title: Pharmacokinetic and pharmacogenetic predictive markers of irinotecan activity and toxicity.
abstract: After the rapid development of new classes of antineoplastic drugs, research activities have focused their efforts to the identification of predictive markers of drug activity and tolerability. Irinotecan (CPT-11) may induce severe toxicities (diarrhea, neutropenia) that limit its clinical use, but the increasing knowledge of its pharmacokinetics offered a potential approach to treatment optimization. Pharmacokinetics, the first area of investigation, has identified markers such as biliary index, the relative extent of conversion and the glucuronidation ratio, which are capable to define the risk for severe adverse effects. Because of the existence of some issues concerning the adoption of pharmacokinetic strategies to optimize CPT-11 dose and schedule, analyses of genetic polymorphisms seemed to offer a more reliable and safer approach for the identification of patients at risk than pharmacokinetics. In this view, the uridine diphosphate glucuronosil transferase isoform 1A1 (UGT1A1) was associated with significant changes in disposition of CPT-11 and its metabolites, and consequently with treatment-induced toxicities. However, the complex pharmacokinetics of irinotecan and the involvement of several enzymes other than UGT (i.e., carboxyl estherases, CYP450 isoforms), and transmembrane transporters (ABCB1, ABCC1, ABCG2, SLCO1B1) make difficult the identification of patients with an optimal sensitivity and specificity, and a large part of variability among patients still remains unexplained. Furthermore, prospective clinical studies that should demonstrate the reliability of those pharmacokinetic and pharmacogenetic markers are still lacking. In the present review, pharmacokinetic and pharmacogenetic markers will be discussed.
authors.affiliation: Division of Pharmacology, Department of Internal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy. antonello.dipaolo@gmail.com
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Polillo
authors.forename: Marzia
authors.initials: M
authors.lastname: Del Re
authors.forename: Teresa
authors.initials: T
authors.lastname: Di Desidero
authors.forename: Marianna
authors.initials: M
authors.lastname: Lastella
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D011110:Polymorphism, Genetic; D057285:Precision Medicine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D000077146:Irinotecan; D002166:Camptothecin