Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin

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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/m2) plus a 22-hour infusion (600 mg/m2) of 5FU/leucovorin in the standard de Gramont regimen or the same regimen with oxaliplatin (85 mg/m2) 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/m2) plus a 46-hour infusion (2400 mg/m2) of 5FU. During 1 of these cycles, oxaliplatin (85 mg/m2) 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 · h−1, 14.9 ± 4.2 mg · h/L, and 0.17 ± 0.06 mg/L, respectively, for 5FU alone versus 9.4 ± 2.6 mg/L · h−1, 13.3 ± 2.3 mg · h/L, and 0.16 ± 0.04, respectively, for 5FU plus oxaliplatin) or modified de Gramont regimens (13.4 ± 2.2 mg · h/L, 35.4 ± 4.2 mg · h/L, and 0.46 ± 0.08 mg/L, respectively, for 5FU alone versus 13.9 ± 3.3 mg · h/L, 38.1 ± 7.4 mg · 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 · h−1), day 1 Michaelis-Menten constant (7.8 mg · h−1), and day 2 Michaelis-Menten constant (11.9 mg · h−1).

Conclusions

The coadministration of oxaliplatin in either the standard or modified de Gramont regimen does not significantly affect the pharmacokinetics of 5FU.

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