Plasma disposition of capecitabine and its metabolites 5'DFCR and 5'DFUR in a standard and dose-intensified monotherapy regimen.
OBJECTIVE
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).


METHODS
Seven patients suffering from ACRC received subsequently two CCB schedules: In the standard schedule, 1,250 mg/m² CCB p.o. twice daily for 2 weeks was administered, after a pause of 1 week, a dose-intensified CCB 2 schedule was given: 1,750 mg/m² CCB p.o. twice daily for 1 week to be followed by 1 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 AUC(last) values increased by 34% (CCB), 20% (DFCR) and 58% (DFUR), respectively.


CONCLUSIONS
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. The immediate 5FU precursor DFUR was formed at a 50% higher extent (expressed as AUC(last) values) than in the standard CCB 1 schedule. From the pharmacokinetic point of view, this increased formation rate suggests clinical importance in regard to metabolic activation of CCB.
Czejka
Martin
M
Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria. martin.czejka@univie.ac.at
Schueller
J
J
Farkouh
A
A
Gruenberger
B
B
Scheithauer
W
W
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018592:Cross-Over Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged
D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; C418208:5'-deoxy-5-fluorocytidine; D005472:Fluorouracil; C025034:doxifluridine