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Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison

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Summary

Lenvatinib is an oral, multiple receptor tyrosine kinase inhibitor. Preclinical drug metabolism studies showed unique metabolic pathways for lenvatinib in monkeys and rats. A human mass balance study demonstrated that lenvatinib related material is mainly excreted via feces with a small fraction as unchanged parent drug, but little is reported about its metabolic fate. The objective of the current study was to further elucidate the metabolic pathways of lenvatinib in humans and to compare these results to the metabolism in rats and monkeys. To this end, we used plasma, urine and feces collected in a human mass balance study after a single 24 mg (100 μCi) oral dose of 14C-lenvatinib. Metabolites of 14C-lenvatinib were identified using liquid chromatography (high resolution) mass spectrometry with off-line radioactivity detection. Close to 50 lenvatinib-related compounds were detected. In humans, unchanged lenvatinib accounted for 97 % of the radioactivity in plasma, and comprised 0.38 and 2.5 % of the administered dose excreted in urine and feces, respectively. The primary biotransformation pathways of lenvatinib were hydrolysis, oxidation and hydroxylation, N-oxidation, dealkylation and glucuronidation. Various combinations of these conversions with modifications, including hydrolysis, gluthathione/cysteine conjugation, intramolecular rearrangement and dimerization, were observed. Some metabolites seem to be unique to the investigated species (human, rat, monkey). Because all lenvatinib metabolites in human plasma were at very low levels compared to lenvatinib, only lenvatinib is expected to contribute to the pharmacological effects in humans.

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Abbreviations

2-ME:

2-mercaptoethanol

ACN:

Acetonitrile

HPLC:

High performance liquid chromatography

HR-MS:

High-resolution mass spectrometry

LC-MS:

Liquid chromatography mass spectrometry

LLOQ:

Lower limit of quantitation

LOD:

Limit of detection

LSC:

Liquid scintillation counting

MeOH:

Methanol

TRA:

Total radioactivity

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Acknowledgments

The authors would like to thank the patients who gave their valuable time to participate in the human mass balance study.

Authorship contributions

ᅟ

Participated in research design:

Dubbelman, Jansen, Mizuo, Critchley, Shumaker, Nijenhuis, Rosing

Conducted experiments:

Dubbelman, Jansen, Nijenhuis

Performed data analysis:

Dubbelman, Nijenhuis

Wrote or contributed to the writing of the manuscript:

Dubbelman, Jansen, Mizuo, Kawaguchi, Nijenhuis, Rosing, Schellens, Beijnen

Author information

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. The Netherlands Cancer Institute, Division of Clinical Pharmacology, Department of Medical Oncology, Amsterdam, The Netherlands

    Anne-Charlotte Dubbelman & Jan H. M. Schellens

  2. Antoni van Leeuwenhoek / The Netherlands Cancer Institute and MC Slotervaart, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 CE, Amsterdam, The Netherlands

    Anne-Charlotte Dubbelman, Cynthia M. Nijenhuis, Robert S. Jansen, Hilde Rosing & Jos H. Beijnen

  3. Eisai Co. Ltd., Drug metabolism and Pharmacokinetics Japan, Tsukuba, Japan

    Hitoshi Mizuo & Shinki Kawaguchi

  4. Eisai Ltd., Chief Clinical Officer Department, Clinical Pharmacology, Hatfield, UK

    David Critchley

  5. Eisai Inc., Oncology Product Creation Unit, Clinical Pharmacology and Translational Medicine, Woodcliff Lake, NJ, USA

    Robert Shumaker

  6. Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences Utrecht, Utrecht University, Utrecht, The Netherlands

    Jan H. M. Schellens & Jos H. Beijnen

Authors
  1. Anne-Charlotte Dubbelman
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  2. Cynthia M. Nijenhuis
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Corresponding authors

Correspondence to Anne-Charlotte Dubbelman or Cynthia M. Nijenhuis.

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Conflict of interest

Hitoshi Mizuo and Shinki Kawaguchi are employees of Eisai Co. Ltd., David Critchley is an employee of Eisai Ltd. and Robert Shumaker in an employee of Eisai Inc. All other authors declare no conflict of interest.

Additional information

This work was financially supported by Eisai Co. Ltd.

Anne-Charlotte Dubbelman and Cynthia M. Nijenhuis are co-first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure 1

High-resolution spectra and proposed fragmentation of the most abundant metabolites (MET4, MET27, M2, M3’ and M2’) (DOCX 96 kb)

Supplementary Data 1

Identification of lenvatinib metabolites in humans, rat and monkey (DOCX 20.5 kb)

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Dubbelman, AC., Nijenhuis, C.M., Jansen, R.S. et al. Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison. Invest New Drugs 34, 300–318 (2016). https://doi.org/10.1007/s10637-016-0342-y

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