Clinical and pharmacogenetic factors associated with irinotecan toxicity.
Irinotecan is a topo-isomerase-I inhibitor with broad antitumor activity in solid tumors. Its use may lead to severe toxicities, predominantly neutropenia and diarrhea which can be life-threatening. This review discusses clinical determinants and pharmacogenetic factors associated with irinotecan toxicity. Age, performance status, co-medication and elevated transaminases have been associated with increased risk of diarrhea or neutropenia. Also, elevated bilirubin levels, due to liver impairment, conjugation disorders or UGT1A1 *28 genotype, have been associated with increased incidence of grades 3 intestinal toxicity and neutropenia. UGT1A1 *28 homozygosity is strongly associated with irinotecan-induced neutropenia and polymorphisms in the transporting peptides ABCB1 and OATP1B1 have also been associated with gastrointestinal toxicity and irinotecan pharmacokinetics, respectively. In the irinotecan product label, it is advised to reduce the irinotecan starting dose for UGT1A1 *28 homozygotes. However, due to the lack of prospective data, it is yet unknown whether dose reduction leads to reduced toxicity or altered antitumor effect. Combined toxicity analysis reveals that most patients experiencing grade 3-4 diarrhea and/or neutropenia are not homozygous for UGT1A1 *28. Future studies should combine pharmacogenetics with clinical determinants such as performance status and co-medication as to predict irinotecan toxicity and to develop predefined dosing algorithms.
Kweekel
Dinemarie
D
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. d.m.kweekel@lumc.nl
Guchelaar
Henk-Jan
HJ
Gelderblom
Hans
H
D000328:Adult; D017677:Age Distribution; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D003967:Diarrhea / Q000139:chemically induced* / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced* / Q000453:epidemiology; D010597:Pharmacogenetics; D010601:Pharmacology, Clinical; D018570:Risk Assessment; D017678:Sex Distribution; D016019:Survival Analysis; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin