title: Pharmacokinetics of Irinotecan, Oxaliplatin and 5-Fluorouracil During Hepatic Artery Chronomodulated Infusion: A Translational European OPTILIV Study.
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 (Cmax) 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.
authors.affiliation: INSERM, UMRS 935, Team «Cancer Chronotherapy and Postoperative Liver Function», Campus CNRS, 7 rue Guy Môquet, Villejuif, France. F.Levi@warwick.ac.uk.|Assistance Publique-Hopitaux de Paris, Medical Oncology Department, Hepatobiliary Centre, and Radiology Department, Paul Brousse Hospital, 14 avenue Paul Vaillant Couturier, Villejuif, France. F.Levi@warwick.ac.uk.|Cancer Chronotherapy Unit, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry, CV4 7AL, UK. F.Levi@warwick.ac.uk.
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
authors.affiliation: INSERM, UMRS 935, Team «Cancer Chronotherapy and Postoperative Liver Function», Campus CNRS, 7 rue Guy Môquet, Villejuif, France.|AK-SCIENCE, Research and Therapeutic Innovation, Vitry-sur-Seine, France.
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Karaboué
authors.affiliation: Laboratory of Oncopharmacology, Antoine Lacassagne Centre, Nice, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.affiliation: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, Service de Pharmacologie-Toxicologie, Tours, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
authors.affiliation: Department of Oncology, Centre Hospitalier Chrétien, Clinique Saint-Joseph, Liège, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Focan
authors.affiliation: INSERM, UMRS 935, Team «Cancer Chronotherapy and Postoperative Liver Function», Campus CNRS, 7 rue Guy Môquet, Villejuif, France.|Assistance Publique-Hopitaux de Paris, Medical Oncology Department, Hepatobiliary Centre, and Radiology Department, Paul Brousse Hospital, 14 avenue Paul Vaillant Couturier, Villejuif, France.|Cancer Chronotherapy Unit, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry, CV4 7AL, UK.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Innominato
authors.affiliation: INSERM, UMRS 935, Team «Cancer Chronotherapy and Postoperative Liver Function», Campus CNRS, 7 rue Guy Môquet, Villejuif, France.|Assistance Publique-Hopitaux de Paris, Medical Oncology Department, Hepatobiliary Centre, and Radiology Department, Paul Brousse Hospital, 14 avenue Paul Vaillant Couturier, Villejuif, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bouchahda
authors.affiliation: Laboratory of Oncopharmacology, Antoine Lacassagne Centre, Nice, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.affiliation: Institut Claudius-Regaud, CRCT, Université de Toulouse, Inserm, UPS, Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy; D055870:Drug Chronotherapy; D005060:Europe / Q000453:epidemiology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006499:Hepatic Artery / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007261:Infusions, Intra-Arterial / Q000379:methods; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077150:Oxaliplatin
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin