Abstract: Purpose: In view of a potential gain in anticancer activity in advanced colorectal cancer (ACRC), there has been considerable interest in using a higher than the approved standard dose of capecitabine (CCB) combined with oxaliplatin. This pharmacokinetic study was designed to evaluate whether CCB is metabolized at the same extent when administered as a monotherapy in two different dose regimens, comparing standard dose (CCB 1) and intensified dose (CCB 2).
Patients and methods: Seven patients suffering from ACRC received subsequently two CCB schedules: In the standard schedule 1250 mg/m2 CCB p.o. twice daily for two weeks was administered, after a pause of one week a dose intensified CCB 2 schedule was given: 1750 mg/m2 CCB p.o. twice daily for one week to be followed by one week rest. Due to this paired cross over design a direct comparison for each single patient was feasible.
Results: In both schedules, mean peak plasma concentrations of CCB occurred at about 50 min, those of metabolites shortly later (range, 54 – 80 min). Peak plasma concentrations were about 10 % (CCB, DFCR) and 40 % (DFUR) higher in the CCB 2 regimen. According to the higher dose of CCB in the dose intensified regimen (+ 40 %), the AUClast values increased by 34 % (CCB), 20 % (DFCR) and 58 % (DFUR), respectively..
Conclusion: The results indicate that higher doses of CCB are metabolized approximately dose-dependent compared to the standard dose. No indices for a saturation of metabolizing processes or any significant delay of elimination rate was observed. Therefore from the pharmacokinetic points of view the CCB 2 schedule could contribute to an increased efficacy of CCB; moreover the immediate 5FU precursor DFUR (expressed as AUClast values) was formed at a 50 % higher extent than in the standard CCB 1 schedule.
