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Pharmacokinetics of Irinotecan, Oxaliplatin and 5-Fluorouracil During Hepatic Artery Chronomodulated Infusion: A Translational European OPTILIV Study

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Abstract

The combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin with intravenous cetuximab has safely achieved prolonged survival in colorectal cancer patients with extensive liver metastases and prior treatment. Systemic exposure to the drugs or their main metabolites was determined during the first course of chronomodulated triplet HAI in 11 patients and related to toxicities after one or three courses. Consistent trends were found between the area under the plasma concentration–time curve (AUC) values of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN38; a bioactive metabolite), total oxaliplatin and platinum ultrafiltrate (P-UF), on the one hand, and subsequent leukopenia severity, on the other hand. Moreover, the maximum plasma concentration (C max) and the AUC of P-UF significantly predicted grades of diarrhoea (p = 0.004 and 0.017, respectively) and anaemia (p = 0.001 and 0.008, respectively) after the first course. Systemic drug exposure helps explain both the adverse events and the low rate of extrahepatic progression—a usual drawback of HAI chemotherapy—thus supporting upfront testing of the regimen. Systems optimization of chronomodulated HAI delivery could further reduce adverse events.

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Acknowledgments

The authors sincerely acknowledge the contribution of the patients who participated in this companion translational study and the nurses who performed blood sampling.

Author contributions

Francis Lévi designed the study, collected clinical and/or pharmacokinetic data, and analysed and interpreted the data. Abdoulaye Karaboué designed the study, collected clinical and/or pharmacokinetic data, and analysed and interpreted the data. Marie-Christine Etienne-Grimaldi designed the study and performed the pharmacokinetic determinations. Gilles Paintaud designed the study and performed the pharmacokinetic determinations. Christian Focan collected clinical and/or pharmacokinetic data. Pasquale Innominato designed the study, collected clinical and/or pharmacokinetic data, and analysed and interpreted the data. Mohamed Bouchahda designed the study, collected clinical and/or pharmacokinetic data, and analysed and interpreted the data. Gérard Milano designed the study and performed the pharmacokinetic determinations. Etienne Chatelut designed the study and performed the pharmacokinetics determinations. All co-authors were involved in the drafting or reviewing of the report and approval of the submitted manuscript.

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Correspondence to Francis Lévi.

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The Association pour la Recherche sur le Temps Biologique et la Chronothérapie sponsored the study. Measurement of serum cetuximab concentrations were carried out within the CePiBAc platform, which is cofinanced by the European Regional Development Fund and the French Higher Education and Research Ministry (LabEx MAbImprove ANR-10-LABX-53-01). None of the authors has any conflict of interest.

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Lévi, F., Karaboué, A., Etienne-Grimaldi, MC. et al. Pharmacokinetics of Irinotecan, Oxaliplatin and 5-Fluorouracil During Hepatic Artery Chronomodulated Infusion: A Translational European OPTILIV Study. Clin Pharmacokinet 56, 165–177 (2017). https://doi.org/10.1007/s40262-016-0431-2

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