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Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

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Summary

Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of 14C-lenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.

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Acknowledgments

The authors thank the patients that participated in this study and acknowledge Abadi Gebretensae for his bioanalytical support.

This study was supported by Eisai Inc. Part of this work was previously presented as follows: Dubbelman AC, Rosing Hilde, Mergui-Roelvink M, Gupta A, Verbel D, Sellecchia R, Fan J, Thompson GA, Shumaker R, Huitema ADR, Beijnen JH, Schellens JHM. (2013) A mass balance study of 14C-lenvatinib (E7080) in patients with advanced solid tumours or lymphomas. Scientific Spring Meeting of the Dutch Society for Clinical Pharmacology and Biopharmacy, March 30, 2012; abstract published in British Journal of Clinical Pharmacology 76 (5): pp. 831–831.

Conflict of interest

A.C. Dubbelman, H. Rosing, C. Nijenhuis, A.D.R. Huitema, M. Mergui-Roelvink, J. H.M. Schellens and J.H. Beijnen declare they have no conflict of interest. A. Gupta is employee of Eisai Ltd., D. Verbel and R. Shumaker are employees of Eisai Inc. G.A. Thompson is a paid consultant to Eisai Inc.

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Author notes

  1. Anne-Charlotte Dubbelman

    Present address: Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

Authors and Affiliations

  1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Anne-Charlotte Dubbelman, Marja Mergui-Roelvink & Jan H. M. Schellens

  2. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands

    Anne-Charlotte Dubbelman, Hilde Rosing, Cynthia Nijenhuis, Alwin D. R. Huitema & Jos H. Beijnen

  3. Eisai Ltd., Mosquito Way Hatfield, Hertfordshire, AL10 9SN, UK

    Anubha Gupta

  4. Eisai Inc., Woodcliff Lake, NJ, USA

    David Verbel & Robert Shumaker

  5. GA Thompson Consulting, West Chester, OH, USA

    Gary Thompson

  6. Science Faculty, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jan H. M. Schellens & Jos H. Beijnen

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  1. Anne-Charlotte Dubbelman
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Correspondence to Anne-Charlotte Dubbelman.

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Dubbelman, AC., Rosing, H., Nijenhuis, C. et al. Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas. Invest New Drugs 33, 233–240 (2015). https://doi.org/10.1007/s10637-014-0181-7

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  • DOI: https://doi.org/10.1007/s10637-014-0181-7

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