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Clinical Pharmacokinetic and Pharmacodynamic Profile of Lenvatinib, an Orally Active, Small-Molecule, Multitargeted Tyrosine Kinase Inhibitor

European Journal of Drug Metabolism and Pharmacokinetics volume 42, pages 903–914 (2017)Cite this article

Abstract

Lenvatinib is a multikinase inhibitor that targets vascular endothelial growth factor (VEGF) receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor-alpha, and RET and KIT proto-oncogenes. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer in the United States (US), European Union (EU), Canada, Japan, and Switzerland. It is also approved in combination with everolimus for the treatment of advanced renal cell carcinoma following ≥1 VEGF-targeted treatment in the US and EU. In addition, lenvatinib is under investigation for the treatment of hepatocellular carcinoma. As lenvatinib becomes more widely available, a better understanding of its pharmacokinetic profile has become increasingly important. Following oral administration, lenvatinib is absorbed rapidly and is metabolized extensively prior to excretion. This metabolism is mediated by multiple pathways, and several metabolites of lenvatinib have been identified. The effect of food intake on lenvatinib exposure has also been studied and was found to not significantly influence overall exposure to the drug. Exposure to lenvatinib is increased in patients with severe hepatic impairment, indicating that dose reduction must be considered for those patients. The findings summarized here indicate that the clinical pharmacokinetic and pharmacodynamic profile for lenvatinib are predictable, with a dose-independent absorption and elimination profile that supports once-daily administration, and has minimal effects due to mild or moderate renal or hepatic impairment or drug interactions.

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Acknowledgements

The authors thank Anubha Gupta, PhD, formerly of Eisai, Inc., for contributions to the analyses and Nicolette Belletier, PhD, an employee of Oxford PharmaGenesis, for medical writing assistance.

Some of the data included in this review come from clinical studies that were sponsored by Eisai Inc. (Woodcliff Lake, NJ, USA).

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Affiliations

  1. Eisai Ltd., Hatfield, Hertfordshire, UK

    Ziad Hussein

  2. Eisai Co., Ltd., Tsukuba, Ibaraki, Japan

    Hitoshi Mizuo

  3. Eisai Co., Ltd., Tokyo, Japan

    Seiichi Hayato & Masayuki Namiki

  4. Clinical Pharmacology and Translational Medicine, Oncology, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ, 07677, USA

    Robert Shumaker

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  1. Ziad Hussein
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  2. Hitoshi Mizuo
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  3. Seiichi Hayato
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  4. Masayuki Namiki
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  5. Robert Shumaker
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Corresponding author

Correspondence to Robert Shumaker.

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Conflicts of interest

Ziad Hussein, Hitoshi Mizuo, Seiichi Hayato, Masayuki Namiki, and Robert Shumaker are employees of Eisai.

Funding

Editorial assistance was provided by Oxford PharmaGenesis Inc. and was funded by Eisai Inc.

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Hussein, Z., Mizuo, H., Hayato, S. et al. Clinical Pharmacokinetic and Pharmacodynamic Profile of Lenvatinib, an Orally Active, Small-Molecule, Multitargeted Tyrosine Kinase Inhibitor. Eur J Drug Metab Pharmacokinet 42, 903–914 (2017). https://doi.org/10.1007/s13318-017-0403-4

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  • DOI: https://doi.org/10.1007/s13318-017-0403-4

Keywords

  • Vascular Endothelial Growth Factor
  • Everolimus
  • Hepatic Impairment
  • Stem Cell Factor
  • Metastatic Renal Cell Carcinoma