title: The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity.
abstract: Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, WO21 Rm 3667, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA. roshni.ramchandani@fda.hhs.gov
authors.forename: Roshni P
authors.initials: RP
authors.lastname: Ramchandani
authors.forename: Yaning
authors.initials: Y
authors.lastname: Wang
authors.forename: Brian P
authors.initials: BP
authors.lastname: Booth
authors.forename: Amna
authors.initials: A
authors.lastname: Ibrahim
authors.forename: John R
authors.initials: JR
authors.lastname: Johnson
authors.forename: Atiqur
authors.initials: A
authors.lastname: Rahman
authors.forename: Mehul
authors.initials: M
authors.lastname: Mehta
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Jogarao V S
authors.initials: JV
authors.lastname: Gobburu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D019540:Area Under Curve; D001663:Bilirubin / Q000378:metabolism*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced*; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001663:Bilirubin; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme