Clinical pharmacokinetics of irinotecan-based chemotherapy in colorectal cancer patients.
Irinotecan (CPT-11) significantly improves the efficacy of colorectal cancer treatment, demonstrating a superior efficacy with respect to leucovorin-modulated 5-fluorouracil (5-FU), also in fluoropyrimidine-resistant neoplasms. Preclinical studies demonstrated the inhibition of topoisomerase I by CPT-11 active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), and the possible synergistic interaction with other drugs effective against colorectal cancer, including 5-FU and oxaliplatin. Because of the occurrence of toxicities due to the large interpatient variability in drug metabolism, irinotecan is a candidate for therapeutic drug monitoring and pharmacokinetic optimisation. New schedules of drug administration (i.e. prolonged infusion) have led to improved cytotoxic effect of irinotecan, which resulted in improved overall survival and time to relapse together with reduced toxicity in comparison with 5-FU-based regimens. Furthermore, the analysis of the conversion of irinotecan into SN-38 by carboxylesterase, the detoxification of irinotecan and SN-38 by CYP3A4 and UDP-glucuronosyl transferases, and the activity of excretory systems (i.e., cMOAT, P-gp and MRP) seems able to predict the interindividual variability in pharmacokinetics and pharmacodynamics, being possible to predict untolerable toxicities. Finally, pharmacogenetics may elucidate drug interaction and gene expression modulation by irinotecan, while pharmacokinetic/pharmacodynamic models represent a valuable approach to further define the pharmacologic profile ofirinotecan and improve its therapeutic index.
Di Paolo
Antonello
A
Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy.
Bocci
Guido
G
Danesi
Romano
R
Del Tacca
Mario
M
D000284:Administration, Oral; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin