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Excretion balance and pharmacokinetics following a single oral dose of [14C]-fedratinib in healthy subjects

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Abstract

Purpose

Fedratinib is an oral and selective kinase inhibitor with activity against wild type and mutationally activated Janus kinase 2 and FMS-like tyrosine kinase 3, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. This open-label mass balance study in healthy subjects investigated the excretion balance and systemic exposure of radioactivity after oral administration of [14C]-fedratinib; and the pharmacokinetics of fedratinib and its contribution to overall exposure of radioactivity.

Methods

Six healthy males received a single oral dose of 200 mg [14C]-fedratinib base (2.775 MBq, 75 μCi) as a solution. Blood, urine and feces samples were collected for up to 35 day postdose. Urine and feces samples were collected until the 24-h excretion of radioactivity fell below 0.5% of administered dose (at least 14 day postdose). Expired air was collected up to 8-h postdose. Total radioactivity (blood, plasma, urine, feces, and expired air) and fedratinib concentrations (plasma) were measured.

Results

Approximately 77% (23% unchanged) of fedratinib derived radioactivity was excreted in feces and 5% (3% unchanged) was excreted in urine. Excretion via expired air was negligible. The time to maximum concentration for both total radioactivity and parent drug was similar, with unchanged drug representing the majority of the circulating radioactivity. The ratio of blood to plasma concentration of radioactivity ranged from 0.615 to 0.753 indicating limited distribution of fedratinib and/or its metabolites into red blood cells.

Conclusions

Fedratinib derived radioactivity was primarily excreted in feces following a single oral dose of radiolabeled fedratinib to healthy subjects.

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Acknowledgements

The authors thank all study participants, their families and clinical study team members.

Funding

The clinical pharmacology study was sponsored by Sanofi.

Author information

Authors and Affiliations

  1. Translational Development and Clinical Pharmacology, Bristol Myers Squibb, 556 Morris Ave, Summit, NJ, 07901, USA

    Ken Ogasawara, Sekhar Surapaneni, Maria Palmisano & Gopal Krishna

  2. Sanofi, Bridgewater, NJ, USA

    Christine Xu & Vanaja Kanamaluru

  3. Covance Clinical Research Inc, Madison, WI, USA

    Nicholas Siebers

  4. Sanofi, Chilly-Mazarin, France

    Laurence Ridoux

Authors
  1. Ken Ogasawara
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  2. Christine Xu
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  3. Vanaja Kanamaluru
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  4. Nicholas Siebers
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  5. Sekhar Surapaneni
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  6. Laurence Ridoux
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  7. Maria Palmisano
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  8. Gopal Krishna
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Corresponding author

Correspondence to Gopal Krishna.

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Conflict of interest

K.O., S.S., M.P., and G.K. are employees and hold equity ownership in Bristol Myers Squibb. C.X., V.K., and L.R. are employees and hold equity ownership in Sanofi. N.S. is an employee of Covance, which was paid by Sanofi to conduct the study.

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Ogasawara, K., Xu, C., Kanamaluru, V. et al. Excretion balance and pharmacokinetics following a single oral dose of [14C]-fedratinib in healthy subjects. Cancer Chemother Pharmacol 86, 307–314 (2020). https://doi.org/10.1007/s00280-020-04121-0

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  • DOI: https://doi.org/10.1007/s00280-020-04121-0

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