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

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Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

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Data availability

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

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ACKNOWLEDGMENTS AND DISCLOSURES

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).

Funding

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

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Authors and Affiliations

  1. Institut Claudius-Regaud, IUCT-Oncopole, Toulouse, France

    Sotheara Moeung, Christine Chevreau, Sabrina Marsili, Thomas Filleron, Caroline Delmas, Thierry Lafont, Etienne Chatelut & Fabienne Thomas

  2. CRCT, Université de Toulouse, Inserm, Toulouse, France

    Sotheara Moeung, Sabrina Marsili, Caroline Delmas, Thierry Lafont, Etienne Chatelut & Fabienne Thomas

  3. Oncologie Médicale, Institut Gustave Roussy, Villejuif, France

    Christophe Massart

  4. Centre Léon Bérard, Lyon, France

    Aude Fléchon

  5. Institut De Cancérologie de l’Ouest Paul Papin, Angers, France

    Rémy Delva

  6. Institut Paoli Calmettes, Marseille, France

    Gwenaëlle Gravis

  7. Hôpital Tenon, Paris, France

    Jean-Pierre Lotz

  8. CHU, Clermont Ferrand, France

    Jacques-Olivier Bay

  9. Hôpital Saint André, Bordeaux, France

    Marine Gross-Goupil

Authors
  1. Sotheara Moeung
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  2. Christine Chevreau
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  3. Sabrina Marsili
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  4. Christophe Massart
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  5. Aude Fléchon
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  6. Rémy Delva
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  7. Gwenaëlle Gravis
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  8. Jean-Pierre Lotz
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  9. Jacques-Olivier Bay
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  10. Marine Gross-Goupil
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  11. Thomas Filleron
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  12. Caroline Delmas
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  13. Thierry Lafont
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  14. Etienne Chatelut
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  15. Fabienne Thomas
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Contributions

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.

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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). https://doi.org/10.1007/s11095-020-02861-5

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  • DOI: https://doi.org/10.1007/s11095-020-02861-5

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