Irinotecan-induced neutropenia and UGT1A1*28: Does dose matter?

Abstract

4023 Background: On July 7 2005, the Food and Drug Administration (FDA) of the U.S.A. and Pfizer Pharmaceuticals changed the package insert information for irinotecan to include a patient’s UGT1A1*28 genotype as a risk factor for severe neutropenia. This change resulted from the findings of four pharmacogenetic studies that identified a 2.5 to 17-fold risk of toxicity in homozygous UGT1A1*28 patients receiving irinotecan. Notably, a total number of 34 patients in the four studies were homozygous for the UGT1A1*28 allele. Subsequent studies on larger patient cohorts treated with other dosage regimens have failed to consistently replicate the UGT1A1*28 genotype-toxicity associations, thus confounding the development of dosing recommendations. This has contributed to confusion on how best to select a safe dose of irinotecan for a patient who is homozygous for UGT1A1*28. Methods: We reviewed the data presented in ten irinotecan pharmacogenetic studies (825 patients) and assessed the correlations between the incidence of irinotecan-induced hematological toxicities (grade III/IV) in UGT1A1*28/*28 patients, irinotecan dose, and overall toxicity. Results: We found that the incidence of grade III/IV hematological toxicities in UGT1A1*28/*28 patients was positively related to both irinotecan dose (Spearman Rank correlation rS=0.68; P=0.04; N=10 studies) and the overall incidence of toxicity of a regimen (rS=0.88; P=0.002; N=10 studies). The incidence of severe hematological toxicity amongst all patients was not related to irinotecan dose (rS=0.44; P=0.20, N=10 studies). Conclusions: Our results suggest that the risk of experiencing irinotecan-induced hematological toxicity for UGT1A1*28/*28 patients is a function of the dose of irinotecan administered. In the spirit of maximizing patient safety, we support the use of genotype-based dosing of irinotecan for high doses of irinotecan, but believe it may not be as useful for lower doses and suggest strategies for dosing patients with irinotecan. [Table: see text] No significant financial relationships to disclose.