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/m2 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.
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 irinotecantoxicity 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/m2 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.
Authors: Eun Hye Ji; Young Min Kim; Soo Jeong Kim; Soo Jeong Yeom; Sung Eun Ha; Hyeon Hui Kang; Ji Young Kang; Sang Haak Lee; Hwa Sik Moon Journal: Tuberc Respir Dis (Seoul) Date: 2012-11-30
Authors: Amal E Mohammed; Eman G Behiry; Akram E El-Sadek; Waleed E Abdulghany; Dalia M Mahmoud; Abdelfattah A Elkholy Journal: Ann Med Surg (Lond) Date: 2016-12-01
Authors: Marianne K Kringen; Armin P Piehler; Runa M Grimholt; Mimi S Opdal; Kari Bente F Haug; Petter Urdal Journal: PLoS One Date: 2014-02-28 Impact factor: 3.240