Abstract
Purpose
QT assessment of oncology drugs is generally challenging because they are genotoxic and, of necessity, they require multisite evaluation in cancer patients. Lenvatinib is not genotoxic, therefore, this thorough QT (TQT) study with lenvatinib, a multityrosine kinase inhibitor, was undertaken utilizing healthy volunteers and concentration-effect modeling to project the TQT effect at high plasma levels.
Methods
Fifty-two healthy subjects randomly received single doses of lenvatinib 32 mg, placebo, or moxifloxacin 400 mg in a three-way crossover study. Serial electrocardiograms were recorded, and the effect on placebo-corrected change-from-baseline QTcF (∆∆QTcF) was evaluated. The relationship between lenvatinib plasma concentrations and QTcF was analyzed with linear mixed-effects modeling.
Results
Lenvatinib mildly lowered the heart rate by 5–8 bpm during the first 12 h after dosing. ∆∆QTcF was shortened with a peak effect of −5.72 ms (90 % confidence interval (90 % CI) −7.76 to −3.69 ms) at 6 h postdosing. The upper bound of mean ∆∆QTcF did not exceed 2 ms at any time point postdosing. A concentration-dependent effect of lenvatinib on ∆∆QTcF was identified with an estimated population intercept of −2.96 ms (90 % CI −4.49 to −1.43 ms; P = 0.0016) and a negative slope of −0.0045 (90 % CI −4.49 to −1.43) ms per ng/mL, respectively. The safety profile after a single dose of lenvatinib was acceptable, with adverse events (AEs) of mild-to-moderate severity and no serious AEs.
Conclusions
Lenvatinib had no clinically relevant effect on the QTc interval. Concentration-effect modeling supports the lack of QTc prolongation at high plasma concentrations.
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Acknowledgments
The authors thank the lenvatinib clinical team for their assistance in the conduct, reporting, and quality control of the studies; the study site investigator, Steven F. Komjathy, MD; the study site, Charles River Clinical Services northwest, Inc., Tacoma, WA, and their staff, for conducting the study; and the study subjects for their participation. The authors gratefully acknowledge editorial contributions by Phase Five Communications Inc.
Conflict of interest
B Darpo: consultant to Eisai Product Creation Systems and iCardiac Technologies, Inc.; stock holdings of iCardiac. M Zhou: employee of iCardiac Technologies, Inc. RC Shumaker, J Fan, M Ren, G Martinez, J Aluri: employees of Eisai Product Creation Systems.
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Shumaker, R.C., Zhou, M., Ren, M. et al. Effect of lenvatinib (E7080) on the QTc interval: results from a thorough QT study in healthy volunteers. Cancer Chemother Pharmacol 73, 1109–1117 (2014). https://doi.org/10.1007/s00280-014-2444-6
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DOI: https://doi.org/10.1007/s00280-014-2444-6