Population pharmacokinetics of trabectedin in adolescent patients with cancer

  • Italo PoggesiEmail author
  • Belén Valenzuela
  • Daniele Ouellet
  • Martha Gonzalez
  • Vera Hillewaert
  • Sylvain Baruchel
  • Elizabeth Fox
  • Juan Jose Perez-Ruixo
Original Article



To characterize the trabectedin population pharmacokinetics in children and adolescent patients with cancer and compare it with the trabectedin pharmacokinetics in adults.


Plasma concentrations from ten adolescent and three children with cancer (age range 4.0–17.0 years) treated with trabectedin at doses ranging from 1.1 to 1.7 mg/m2, administered as a 24-h continuous intravenous infusion every 3 weeks, were available for the analysis. An external model evaluation was performed to verify whether a previously developed adult population pharmacokinetic model was predictive of the pediatric plasma concentrations of trabectedin. The maximum a posteriori estimation of the individual pharmacokinetic parameters for pediatric patients was conducted, after successful completion of the external evaluation step. The relationships between pharmacokinetic parameters and body size were evaluated.


External evaluation methods showed no major differences between the adult population and children and adolescent patients of this study. The mean ± standard deviation (SD) of the individual estimated clearance and central volume of distribution in these children/adolescent patients was 36.4 ± 16.1 L/h and 13.2 ± 6.54 L, respectively. These values were similar to the typical values reported for adult patients—37.6 L/h and 13.9 L (for females) and 16.1 L (for males). The median area under the plasma concentration versus time curve (AUC) in children/adolescent patients was 55.1 µg h/L, while in the adult population the median AUC was 61.3 µg h/L, both administered a 1.5 mg/m2 dose regimen with mean (range) BSA for adults = 1.86 (0.90–2.80) vs children/adolescent patients = 1.49 (0.66–2.54).


The adult population pharmacokinetic model adequately described the trabectedin plasma concentrations and its variability in the pediatric population of patients involved in this assessment that mostly comprised adolescents. The trabectedin systemic exposure achieved in this population was comparable (within 12%) to the exposure obtained in adult population when the same dose, expressed in mg/m2, was administered.


Trabectedin Cancer Pediatric Nonlinear mixed-effects modeling 



The authors would like to thank all pediatric patients and their families, nurses, and physician who participated in the studies included in the analysis for their valuable contributions. The authors also thank Priya Ganpathy, MPharm, ISMPP CMPP™ (SIRO Clinpharm Pvt. Ltd, Thane, India) for writing assistance and Namit Ghildyal, Ph.D. (Janssen Global Services, LLC) for additional editorial assistance.

Author contributions

All authors met the ICMJE criteria and those who fulfilled the criteria are listed as authors. All authors provided substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; and drafted the work or revised it critically for important intellectual content; and made the final decision about where to publish these data. All authors agreed to be accountable for all aspects of the work.


The population PK modeling study was supported by funding from Janssen Research and Development, LLC. The sponsor also provided funding for development of this manuscript. Pediatric clinical trials of trabectedin were supported by the NCI intramural program or the Children’s Oncology Group, an NCI funded cooperative group.

Compliance with ethical standards

Conflict of interest

IP is an employee of Janssen-Cilag, Italy; JJPR and VH are employees of Janssen Pharmaceutica NV, Belgium; DO and MG are employees of Janssen Research and Development, LLC, USA (parent company Johnson and Johnson). BV received fees from Janssen as a consultant on this analysis. EF was a government employee at the time of the clinical trial and is currently a faculty member at the Perelman School of Medicine at the University of Pennsylvania, she received no funding from Janssen Pharmaceutica or Johnson and Johnson for conduct of the clinical trial or preparation of this manuscript.


  1. 1.
    Cuevas C, Francesch A (2009) Development of Yondelis (trabectedin, ET-743). A semisynthetic process solves the supply problem. Nat Prod Rep 26(3):322–337. CrossRefGoogle Scholar
  2. 2.
    D’Incalci M, Galmarini CM (2010) A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther 9(8):2157–2163. CrossRefGoogle Scholar
  3. 3.
    Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW (1996) DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 35(41):13303–13309. CrossRefGoogle Scholar
  4. 4.
    Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, Erba E, Uboldi S, Zucchetti M, Pasqualini F, Nebuloni M, van Rooijen N, Mortarini R, Beltrame L, Marchini S, Fuso Nerini I, Sanfilippo R, Casali PG, Pilotti S, Galmarini CM, Anichini A, Mantovani A, D’Incalci M, Allavena P (2013) Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23(2):249–262. CrossRefGoogle Scholar
  5. 5.
    Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR (2016) Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol 34(8):786–793. CrossRefGoogle Scholar
  6. 6.
    Khalifa J, Ouali M, Chaltiel L, Le Guellec S, Le Cesne A, Blay JY, Cousin P, Chaigneau L, Bompas E, Piperno-Neumann S, Bui-Nguyen B, Rios M, Delord JP, Penel N, Chevreau C (2015) Efficacy of trabectedin in malignant solitary fibrous tumors: a retrospective analysis from the French Sarcoma Group. BMC Cancer 15:700. CrossRefGoogle Scholar
  7. 7.
    Le Cesne A, Cresta S, Maki RG, Blay JY, Verweij J, Poveda A, Casali PG, Balana C, Schoffski P, Grosso F, Lardelli P, Nieto A, Alfaro V, Demetri GD (2012) A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas. Eur J Cancer 48(16):3036–3044. CrossRefGoogle Scholar
  8. 8.
    Yondelis Prescribing Information. Accessed 27 Sep 2018
  9. 9.
    Beumer JH, Lopez-Lazaro L, Schellens JH, Beijnen JH, van Tellingen O (2009) Evaluation of human plasma protein binding of trabectedin (Yondelis, ET-743). Curr Clin Pharmacol 4(1):38–42CrossRefGoogle Scholar
  10. 10.
    Vermeir M, Hemeryck A, Cuyckens F, Francesch A, Bockx M, Van Houdt J, Steemans K, Mannens G, Aviles P, De Coster R (2009) In vitro studies on the metabolism of trabectedin (YONDELIS) in monkey and man, including human CYP reaction phenotyping. Biochem Pharmacol 77(10):1642–1654. CrossRefGoogle Scholar
  11. 11.
    Beumer JH, Rademaker-Lakhai JM, Rosing H, Lopez-Lazaro L, Beijnen JH, Schellens JH (2005) Trabectedin (Yondelis, formerly ET-743), a mass balance study in patients with advanced cancer. Investig New Drugs 23(5):429–436. CrossRefGoogle Scholar
  12. 12.
    Perez-Ruixo JJ, Zannikos P, Hirankarn S, Stuyckens K, Ludwig EA, Soto-Matos A, Lopez-Lazaro L, Owen JS (2007) Population pharmacokinetic meta-analysis of trabectedin (ET-743, Yondelis) in cancer patients. Clin Pharmacokinet 46(10):867–884CrossRefGoogle Scholar
  13. 13.
    Chuk MK, Aikin A, Whitcomb T, Widemann BC, Zannikos P, Bayever E, Balis FM, Fox E (2012) A phase I trial and pharmacokinetic study of a 24-hour infusion of trabectedin (Yondelis(R), ET-743) in children and adolescents with relapsed or refractory solid tumors. Pediatr Blood Cancer 59(5):865–869. CrossRefGoogle Scholar
  14. 14.
    Lau L, Supko JG, Blaney S, Hershon L, Seibel N, Krailo M, Qu W, Malkin D, Jimeno J, Bernstein M, Baruchel S (2005) 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 11(2 Pt 1):672–677Google Scholar
  15. 15.
    Food and Drug Administration. Clinical Pharmacology Review. NDA207953.…/DevelopmentResources/UCM614989.pdf. Accessed 25 Sept 2018
  16. 16.
    Baruchel S, Pappo A, Krailo M, Baker KS, Wu B, Villaluna D, Lee-Scott M, Adamson PC, Blaney SM (2012) A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children’s Oncology Group. Eur J Cancer 48(4):579–585. CrossRefGoogle Scholar
  17. 17.
    NONMEM Users Guides (1989–2011). Icon Development Solutions, Ellicott CityGoogle Scholar
  18. 18.
    R Development Core Team (2007) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna. ISBN 3-900051-07-0.
  19. 19.
    Ralph LD, Sandstrom M, Twelves C, Dobbs NA, Thomson AH (2006) Assessment of the validity of a population pharmacokinetic model for epirubicin. Br J Clin Pharmacol 62(1):47–55. CrossRefGoogle Scholar
  20. 20.
    Yano Y, Beal SL, Sheiner LB (2001) Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn 28(2):171–192CrossRefGoogle Scholar
  21. 21.
    Post TM, Freijer JI, Ploeger BA, Danhof M (2008) Extensions to the visual predictive check to facilitate model performance evaluation. J Pharmacokinet Pharmacodyn 35(2):185–202. CrossRefGoogle Scholar
  22. 22.
    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med 349(12):1157–1167. CrossRefGoogle Scholar
  23. 23.
    De Cock RF, Piana C, Krekels EH, Danhof M, Allegaert K, Knibbe CA (2011) The role of population PK-PD modelling in paediatric clinical research. Eur J Clin Pharmacol 67(Suppl 1):5–16. CrossRefGoogle Scholar
  24. 24.
    Meibohm B, Laer S, Panetta JC, Barrett JS (2005) Population pharmacokinetic studies in pediatrics: issues in design and analysis. AAPS J 7(2):E475–E487. CrossRefGoogle Scholar
  25. 25.
    Merchant MS, Mackall CL (2009) Current approach to pediatric soft tissue sarcomas. Oncologist 14(11):1139–1153. CrossRefGoogle Scholar
  26. 26.
    van Kesteren C, Cvitkovic E, Taamma A, Lopez-Lazaro L, Jimeno JM, Guzman C, Math t RA, Schellens JH, Misset JL, Brain E, Hillebrand MJ, Rosing H, Beijnen JH (2000) Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study. Clin Cancer Res 6(12):4725–4732Google Scholar
  27. 27.
    Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20(3):629–637. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Italo Poggesi
    • 1
    Email author
  • Belén Valenzuela
    • 2
    • 3
  • Daniele Ouellet
    • 4
  • Martha Gonzalez
    • 4
  • Vera Hillewaert
    • 5
  • Sylvain Baruchel
    • 6
  • Elizabeth Fox
    • 7
  • Juan Jose Perez-Ruixo
    • 5
  1. 1.Janssen-CilagCologno MonzeseItaly
  2. 2.SGS Exprimo, NVMechelenBelgium
  3. 3.Janssen Research and DevelopmentBeerseBelgium
  4. 4.Janssen Research and Development, LLCRaritanUSA
  5. 5.Janssen Research and DevelopmentBeerseBelgium
  6. 6.The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
  7. 7.The Children’s Hospital of PhiladelphiaThe Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA

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