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Invited Abstract (Plenary Session): Germline Determinants of Therapeutic Efficacy and Toxicity

Case History: The First Drug-Specific FDA-Approved Pharmacogenetic Test: UGT1A1 Genotyping for Irinotecan

University of Chicago, Chicago, IL

Abstract

PL-15

Irinotecan, a camptothecin prodrug, has had a checkered past, as early clinical investigators reported that the drug's administration was associated with severe and unpredictable diarrhea and myelosuppression. Furthermore, the initial pharmacokinetic studies of this agent were unable to demonstrate a consistent relationship between drug and metabolite (SN-38) disposition and toxicity. Thus, the 1994 Cancer Research paper by Gupta and colleagues, demonstrating an inverse relationship between glucuronidation of SN-38 and toxicity, was of great interest. Subsequent studies demonstrated that SN-38 was a substrate for UGT1A1, the same enzyme responsible for bilirubin glucuronidation. These findings led to the hypothesis that heritable genetic variability in the UGT1A1 promoter (a variable number of TA repeats), which had been recently associated with serum bilirubin concentrations, was responsible for much of the interindividual variability in irinotecan's pharmacokinetics and toxicity. This hypothesis was tested by our group and others, using a combination of in vitro, prospective clinical, and retrospective clinical studies. In general, there was agreement that there was a relationship between UGT1A1 genotype and phenotype (toxicity and pharmacokinetics), which led to an FDA-initiated change in the irinotecan label in 2005. Subsequently, the FDA approved a 510(k) application from Third Wave Technologies for UGT1A1 genotyping in the context of planned irinotecan therapy. More recent studies have confirmed the relationship of genotype to toxicity, although the optimal clinical use of this test has not been established.