In vivo disposition of irinotecan (CPT-11) and its metabolites in combination with the monoclonal antibody cetuximab.
BACKGROUND
The present study was designed to investigate whether a combination of irinotecan and the monoclonal antibody cetuximab shows potential to modulate the pharmacokinetics of irinotecan and its metabolites.


METHODS
All patients, suffering from advanced colorectal cancer, received irinotecan (350 mg/m2) every third week and cetuximab as a loading dose (400 mg/m2) on day 2, followed by a weekly maintenance dose (250 mg/m2). Plasma samples were analysed after the first (MONO) and second (CMAB) irinotecan infusions.


RESULTS
No significant alterations in the plasma concentrations and pharmacokinetics of irinotecan and its metabolites were observed after combination with cetuximab. Only differentiation of irinotecan into lactone and carboxylate plasma concentrations resulted in a distinctly lower cmax of the active lactone in the CMAB and a significantly higherAUClast in the MONO schedule (p<0.02).


CONCLUSIONS
The results of this study indicated that cetuximab has no clinically relevant impact on the pharmacokinetics of irinotecan, its activation into SN-38, or its detoxification by beta-D-glucuronidation.
Ettlinger
Dagmar E
DE
Department of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna. dagmar.ettlinger@meduniwien.ac.at
Mitterhauser
Markus
M
Wadsak
Wolfgang
W
Ostermann
Eva
E
Farkouh
André
A
Schueller
Johann
J
Czejka
Martin
M
D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D020719:Glucuronides / Q000097:blood; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011446:Prospective Studies
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D020719:Glucuronides; D011355:Prodrugs; D000077146:Irinotecan; D000068818:Cetuximab; D002166:Camptothecin