial drug exposures in cancer patients and mitigates confounding effects of disease state and concomitant medications.

Methods

Three studies were conducted in healthy subjects, assessing safety, pharmacokinetics, effect on QT interval, and relative and absolute bioavailability of crenigacestat. Crenigacestat was administered as single 25, 50, or 75 mg oral doses or as an intravenous dose of 350 µg 13C15N2H-crenigacestat. Electrocardiogram measurements, and plasma and urine samples were collected up to 48 h postdose, and safety assessments were conducted up to 14 days postdose.

Results and conclusions

Exposures were dose proportional in the 25 to 75 mg dose range and mean elimination half-life was approximately 5–6 h. The exposure achieved from the new formulated capsule was approximately 30% and 20% higher for area under the plasma concentration time curve from time zero to infinity [AUC(0–∞)] and maximum plasma concentration (Cmax), respectively, compared to the reference drug in capsule formulation. The geometric least-squares mean [90% confidence interval (CI)] absolute bioavailability of crenigacestat was 0.572 (0.532, 0.615). The regression slope (90% CI) of placebo-adjusted QTcF against crenigacestat plasma concentration was − 0.001 (− 0.006, 0.003), suggesting no significant linear association. Thirty-nine subjects completed the studies and the majority of adverse events were mild. Single oral doses of 25 to 75 mg crenigacestat and an IV dose of 350 µg 13C15N2H-crenigacestat were well tolerated in healthy subjects.

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Funding

This study was funded by Eli Lilly and Company.

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Authors and Affiliations

  1. Eli Lilly and Company, Erl Wood Manor, Windlesham Surrey, GU20 6PH, UK

    Eunice Yuen, Claire Smith, Katharine Thorn & Louise Chinchen

  2. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Maria Posada, Dale Greenwood, Michelle Burgess, Karim A. Benhadji, Demetrio Ortega & Jeffrey Suico

Authors
  1. Eunice Yuen
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  2. Maria Posada
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  3. Claire Smith
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  4. Katharine Thorn
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  5. Dale Greenwood
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  6. Michelle Burgess
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  7. Karim A. Benhadji
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  8. Demetrio Ortega
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  9. Louise Chinchen
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  10. Jeffrey Suico
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Corresponding author

Correspondence to Eunice Yuen.

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Conflict of interest

All authors are employees of Eli Lilly and Company.

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.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Yuen, E., Posada, M., Smith, C. et al. Evaluation of the effects of an oral notch inhibitor, crenigacestat (LY3039478), on QT interval, and bioavailability studies conducted in healthy subjects. Cancer Chemother Pharmacol 83, 483–492 (2019). https://doi.org/10.1007/s00280-018-3750-1

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  • DOI: https://doi.org/10.1007/s00280-018-3750-1

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