Skip to main content

Population Pharmacokinetic Meta-Analysis of Trabectedin (ET-743, Yondelis®) in Cancer Patients



To characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis®) in cancer patients.


A total of 603 patients (945 cycles) receiving intravenous trabectedin as monotherapy at doses ranging from 0.024 to 1.8 mg/m2 and given as a 1-, 3- or 24-hour infusion every 21 days; a 1- or 3-hour infusion on days 1, 8 and 15 of a 28-day cycle; or a 1-hour infusion daily for 5 consecutive days every 21 days were included in the analysis. An open four-compartment pharmacokinetic model with linear elimination, linear and nonlinear distribution to the deep and shallow peripheral compartments, respectively, and a catenary compartment off the shallow compartment was developed to best describe the index dataset using NONMEM V software. The effect of selected patient covariates on trabectedin pharmacokinetics was investigated. Model evaluation was performed using good-ness-of-fit plots and relative error measurements for the test dataset. Simulations were undertaken to evaluate covariate effects on trabectedin pharmacokinetics.


The mean (SD) trabectedin elimination half-life was approximately 180 (61.4) hours. Plasma accumulation was limited when trabectedin was given every 3 weeks. Systemic clearance (31.5 L/h, coefficient of variation 51%) was 19.2% higher in patients receiving concomitant dexamethasone. The typical values of the volume of distribution at steady state for male and female patients were 6070L and 5240L, respectively. Within the range studied, age, body size variables, AST, ALT, alkaline Phosphatase, lactate dehydrogenase, total bilirubin, Creatinine clearance, albumin, total protein, Eastern Cooperative Oncology Group performance status and presence of liver metastases were not statistically related to trabectedin pharmacokinetic parameters. The pharmacokinetic parameters of trabectedin were consistent across the infusion durations and dose regimens evaluated.


The integration of trabectedin pharmacokinetic data demonstrated linear elimination, dose-proportionality up to 1.8 mg/m2 and time-independent pharmacokinetics. The pharmacokinetic impact of dexamethasone and sex covariates is probably limited given the moderate to large interindividual pharmacokinetic variability of trabectedin. The antiemetic and hepatoprotective effects are still a valid rationale to recommend dexamethasone as a supportive treatment for trabectedin.

This is a preview of subscription content, access via your institution.

Table I
Table II
Fig. 1
Table III
Table IV
Fig. 2
Fig. 3
Fig. 4
Table V


  1. 1.

    The use of trade names is for product identification purposes only and does not imply endorsement.


  1. 1.

    Guan Y, Sakai R, Rinehart KL, et al. Molecular and crystal structures of ecteinascidins: potent antitumor compounds from the Caribbean tunicate Ecteinascidia turbinata. J Biomol Struct Dyn 1993; 10: 793–818

    PubMed  CAS  Google Scholar 

  2. 2.

    Lau L, Supko JG, Blaney S, et al. A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors: a Children’s Oncology Group study. Clin Cancer Res 2005; 11: 672–7

    PubMed  CAS  Google Scholar 

  3. 3.

    Zewail-Foote M, Hurley LH. Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J Med Chem 1999; 42: 2493–7

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Erba E, Bergamaschi D, Bassano L, et al. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer 2001; 37: 97–105

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Minuzzo M, Marchini S, Broggini M, et al. Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci U S A 2000; 97: 6780–4

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Takebayashi Y, Pourquier P, Zimonjic DB, et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair [published erratum appears in Nat Med 2001; 7 (11): 1255]. Nat Med 2001; 7(8): 961–6

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Izbicka E, Lawrence R, Raymond E, et al. In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann Oncol 1998; 9: 981–7

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Le Cesne A, Blay JY, Judson I, et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol 2005; 23: 576–84

    PubMed  Article  Google Scholar 

  9. 9.

    Villalona-Calero MA, Eckhardt SG, Weiss G, et al. A phase I and pharmacokinetic study of ecteinascidin-743 on a daily × 5 schedule in patients with solid malignancies. Clin Cancer Res 2002; 8: 75–85

    PubMed  CAS  Google Scholar 

  10. 10.

    Twelves C, Hoekman K, Bowman A, et al. Phase I and pharmacokinetic study of Yondelis (ecteinascidin-743; ET-743) administered as an infusion over 1h or 3h every 21 days in patients with solid tumours. Eur J Cancer 2003; 39: 1842–51

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Taamma A, Misset JL, Riofrio M, et al. Phase I and pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors. J Clin Oncol 2001; 19: 1256–65

    PubMed  CAS  Google Scholar 

  12. 12.

    van Kesteren C, Twelves C, Bowman A, et al. Clinical pharmacology of the novel marine-derived anticancer agent ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study. Anticancer Drugs 2002; 13: 381–93

    PubMed  Article  Google Scholar 

  13. 13.

    Laverdiere C, Kolb EA, Supko JG, et al. Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer 2003; 98: 832–40

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Garcia-Carbonero R, Supko JG, Manola J, et al. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol 2004; 22: 1480–90

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    van Kesteren C, Mathjt RA, Lopez-Lazaro L, et al. A comparison of limited sampling strategies for prediction of ecteinascidin 743 clearance when administered as a 24-h infusion. Cancer Chemother Pharmacol 2001; 48: 459–66

    PubMed  Article  Google Scholar 

  16. 16.

    Puchalski TA, Ryan DP, Garcia-Carbonero R, et al. Pharmacokinetics of ecteinascidin 743 administered as a 24-h continuous infusion to adult patients with soft tissue sarcomas: associations with clinical characteristics, pathophysiological variables and toxicity. Cancer Chemother Pharmacol 2002; 50: 309–19

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Data on file, Johnson and Johnson Pharmaceutical Research and Development, 2006

  18. 18.

    Johnson & Johnson Pharmaceutical Research & Development. R279741 Yondelis™ intravenous formulation (Trabectedin) Investigator’s brochure. Edition 3. Raritan (NJ): Johnson & Johnson Pharmaceutical Research & Development, 2006 Apr

    Google Scholar 

  19. 19.

    Beumer JH, Rademaker-Lakhai JM, Rosing H, et al. Trabectedin (Yondelis™, formerly ET-743), a mass balance study in patients with advanced cancer. Invest New Drugs 2005; 23: 429–36

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Kuffel MJ, Reid JM, Ames MM. Cytochrome P450 catalyzed metabolism of ecteinascidin 743 by rat and human liver microsomes. Proc Am Assoc Cancer Res 1997; 38: 596

    Google Scholar 

  21. 21.

    Reid JM, Kuffel MJ, Squillace DP, et al. Characterization of the in vitro metabolism, pharmacokinetics, and biliary excretion of ecteinascidin 743 (NSC 648766) in male and female rats. Ann Oncol 1998; 9: 50

    Google Scholar 

  22. 22.

    Brandon EF, Sparidans RW, Guijt KJ, et al. In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis, Trabectidin), a novel marine anticancer drug. Invest New Drugs 2006; 24: 3–14

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 1993; 21: 735–50

    PubMed  CAS  Google Scholar 

  24. 24.

    Delaloge S, Yovine A, Taamma A, et al. Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients. Preliminary evidence of activity. J Clin Oncol 2001; 19: 1248–55

    PubMed  CAS  Google Scholar 

  25. 25.

    Yovine A, Riofrio M, Blay JY, et al. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol 2004; 22: 890–9

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Zelek L, Yovine A, Brain E, et al. A phase II study of Yondelis (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer. Br J Cancer 2006; 94: 1610–4

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Sessa C, De Braud F, Perotti A, et al. Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails. J Clin Oncol 2005; 23: 1867–74

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Stokvis E, Rosing H, Lopez-Lazaro L, et al. Simple and sensitive liquid Chromatographic quantitative analysis of the novel marine anticancer drug Yondelis (ET-743, trabectedin) in human plasma using column switching and tandem mass spectrometric detection. J Mass Spectrom 2004; 39: 431–6

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Rosing H, Hillebrand MJ, Jimeno JM, et al. Quantitative determination of ecteinascidin 743 in human plasma by miniaturized high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. J Mass Spectrom 1998; 33: 1134–40

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Beal SL, Sheiner LB. NONMEM users guides. Hanover (MD): GloboMax, LLC, 1992

    Google Scholar 

  31. 31.

    Frame B, Miller R, Lalonde RL. Evaluation of mixture modeling with count data using NONMEM. J Pharmacokinetic Pharmacodyn 2003; 30: 167–83

    Article  CAS  Google Scholar 

  32. 32.

    Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults. J Pediatr 1978; 93: 62–6

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Martin L, Chatelut E, Boneu A, et al. Improvement of the Cockcroft-Gault equation for predicting glomerular filtration in cancer patients. Bulletin Du Cancer 1998; 85: 631–6

    PubMed  CAS  Google Scholar 

  34. 34.

    Wählby U, Jonsson EN, Karlsson MO. Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis. AAPS PharmSci 2002; 4(4): E27

    PubMed  Article  Google Scholar 

  35. 35.

    Verweij J. Ecteinascidin-743 (ET-743): early test or effective treatment in soft tissue sarcomas? J Clin Oncol 2005; 23: 5420–3

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Hing J, Perez-Ruixo JJ, Stuyckens K, et al. Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of trabectedin (ET-743, Yondelis) induced neutropenia. Clin Pharmacol Ther. Epub 2007 Jun 27

  37. 37.

    Fetterly G, Owen JS, Stuyckens K, et al. Semi-mechanistic pharmacokinetic and pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment. Cancer Chemother Pharmacol. In press

  38. 38.

    Schuetz EG, Wrighton SA, Barwick JL, et al. Induction of cytochrome P-450 by glucocorticoids and pregnenolone 16 alpha-carbonitrile regulate de novo synthesis of a common form of cytochrome P-450 in cultures of adult rat hepatocytes and in the liver in vivo. J Biol Chem 1984; 259: 1999–2006

    PubMed  CAS  Google Scholar 

  39. 39.

    Schuetz EG, Guzelian PS. Induction of cytochrome P-450 by glucocorticoids in rat liver. II. Evidence that glucocorticoids regulate induction of cytochrome P-450 by a nonclassical receptor mechanism. J Biol Chem 1984; 259: 2007–12

    PubMed  CAS  Google Scholar 

  40. 40.

    Grosso F, Dileo P, Sanfilippo R, et al. Steriod premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma. Eur J Cancer 2006 Jul; 42(10): 1484–90

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Beumer JH, Schellens JH, Beijnen JH. Hepatotoxicity and metabolism of trabectedin: a literature review. Pharmacol Res 2005; 51: 391–8

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Donald S, Verschoyle RD, Greaves P, et al. Complete protection by high-dose dexamethasone against the hepatotoxicity of the novel antitumor drug Yondelis (ET-743) in the rat. Cancer Res 2003; 63: 5902–8

    PubMed  CAS  Google Scholar 

  43. 43.

    Bruno R, Vivier N, Vergniol JC, et al. A population pharmacokinetic model for docetaxel (Taxotere): model building and validation. J Pharmacokinet Biopharm 1996; 24(2): 153–72

    PubMed  CAS  Google Scholar 

  44. 44.

    Morgan JA, Le Cesne A, Chawla S, et al. Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma (L-sarcomas) after failure of prior anthracylines (A) and ifosfamide (I). In: 2007 ASCO Annual Meeting Proceedings; 2007 Jun 1–5; Chicago (IL). J Clin Oncol 2007 Jun 20; 25(18S): 10060

    Google Scholar 

Download references


This study was presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, USA, June 2–6, 2006.

The authors would like to thank the hundreds of patients and the investigators and their medical, nursing, and laboratory staff who participated in the clinical studies included in the present study. The authors also thank Andrew Chow and Paul Soons for the comments and suggestions they provided during this analysis. During the conduct of the present work, Juan Jose Perez-Ruixo, Peter Zannikos and Kim Stuyckens were employees at Johnson & Johnson Pharmaceutical Research & Development, Arturo Soto-Matos and Luis Lopez-Lazaro were employees at PharmaMar, and Sarapee Hirankarn, Elizabeth Ludwig and Joel Owen were employees at Cognigen, who received consultation fees from Johnson & Johnson Pharmaceutical Research & Development. This study was supported by Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium, and PharmaMar, Madrid, Spain. The authors have no other conflicts of interest to declare.

Author information



Corresponding author

Correspondence to Juan Jose Perez-Ruixo.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Perez-Ruixo, J.J., Zannikos, P., Hirankam, S. et al. Population Pharmacokinetic Meta-Analysis of Trabectedin (ET-743, Yondelis®) in Cancer Patients. Clin Pharmacokinet 46, 867–884 (2007).

Download citation


  • Dexamethasone
  • Trabectedin
  • Population Pharmacokinetic Model
  • Linear Elimination
  • Yondelis