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Population pharmacokinetics of FOLFIRINOX: a review of studies and parameters

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Abstract

Purpose

FOLFIRINOX regimen is commonly used in colorectal and more recently pancreatic cancer. However, FOLFIRINOX induces significant and dose-limiting toxic effects leading to empirical dose reduction and sometimes treatment discontinuation. Model-based FOLFIRINOX regimen optimization might help improving patients’ outcome. As a first step, the current review aims at bringing together all published population pharmacokinetics models for FOLFIRINOX anticancer drugs.

Methods

A literature search was conducted in the PubMed database from inception to February 2018, using the following terms: population pharmacokinetic(s), irinotecan, oxaliplatin, fluorouracil, FOLFIRI, FOLFOX, FOLFIRINOX. Only articles displaying nonlinear mixed effect models were included. Study description, pharmacokinetic parameter values and influential covariates are reported. For each model, the typical pharmacokinetic profile was simulated for the standard FOLFIRINOX protocol.

Results

The FOLFIRINOX compounds have been studied only separately so far. A total of six articles were retained for 5-fluorouracil, 6 for oxaliplatin and 5 for irinotecan (also including metabolites). Either one- or two-compartment models have been described for 5-fluorouracil, while two- or three-compartment models were reported for oxaliplatin and irinotecan pharmacokinetics. Non-linear elimination was sometimes reported for 5-fluorouracil. Sex and body size were found as influential covariates for all molecules in some publications. Despite some differences in model structures and parameter values, the simulated profiles and subsequent exposure were consistent between studies.

Conclusions

The current review allows for a global understanding of FOLFIRINOX pharmacokinetics, and will provide a basis for further development of pharmacokinetics–pharmacodynamics–toxicity models for model-driven FOLFIRINOX protocol optimization to reach the best benefit-to-risk ratio.

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Acknowledgements

The authors would also like to thank the Ligue Contre le Cancer French association who generously provided a grant to Laure Deyme. We are grateful to E. Chatelut (Institut Claudius-Regaud, IUCT-Oncopole, CRCT, Université de Toulouse, Inserm, Toulouse, France) for providing us with the original data and model from the Delord et al. study.

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No funding was sought for this manuscript.

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Authors and Affiliations

  1. SMARTc Unit, Centre de Recherche en Cancérologie de Marseille, U1068, Institut National de la santé et de la recherche médicale, Marseille, France

    Laure Deyme, Dominique Barbolosi & Florence Gattacceca

  2. Institut Paoli-Calmette, Marseille, France

    Laure Deyme, Dominique Barbolosi & Florence Gattacceca

  3. Unité Mixte de Recherche (UMR 7258), Centre National de la Recherche Scientifique (CNRS), Marseille, France

    Laure Deyme, Dominique Barbolosi & Florence Gattacceca

  4. Aix Marseille Université, Marseille, France

    Laure Deyme, Dominique Barbolosi & Florence Gattacceca

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  1. Laure Deyme
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Correspondence to Laure Deyme.

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Deyme, L., Barbolosi, D. & Gattacceca, F. Population pharmacokinetics of FOLFIRINOX: a review of studies and parameters. Cancer Chemother Pharmacol 83, 27–42 (2019). https://doi.org/10.1007/s00280-018-3722-5

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  • DOI: https://doi.org/10.1007/s00280-018-3722-5

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