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Investigational New Drugs

, Volume 23, Issue 5, pp 429–436 | Cite as

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

  • J. H. Beumer
  • J. M. Rademaker-Lakhai
  • H. Rosing
  • L. Lopez-Lazaro
  • J. H. Beijnen
  • J. H. M. Schellens
Article

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.

Keywords

trabectedin ET-743 mass balance disposition human 

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

Cmax

maximum plasma concentration

LC-MS/MS

liquid chromatography with tandem mass spectrometry

LSC

liquid scintillation counting

t1/2

terminal half-life

tmax

time of maximum plasma concentration

TRA

total radioactivity

ULN

upper limit of normal

Vss

volume of distribution at steady state

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • J. H. Beumer
    • 1
    • 5
  • J. M. Rademaker-Lakhai
    • 2
  • H. Rosing
    • 1
  • L. Lopez-Lazaro
    • 3
  • J. H. Beijnen
    • 1
    • 4
  • J. H. M. Schellens
    • 2
    • 4
  1. 1.Department of Pharmacy & PharmacologySlotervaart Hospital/The Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Department of Medical OncologyAntoni van Leeuwenhoek Hospital/The Netherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.PharmaMar, Clinical PharmacologyColmenar ViejoMadridSpain
  4. 4.Department of Biomedical Analysis, Division of Drug Toxicology, Faculty of Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  5. 5.University of Pittsburgh Cancer InstitutePittsburghUSA

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