Pharmacogenetic Testing for Uridine Diphosphate Glucuronosyltransferase 1A1 Polymorphisms: Are We There Yet?

Abstract

Recent changes to the labels of three prescription drugs--irinotecan, 6-mercaptopurine, and warfarin--include recommendations for pharmacogenetic testing in patients. Thus, clinicians are faced with determining the utility and practicality of pharmacogenetic testing in clinical practice. We illustrate the clinical implications that this testing may have using irinotecan, an agent approved for the treatment of metastatic colorectal cancer, as an example. A clinical association between the drug's active metabolite and toxicity has been found. By performing uridine diphosphate glucuronosyltransferase (UGT) 1A1 genetic testing, some studies have been able to predict which patients receiving irinotecan will experience the toxicity. Thus, irinotecan's package insert was revised to include a recommendation for such testing. In addition, the United States Food and Drug Administration approved a clinical test for the UGT1A1*28 allele. These events demonstrate that pharmacogenetics has entered the realm of clinical practice. However, the transition from bench to bedside of these tests has distinct challenges such as population differences, test sensitivity, and the role of other genetic and nongenetic factors that influence drug toxicity. In addition, ethical and logistic implications of pharmacogenetic testing exist.

S3-Leitlinie – Kolorektales Karzinom

“…Etwa 10 -20 % Kaukasier und Amerikaner mit afrikanischem Ursprung sind homozygot für *28, während dies für weniger als 5 % der Asiaten zutrifft [1063].…”

Personalizing chemotherapy dosing using pharmacological methods

“…The frequency of the *28 allele is approximately 39 % in patients of European, 16 % of Asian, and 43 % of African origins. Roughly 10-20 % of Caucasians and African Americans are homozygous for *28, while less than 5 % of Asians are homozygous for *28 [47]. A meta-analysis demonstrated a significantly higher risk of grade 3/4 neutropenia in*28/*28 patients at medium (150-250 mg/m 2 ) and high doses (>250 mg/ m 2 ) (OR = 3.22, P = 0.008 and OR = 27.8, P = 0.005, respectively) [48].…”

The Canadian Pharmacogenomics Network for Drug Safety: A Model for Safety Pharmacology

“…Examples of diagnostic tests to guide pharmacotherapy and prevent severe ADRs include tests for UGT1A1 variants for life-threatening irinotecan-induced toxicity (19,20), thiopurine S-methyltransferase (TPMT) variants azathioprinerelated myelosuppression (21,22), CYP2C9 and VKORC1 variants to guide warfarin dosing (23,24), HLA-B*1502 testing for carbamazepine-related Stevens-Johnson syndrome and toxic epidermal necrolysis (25), and HLA-B*5701 testing to predict severe hypersensitivity to abacavir (26)(27)(28). These tests are recommended by the FDA in the United States or are in the process of being introduced into the clinic.…”