Pharmacokinetics and metabolism of irinotecan combined with capecitabine in patients with advanced colorectal cancer.
BACKGROUND
Irinotecan (CPT-11) in combination with 5-fluorouracil/folinic acid is used successfully for first-line treatment of metastatic colorectal cancer. Capecitabine (CCB) represents a very convenient alternative to 5-fluorouracil, either as single agent or in a combination of regimens acting synergistically and with the potential to further improve efficacy. Both CPT-11 and CCB need to be activated by human carboxyl esterases, therefore a probable pharmacokinetic drug interaction was checked.


METHODS
Ten patients suffering from advanced colorectal cancer were enrolled in this trial. CPT-11 was administered as a 30-min i.v.-infusion (70 mg/m2) weekly. CCB was given p.o. twice daily for two weeks (2,000 mg/m2 daily) starting the day after the first CPT-11 infusion. Plasma samples were analysed during/after the first (MONO) and third (CAPIRI) CPT-11 infusion.


RESULTS
CCB did not alter CPT-11 plasma disposition, and no significant changes in c(max), AUC(last), Vdss and Cl(tot) during CAPIRI treatment could be observed. However, co-administration of CCB appeared to decrease SN-38 (the cytotoxic CPT-11 metabolite) plasma concentrations during the first three hours after initiation of CPT-11 infusion, with strongly time-dependent plasma percentage differences between control and CAPIRI treatment (p < 0.005, R = 0.981). Co-administration of CCB also had a similar impact on the initial plasma disposition of SN-38gluc, but not on that of the APC metabolite.


CONCLUSIONS
Overall, our findings indicate that, while the administration of CCB resulted in reversible lower formation rates of SN-38 and SN-38gluc, it did not have a significant impact on CPT-11 pharmacokinetics.
Czejka
Martin
M
Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. martin.czejka@univie.ac.at
Schueller
Johannes
J
Hauer
Katharina
K
Ostermann
Eva
E
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D020719:Glucuronides / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D020719:Glucuronides; D011355:Prodrugs; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin