Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin

Abstract

Objective: Our objective was to investigate the influence of oxaliplatin on the pharmacokinetics of 5-fluorouracil (5FU) administered in a bolus plus infusional regimen.

Patients and 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.