Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin.
OBJECTIVE
Our objective was to investigate the influence of oxaliplatin on the pharmacokinetics of 5-fluorouracil (5FU) administered in a bolus plus infusional regimen.


METHODS
All patients had advanced/metastatic colorectal cancer. In study 1, 19 patients were studied after bolus (400 mg/m(2)) plus a 22-hour infusion (600 mg/m(2)) of 5FU/leucovorin in the standard de Gramont regimen or the same regimen with oxaliplatin (85 mg/m(2)) given before 5FU. In study 2, 12 patients were studied for 2 treatment cycles, with 5FU given in a modified de Gramont regimen comprising bolus (400 mg/m(2)) plus a 46-hour infusion (2400 mg/m(2)) of 5FU. During 1 of these cycles, oxaliplatin (85 mg/m(2)) was given before 5FU.


RESULTS
The coadministration of oxaliplatin did not significantly alter 5FU area under the plasma concentration-time curve from 0 to 1 hour, area under the plasma concentration-time curve from time 0 to the last time point, or steady-state concentration in either the de Gramont (11.6 +/- 3.8 mg/L x h(-1), 14.9 +/- 4.2 mg x h/L, and 0.17 +/- 0.06 mg/L, respectively, for 5FU alone versus 9.4 +/- 2.6 mg/L x h(-1), 13.3 +/- 2.3 mg x h/L, and 0.16 +/- 0.04, respectively, for 5FU plus oxaliplatin) or modified de Gramont regimens (13.4 +/- 2.2 mg x h/L, 35.4 +/- 4.2 mg x h/L, and 0.46 +/- 0.08 mg/L, respectively, for 5FU alone versus 13.9 +/- 3.3 mg x h/L, 38.1 +/- 7.4 mg x h/L, and 0.53 +/- 0.12, respectively, for 5FU plus oxaliplatin). The inclusion of oxaliplatin coadministration as a covariate in a NONMEM analysis did not result in any change in the objective function or mean values for the following derived parameters: maximum velocity (1590 mg x h(-1)), day 1 Michaelis-Menten constant (7.8 mg x h(-1)), and day 2 Michaelis-Menten constant (11.9 mg x h(-1)).


CONCLUSIONS
The coadministration of oxaliplatin in either the standard or modified de Gramont regimen does not significantly affect the pharmacokinetics of 5FU.
Joel
Simon P
SP
Department of Medical Oncology, St Bartholomew's Hospital, London, United Kingdom. S.P.Joel@qmul.ac.uk
Papamichael
Dimitri
D
Richards
Fiona
F
Davis
Theresa
T
Aslanis
Vassili
V
Chatelut
Etienne
E
Locke
Kathryn
K
Slevin
Maurice L
ML
Seymour
Matthew T
MT
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077150:Oxaliplatin
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005472:Fluorouracil