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The Role of SN-38 Exposure, UGT1A1^*28 Polymorphism, and Baseline Bilirubin Level in Predicting Severe Irinotecan Toxicity

From the Office of Clinical Pharmacology (Dr Ramchandani, Dr Wang, Dr Booth, Dr Rahman, Dr Mehta, Dr Gobburu) and the Office of Oncology Drug Products (Dr Ibrahim, Dr Johnson), Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, Maryland, and the Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics and Cancer Research Center, University of Chicago, Chicago, Illinois (Dr Innocenti, Dr Ratain).

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.

Key Words: Irinotecan • SN-38 • neutropenia • UDP-glucuronosyltransferase • genetic polymorphisms

Address for reprints: Roshni P. Ramchandani, PhD, 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; e-mail: roshni.ramchandani{at}fda.hhs.gov.

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