Skip to main content
Log in

Pharmacokinetic and Pharmacogenetic Study of Etoposide in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors

Pharmaceutical Research Aims and scope Submit manuscript

Cite this article



Etoposide dosing is based on body surface area. We evaluated if further dose individualization would be required for high dose (HD) etoposide within the TI-CE (taxol, ifosfamide, carboplatin, and etoposide) protocol.


Eighty-eight patients received 400 mg/m2/day of etoposide as a 1-hour IV infusion on 3 consecutive days over 3 cycles as part of a phase II trial evaluating efficacy of therapeutic drug monitoring (TDM) of carboplatin in the TI-CE HD protocol. Pharmacokinetic (PK) data were analyzed using population PK model on NONMEM to quantify inter- and intra-individual variabilities. Relationship between etoposide exposure and pharmacodynamic (PD) endpoints, and between selected genetic polymorphisms and tumor response or toxicity were evaluated.


The inter-patient, inter- and intra-cycle variabilities of clearance were 16%, 9% and 0.1%, respectively. The PK-PD relationship was not significant despite a trend toward higher etoposide exposure in patients responding to treatment. A significant correlation was found between exposure and extended neutropenia at cycle 3. A significant association between UGT1A1*28 polymorphism and late neutropenia was observed but needs further evaluation.


The present study suggests that neither a priori dose individualization nor dose adaptation using TDM is required validating body surface area dosing of etoposide in the TI-CE protocol.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Data availability

Data can be made available on request to the corresponding author.


  1. Herzig RH. High-dose etoposide and marrow transplantation. Cancer. 1991;67(1 Suppl):292–8.

    Article  CAS  Google Scholar 

  2. Birsen R, Willems L, Pallud J, Blanc E, Burroni B, Legoff M, et al. Efficacy and safety of high-dose etoposide cytarabine as consolidation following rituximab methotrexate temozolomide induction in newly diagnosed primary central nervous system lymphoma in immunocompetent patients. Haematologica. 2018;103(7):e296–9.

    Article  CAS  Google Scholar 

  3. Fleming DR, Wolff SN, Fay JW, Brown RA, Lynch JP, Bolwell BJ, et al. Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin’s disease: a phase II study from the North American Marrow Transplant Group. Leuk Lymphoma. 1999;35(1–2):91–8.

    Article  CAS  Google Scholar 

  4. Long GD, Chao NJ, Hu WW, Negrin RS, Wong RM, Blume KG. High dose etoposide-based myeloablative therapy followed by autologous blood progenitor cell rescue in the treatment of multiple myeloma. Cancer. 1996;78(12):2502–9.

    Article  CAS  Google Scholar 

  5. Brown RA, Wolff SN, Fay JW, Pineiro L, Collins RH, Lynch JP, et al. High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group. Blood. 1995;85(5):1391–5.

    Article  CAS  Google Scholar 

  6. Horning SJ, Negrin RS, Chao JC, Long GD, Hoppe RT, Blume KG. Fractionated total-body irradiation, etoposide, and cyclophosphamide plus autografting in Hodgkin’s disease and non-Hodgkin’s lymphoma. J Clin Oncol. 1994;12(12):2552–8.

    Article  CAS  Google Scholar 

  7. Phillips GL, Wolff SN, Herzig RH, Lazarus HM, Fay JW, Lin HS, et al. Treatment of progressive Hodgkin’s disease with intensive chemoradiotherapy and autologous bone marrow transplantation. Blood. 1989;73(8):2086–92.

    Article  CAS  Google Scholar 

  8. Motzer RJ, Mazumdar M, Sheinfeld J, Bajorin DF, Macapinlac HA, Bains M, et al. Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol. 2000;18(6):1173–80.

    Article  CAS  Google Scholar 

  9. Ratain MJ, Mick R, Schilsky RL, Vogelzang NJ, Berezin F. Pharmacologically based dosing of etoposide: a means of safely increasing dose intensity. J Clin Oncol. 1991;9(8):1480–6.

    Article  CAS  Google Scholar 

  10. Miller AA, Tolley EA, Niell HB, Stewart CF, Griffin JP. Pharmacodynamics of three daily infusions of etoposide in patients with extensive-stage small-cell lung cancer. Cancer Chemother Pharmacol. 1992;31(2):161–6.

    Article  CAS  Google Scholar 

  11. Minami H, Ando Y, Sakai S, Shimokata K. Clinical and pharmacologic analysis of hyperfractionated daily oral etoposide. J Clin Oncol. 1995;13(1):191–9.

    Article  CAS  Google Scholar 

  12. Toffoli G, Corona G, Sorio R, Robieux I, Basso B, Colussi AM, et al. Population pharmacokinetics and pharmacodynamics of oral etoposide. Br J Clin Pharmacol. 2001;52(5):511–9.

    Article  CAS  Google Scholar 

  13. Nguyen L, Chatelut E, Chevreau C, Tranchand B, Lochon I, Bachaud JM, et al. Population pharmacokinetics of total and unbound etoposide. Cancer Chemother Pharmacol. 1998;41(2):125–32.

    Article  CAS  Google Scholar 

  14. Hande K, Messenger M, Wagner J, Krozely M, Kaul S. Inter- and intrapatient variability in etoposide kinetics with oral and intravenous drug administration. Clin Cancer Res. 1999;5(10):2742–7.

    CAS  PubMed  Google Scholar 

  15. Joel SP, Shah R, Clark PI, Slevin ML. Predicting etoposide toxicity: relationship to organ function and protein binding. J Clin Oncol. 1996;14(1):257–67.

    Article  CAS  Google Scholar 

  16. Ciccolini J, Monjanel-Mouterde S, Bun S-S, Blanc C, Duffaud F, Favre R, et al. Population pharmacokinetics of etoposide: application to therapeutic drug monitoring. Ther Drug Monit. 2002;24(6):709–14.

    Article  CAS  Google Scholar 

  17. Moeung S, Chevreau C, Broutin S, Guitton J, Lelièvre B, Ciccolini J, et al. Therapeutic Drug Monitoring of Carboplatin in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors: Pharmacokinetic Results of a Phase II Multicenter Study. Clin Cancer Res. 2017;23(23):7171–9.

    Article  CAS  Google Scholar 

  18. Tranchand B, Amsellem C, Chatelut E, Freyer G, Iliadis A, Ligneau B, et al. A limited-sampling strategy for estimation of etoposide pharmacokinetics in cancer patients. Cancer Chemother Pharmacol. 1999;43(4):316–22.

    Article  CAS  Google Scholar 

  19. Canal P, Michel C, Bugat R, Soula G, Carton M. Quantification of teniposide in human serum by high-performance liquid chromatography with electrochemical detection. J Chromatogr. 1986;375(2):451–6.

    Article  CAS  Google Scholar 

  20. Yates CR, Zhang W, Song P, Li S, Gaber AO, Kotb M, et al. The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol. 2003;43(6):555–64.

    Article  CAS  Google Scholar 

  21. Arbuck SG, Douglass HO, Crom WR, Goodwin P, Silk Y, Cooper C, et al. Etoposide pharmacokinetics in patients with normal and abnormal organ function. J Clin Oncol. 1986;4(11):1690–5.

    Article  CAS  Google Scholar 

  22. Stewart CF, Arbuck SG, Fleming RA, Evans WE. Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol. 1990;8(11):1874–9.

    Article  CAS  Google Scholar 

  23. D’Incalci M, Rossi C, Zucchetti M, Urso R, Cavalli F, Mangioni C, et al. Pharmacokinetics of etoposide in patients with abnormal renal and hepatic function. Cancer Res. 1986;46(5):2566–71.

    PubMed  Google Scholar 

  24. Stewart CF, Arbuck SG, Fleming RA, Evans WE. Relation of systemic exposure to unbound etoposide and hematologic toxicity. Clin Pharmacol Ther. 1991;50(4):385–93.

    Article  CAS  Google Scholar 

  25. Wen Z, Tallman MN, Ali SY, Smith PC. UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes: structural characterization of phenolic and alcoholic glucuronides of etoposide and estimation of enzyme kinetics. Drug Metab Dispos. 2007;35(3):371–80.

    Article  CAS  Google Scholar 

  26. Marques SC, Ikediobi ON. The clinical application of UGT1A1 pharmacogenetic testing: Gene-environment interactions. Hum Genomics. 2010;4(4):238–49.

    Article  CAS  Google Scholar 

  27. Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K, et al. Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Pharmacogenet Genomics. 2007;17(7):497–504.

    Article  CAS  Google Scholar 

  28. Goey AKL, Sissung TM, Peer CJ, Trepel JB, Lee M-J, Tomita Y, et al. Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer. J Clin Pharmacol. 2016;56(4):461–73.

    Article  CAS  Google Scholar 

Download references


The authors declare no potential conflicts of interest. The study was approved by the ethical committee Sud-Ouest et Outre-Mer I of Toulouse (reference number: 1-08-49).


This clinical trial (NCT00864318) was funded by a French Programme Hospitalier de Recherche Clinique (PHRC 2008 – project#18-08).

Author information

Authors and Affiliations



Conception and design: C. Chevreau, E. Chatelut, F. Thomas, T Filleron

Study supervision: C. Chevreau

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C. Chevreau, C. Massart, A. Fléchon, R. Delva, G. Gravis, J-P. Lotz, J-O. Bay, M. Gross-Goupil, S. Marsili, T. Lafont, C.Delmas

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S. Moeung, C. Chevreau, T Filleron, E. Chatelut, F. Thomas,

Writing, review, and/or revision of the manuscript: all authors.

Corresponding author

Correspondence to Etienne Chatelut.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moeung, S., Chevreau, C., Marsili, S. et al. Pharmacokinetic and Pharmacogenetic Study of Etoposide in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors. Pharm Res 37, 147 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:

Key words