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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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Lévi, Francis A., Karaboué, Abdoulaye, Etienne-Grimaldi, Marie-Christine, Paintaud, Gilles, Focan, Christian, Innominato, Pasquale F., Bouchahda, Mohamed, Milano, Gérard and Chatelut, Etienne (2017) Pharmacokinetics of Irinotecan, Oxaliplatin and 5-Fluorouracil during hepatic artery chronomodulated infusion : a translational European OPTILIV study. Clinical Pharmacokinetics, 56 (2). pp. 165-177. doi:10.1007/s40262-016-0431-2 ISSN 0312-5963.
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Official URL: http://dx.doi.org/10.1007/s40262-016-0431-2
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.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | ||||||
| Journal or Publication Title: | Clinical Pharmacokinetics | ||||||
| Publisher: | Spring New York LLC | ||||||
| ISSN: | 0312-5963 | ||||||
| Official Date: | 7 February 2017 | ||||||
| Dates: |
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| Volume: | 56 | ||||||
| Number: | 2 | ||||||
| Page Range: | pp. 165-177 | ||||||
| DOI: | 10.1007/s40262-016-0431-2 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access |
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