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Pharmacokinetics and excretion of 14C–Plitidepsin in patients with advanced cancer

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Summary

Plitidepsin (Aplidin®) is a marine-derived anticancer compound currently investigated in phase III clinical trials. This article describes the distribution, metabolism and excretion of this novel agent and it mainly aims to identify the major routes of elimination. Six subjects were enrolled in a mass balance study during which radiolabelled plitidepsin was administered as a 3-h intravenous infusion. Blood samples were taken and urine and faeces were collected. Total radioactivity (TRA) analysis using Liquid Scintillation Counting (LSC) was done to determine the amount of radioactivity excreted from the body and plitidepsin concentrations in whole blood, plasma and urine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. In total, a mean of 77.4% of the administered radioactivity was excreted over a time period of 20 days, of which 71.3% was recovered in faeces and 6.1% was found in urine. The majority excreted in urine was accounted for by unchanged plitidepsin, with only 1.5% of the total administered dose explained by metabolites in urine. Faeces, on the other hand contained low levels of parent compound, which means that most of the TRA excreted in faeces was accounted for by metabolites. TRA levels were 3.7 times higher in whole blood compared to plasma. Plitidepsin was widely distributed and plasma clearance was low. This study shows that red blood cells are a major distribution compartment and that the biliary route is the main route of total radioactivity excretion.

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Authors and Affiliations

  1. Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek / The Netherlands Cancer Institute, P.O. Box 90440, 1006, BK, Amsterdam, The Netherlands

    L. van Andel, H. Rosing, M. M. Tibben, N. de Vries, A. H. M. de Vries Schultink & J. H. Beijnen

  2. Pharma Mar, S.A. Colmenar Viejo, Madrid, Spain

    S. Fudio, S. Munt, B. Miguel-Lillo & I. González

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

    J. H. M. Schellens & J. H. Beijnen

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

    J. H. M. Schellens

Authors
  1. L. van Andel
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  2. S. Fudio
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  3. H. Rosing
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  4. S. Munt
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  5. B. Miguel-Lillo
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  6. I. González
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  7. M. M. Tibben
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  8. N. de Vries
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  9. A. H. M. de Vries Schultink
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  10. J. H. M. Schellens
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  11. J. H. Beijnen
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Corresponding author

Correspondence to L. van Andel.

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Conflict of interest

SF, SM, IG are currently employees, and BM-L was a former employee at Pharma Mar, S.A. LA, HR, MMT, NV, AHMVS, JHMS and JHB are employed at the Netherlands Cancer Institute.

Funding

This study was funded by Pharma Mar, S.A.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the participating institution and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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van Andel, L., Fudio, S., Rosing, H. et al. Pharmacokinetics and excretion of 14C–Plitidepsin in patients with advanced cancer. Invest New Drugs 35, 589–598 (2017). https://doi.org/10.1007/s10637-017-0432-5

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  • DOI: https://doi.org/10.1007/s10637-017-0432-5

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