Population pharmacokinetics of FOLFIRINOX: a review of studies and parameters
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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.
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.
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.
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.
KeywordsFOLFIRINOX 5-Fluorouracil Irinotecan Oxaliplatin Population pharmacokinetics Nonlinear mixed effect modelling
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.
No funding was sought for this manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Human and animal statement
This article does not contain any studies with human participants or animals performed by any of the authors.
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