Pharmacokinetics and Pharmacogenetics of Irinotecan
The Analytical Component has been instrumental to the clinical development of irinotecan, a drug approved by the FDA in 2000 as first-line therapy for the treatment of patients with metastatic colorectal cancer in combination with 5-fluorouracil/leucovorin (5-FU/LV).
The lab began work with irinotecan in 1993, when it analyzed samples from a clinical trial and demonstrated a correlation between diarrhea and glucuronidation of SN-38, the active metabolite of irinotecan. Subsequent work identified UGT1A1 as one of the main enzymes catalyzing the formation of SN-38 glucuronide. Following this, the Core was involved in a pharmacogenetic study aiming to evaluate the association between the prevalence of severe toxicity and UGT1A1 genetic variation. This clinical trial was important in determining that genetic variants UGT1A1*28 (5-8 copies of a TA repeat) and -3156G>A in the promoter of the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.
Based on the study results, the irinotecan label has been revised to warn that homozygosity for UGT1A1*28 is a risk factor for severe neutropenia, and recommends that patients with this genotype should be treated with a reduced starting dose of irnotecan.
For more information: Pfizer's Camptosar: Irinotecan HCI Injection