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01-06-2016 | PHASE I STUDIES

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

Authors: Anne-Charlotte Dubbelman, Cynthia M. Nijenhuis, Robert S. Jansen, Hilde Rosing, Hitoshi Mizuo, Shinki Kawaguchi, David Critchley, Robert Shumaker, Jan H. M. Schellens, Jos H. Beijnen

Published in: Investigational New Drugs | Issue 3/2016

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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Title: Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison
Authors: Anne-Charlotte Dubbelman
Cynthia M. Nijenhuis
Robert S. Jansen
Hilde Rosing
Hitoshi Mizuo
Shinki Kawaguchi
David Critchley
Robert Shumaker
Jan H. M. Schellens
Jos H. Beijnen
Publication date: 01-06-2016
Publisher: Springer US
Published in: Investigational New Drugs / Issue 3/2016
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-016-0342-y

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