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Trabectedin (YondelisTM, formerly ET-743), a mass balance study in patients with advanced cancer

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Abstract

Trabectedin (YondelisTM, formerly ET-743) is an anti-cancer drug currently undergoing phase II development. Despite extensive pharmacokinetic studies, the human disposition and excretory pathways of trabectedin remain largely unknown. Our objective was to determine the mass balance of trabectedin in humans. To this aim, we intravenously administered [14C]trabectedin to 8 cancer patients, followed by collection of whole blood, urine and faeces samples. A 24-h infusion was administered to 2 patients, whereas the other 6 patients received a 3-h infusion. Levels of total radioactivity and unchanged trabectedin were determined and used for calculation of pharmacokinetic parameters. No schedule dependency of pharmacokinetic parameters was observed apart from Cmax. Plasma and whole blood concentrations of [14C]trabectedin related radioactivity were comparable. Only 8% of the plasma exposure to [14C]trabectedin related compounds is accounted for by trabectedin, indicating the importance of metabolism in trabectedin elimination. Trabectedin displays a large volume of distribution (±1700 L), relative to total radioactivity (±220 L). [14C]trabectedin related radioactivity is mainly excreted in the faeces (mean: 55.5% of the dose). Urinary excretion accounts for 5.9% of the dose on average resulting in a mean overall recovery of 61.4% (3-h administration schedule). The excretion of unchanged trabectedin is very low both in faeces and in urine (< 1% of dose). In conclusion, trabectedin is extensively metabolised and principally excreted in the faeces.

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Abbreviations

AUC0-96:

area under the plasma concentration curve extrapolated from 0–96 h

AUCinf:

area under the plasma concentration curve extrapolated to infinity

Cl:

total body clearance

C max :

maximum plasma concentration

LC-MS/MS:

liquid chromatography with tandem mass spectrometry

LSC:

liquid scintillation counting

t1/2:

terminal half-life

t max :

time of maximum plasma concentration

TRA:

total radioactivity

ULN:

upper limit of normal

V ss :

volume of distribution at steady state

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Authors and Affiliations

  1. Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands

    J. H. Beumer, H. Rosing & J. H. Beijnen

  2. Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands

    J. M. Rademaker-Lakhai & J. H. M. Schellens

  3. PharmaMar, Clinical Pharmacology, Colmenar Viejo, Madrid, Spain

    L. Lopez-Lazaro

  4. Department of Biomedical Analysis, Division of Drug Toxicology, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

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

  5. University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G.28. 5117 Centre Avenue, Pittsburgh, PA, USA, 15213-1863

    J. H. Beumer

Authors
  1. J. H. Beumer
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  2. J. M. Rademaker-Lakhai
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  3. H. Rosing
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  4. L. Lopez-Lazaro
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  5. J. H. Beijnen
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  6. J. H. M. Schellens
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Correspondence to J. H. Beumer.

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Beumer, J.H., Rademaker-Lakhai, J.M., Rosing, H. et al. Trabectedin (YondelisTM, formerly ET-743), a mass balance study in patients with advanced cancer. Invest New Drugs 23, 429–436 (2005). https://doi.org/10.1007/s10637-005-2902-4

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  • DOI: https://doi.org/10.1007/s10637-005-2902-4

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