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Population pharmacokinetic model of irinotecan and its four main metabolites in patients treated with FOLFIRI or FOLFIRINOX regimen

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Abstract

Purpose

The aim of the present study was to characterize the pharmacokinetics of irinotecan and its four main metabolites (SN-38, SN-38G, APC and NPC) in metastatic colorectal cancer patients treated with FOLFIRI and FOLFIRINOX regimens and to quantify and explain the inter-individual pharmacokinetic variability in this context.

Methods

A multicenter study including 109 metastatic colorectal cancer patients treated with FOLFIRI or FOLFIRINOX regimen, associated or not with a monoclonal antibody, was conducted. Concentrations of irinotecan and its four main metabolites were measured in 506 blood samples during the first cycle of treatment. Collected data were analyzed using the population approach. First, fixed and random effects models were selected using statistical and graphical methods; second, the impact of covariates on pharmacokinetic parameters was evaluated to explain the inter-individual variability in pharmacokinetic parameters.

Results

A seven-compartment model best described the pharmacokinetics of irinotecan and its four main metabolites. First-order rates were assigned to distribution, elimination, and metabolism processes, except for the transformation of irinotecan to NPC which was nonlinear. Addition of a direct conversion of NPC into SN-38 significantly improved the model. Co-administration of oxaliplatin significantly modified the distribution of SN-38.

Conclusion

To our knowledge, the present model is the first to allow a simultaneous description of irinotecan pharmacokinetics and of its four main metabolites. Moreover, a direct conversion of NPC into SN-38 had never been described before in a population pharmacokinetic model of irinotecan. The model will be useful to develop pharmacokinetic-pharmacodynamic models relating SN-38 concentrations to efficacy and digestive toxicities.

Clinical trials registration number

ClinicalTrials.gov identifier: NCT00559676.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

The model code that we developed is provided as an electronic supplementary information, so the model can be copy-pasted by any reader and run directly on Monolix® software with the users’ own dataset.

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Acknowledgements

The authors gratefully acknowledge Professor A. Iliadis for the assistance and the fruitful discussions regarding the model development. They would also like to thank the ligue Contre le Cancer French association who generously provided a PhD grant to Laure Deyme.

Funding

This work was supported by a Grant from Cancéropôle Grand Sud-Ouest (France).

Author information

Authors and Affiliations

  1. SMARTc, Centre de Recherche en Cancérologie de Marseille (CRCM), Faculté de Pharmacie, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France

    Laure Deyme, Dominique Barbolosi & Florence Gattacceca

  2. Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes-Carémeau, Nîmes, France

    Litaty Céphanoée Mbatchi & Alexandre Evrard

  3. IRCM, Inserm U1194, Université de Montpellier, Montpellier, France

    Litaty Céphanoée Mbatchi & Alexandre Evrard

  4. Centre Hospitalier Universitaire de Limoges, Limoges, France

    Nicole Tubiana-Mathieu

  5. Institut Régional du Cancer de Montpellier (ICM)-Val d’Aurelle, Montpellier, France

    Marc Ychou

Authors
  1. Laure Deyme
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  2. Dominique Barbolosi
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  3. Litaty Céphanoée Mbatchi
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  4. Nicole Tubiana-Mathieu
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  5. Marc Ychou
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  6. Alexandre Evrard
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  7. Florence Gattacceca
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Corresponding author

Correspondence to Laure Deyme.

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Conflict of Interest

Laure Deyme, Dominique Barbolosi, Litaty Céphanoée Mbatchi, Nicole Tubiana-Mathieu, Marc Ychou, Alexandre Evrard, and Florence Gattacceca declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Supplementary Information

Below is the link to the electronic supplementary material.

280_2021_4255_MOESM1_ESM.pdf

Supplementary file1 The model code that we developed is provided as an electronic supplementary information, so the model can be copy-pasted by any reader and run directly on Monolix® software with the users’ own dataset. Additional GOF plots for CPT-11 and metabolites, including normalized prediction distribution errors, are provided in Supplementary File 2 (PDF 16 KB)

Supplementary file2 (PDF 172 KB)

Supplementary file3 (PDF 711 KB)

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Deyme, L., Barbolosi, D., Mbatchi, L.C. et al. Population pharmacokinetic model of irinotecan and its four main metabolites in patients treated with FOLFIRI or FOLFIRINOX regimen. Cancer Chemother Pharmacol 88, 247–258 (2021). https://doi.org/10.1007/s00280-021-04255-9

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  • DOI: https://doi.org/10.1007/s00280-021-04255-9

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