Pharmacogenetics and Irinotecan Therapy
Purpose: Irinotecan metabolism, irinotecan pharmacogenetic research, and the role of genetic testing before administration of the drug are reviewed.
Summary: Irinotecan is approved worldwide for the treatment of metastatic colorectal cancer but causes dose-limiting neutropenia and diarrhea. When severe, these can lead to dehydration, infection, patient discomfort, additional medication requirements, hospitalization, and death. The identification of predictive markers in irinotecan therapy has been a significant goal of pharmacogenetic research. The labeling of irinotecan was recently changed and now includes a warning of greater neutropenia risk in patients with reduced activity in the drug-metabolizing enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). A known marker of reduced UGT1A1 activity is the genetic variant UGT1A1*28. Numerous studies have demonstrated the effects of genetic factors, especially UGT1A1*28, that contribute to interpatient variability in irinotecan pharmacokinetics and toxicity. Irinotecan's new labeling recommends that clinicians consider reducing the dosage of irinotecan in patients homozygous for UGT1A1*28.
Conclusion: At least part of the interpatient variability of irinotecan toxicity can be explained by the UGT1A1*28 polymorphism. Patients who are homozygous for the UGT1A1*28 allele have an increased risk of developing severe neutropenia when receiving irinotecan, especially the 300-350- mg/m regimen. A molecular assay is now available to identify the at-risk subgroup and should be used by health care professionals to help guide irinotecan-treatment decisions.
Colorectal cancer is the third most common cancer among men and women in the United States. It is estimated that in 2006 alone, more than 148,000 new cases of colorectal cancer will be diagnosed, leading to over 55,000 deaths. Irinotecan, effective in the treatment of a variety of malignancies, including colorectal cancer, can cause severe diarrhea and neutropenia, both of which are therapy limiting. The current method of dosing based on body surface area does not correlate with irinotecan clearance and metabolism, leaving patients at risk of developing severe toxicity. The development of irinotecan-associated toxicities is believed to be primarily dependent on polymorphic drug-metabolizing enzymes. An understanding of this genetic variation may aid providers in adjusting the irinotecan dose to provide efficacy while limiting toxicity. The labeling of irinotecan was recently revised to reflect evidence of an increased risk of neutropenia in individuals who are homozygous for the UGT1A1*28 allele. This article reviews how pharmacogenetic characteristics may influence irinotecan therapy.
Abstract and Introduction
Abstract
Purpose: Irinotecan metabolism, irinotecan pharmacogenetic research, and the role of genetic testing before administration of the drug are reviewed.
Summary: Irinotecan is approved worldwide for the treatment of metastatic colorectal cancer but causes dose-limiting neutropenia and diarrhea. When severe, these can lead to dehydration, infection, patient discomfort, additional medication requirements, hospitalization, and death. The identification of predictive markers in irinotecan therapy has been a significant goal of pharmacogenetic research. The labeling of irinotecan was recently changed and now includes a warning of greater neutropenia risk in patients with reduced activity in the drug-metabolizing enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). A known marker of reduced UGT1A1 activity is the genetic variant UGT1A1*28. Numerous studies have demonstrated the effects of genetic factors, especially UGT1A1*28, that contribute to interpatient variability in irinotecan pharmacokinetics and toxicity. Irinotecan's new labeling recommends that clinicians consider reducing the dosage of irinotecan in patients homozygous for UGT1A1*28.
Conclusion: At least part of the interpatient variability of irinotecan toxicity can be explained by the UGT1A1*28 polymorphism. Patients who are homozygous for the UGT1A1*28 allele have an increased risk of developing severe neutropenia when receiving irinotecan, especially the 300-350- mg/m regimen. A molecular assay is now available to identify the at-risk subgroup and should be used by health care professionals to help guide irinotecan-treatment decisions.
Introduction
Colorectal cancer is the third most common cancer among men and women in the United States. It is estimated that in 2006 alone, more than 148,000 new cases of colorectal cancer will be diagnosed, leading to over 55,000 deaths. Irinotecan, effective in the treatment of a variety of malignancies, including colorectal cancer, can cause severe diarrhea and neutropenia, both of which are therapy limiting. The current method of dosing based on body surface area does not correlate with irinotecan clearance and metabolism, leaving patients at risk of developing severe toxicity. The development of irinotecan-associated toxicities is believed to be primarily dependent on polymorphic drug-metabolizing enzymes. An understanding of this genetic variation may aid providers in adjusting the irinotecan dose to provide efficacy while limiting toxicity. The labeling of irinotecan was recently revised to reflect evidence of an increased risk of neutropenia in individuals who are homozygous for the UGT1A1*28 allele. This article reviews how pharmacogenetic characteristics may influence irinotecan therapy.
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