|Values are valid only on day of printing.|
Identifying individuals who are at increased risk of adverse drug reactions with irinotecan and who should be considered for decreased dosing of the drug.
Genotyping patients who prefer not to have venipuncture done
Following primary metabolism by the phase I enzymes (by oxidation, reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II enzymes, uridine diphosphate-glycuronosyl transferase 1A1 (UGT1A1), is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.
UGT1A1 is involved in the metabolism of irinotecan, a topoisomerase I inhibitor. Irinotecan is a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. It is a prodrug that forms an active metabolite, SN-38. SN-38 is normally inactivated by conjugation with glucuronic acid followed by biliary excretion into the gastrointestinal tract. If UGT1A1 activity is impaired or deficient, SN-38 fails to become conjugated with glucuronic acid, increasing the concentration of SN-38. This can result in severe neutropenia. The combination of neutropenia with diarrhea can be life-threatening.
The most common cause of irinotecan-induced neutropenia results from insertion of extra TA (thymine, adenine) repeats in the TATA box of the UGT1A1 promoter. This results in decreased expression of the UGT1A1 gene in individuals homozygous for these promoter polymorphisms. The number of TA repeats is inversely related to gene expression. Individuals with normal levels of UGT1A1 expression have 6 copies of the TA repeat in the promoter (referred to as the *1 allele) or more rarely 5 copies of the TA repeat (referred to as *36). Individuals with decreased expression of UGT1A1 have 7 TA repeats (*28 allele) or 8 TA repeats (*37). Approximately 10% to 15% of Caucasians and African Americans are homozygous for the TA7 repeat (*28/*28), and these individuals have a 50% higher risk of experiencing severe (grade 4 or 5) neutropenia following the administration of irinotecan. Approximately 40% of individuals treated with irinotecan are heterozygous for the TA7 repeat polymorphism (ie, TA6/TA7 or *1/*28). These individuals are also at increased risk of grade 4 neutropenia. Recently, the drug labeling for irinotecan has been changed to indicate that individuals homozygous or heterozygous for polymorphisms present in the TATA box of the UGT1A1 promoter have a higher risk for severe or life-threatening neutropenia. It appears that the risk is greatest for individuals who receive irinotecan once every 3 weeks.
An interpretive report will be provided.
An interpretive report will be provided.
Drug-drug interactions must be considered when predicting the UGT1A1 phenotype, especially in individuals heterozygous for the TA7 polymorphism (see Cautions).
Note that in patients who have received heterologous blood transfusions before a saliva sample was acquired, the saliva samples may contain donor DNA. Return to recipient genotype usually occurs after 6 weeks. Similarly, saliva samples obtained from patients after allogeneic blood or marrow transplantation can contain donor DNA. In both cases, this may result in genotyping results that reflect the genotype of the recipient, the donor, or a blend of the donor and recipient. Results obtained under these circumstances may not accurately reflect the recipient’s genotype.
UGT1A1 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient’s UGT1A1 status.
This test does not detect polymorphisms other than *1, *28, *36, and *37. Numerous polymorphisms and rare mutations have been described that impair UGT1A1 activity. Sequencing of the full gene is also available, order UGT1 / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Irinotecan Hypersensitivity for situations where patients are to be evaluated for irinotecan toxicity. Order UGT2 / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Hyperbilirubinemia, if testing for Gilbert syndrome or Crigler-Najjar syndromes is desired.
Liver or renal dysfunction may result in adverse drug reactions with irinotecan independently of TA-repeat polymorphisms.
Drugs that significantly inhibit cytochrome P450 3A4, such as ketoconazole, increase patient exposure to irinotecan and its active metabolite SN-38, potentially causing or increasing the severity of an adverse drug reaction. The drug labeling should be consulted for additional information.
Drugs that induce the overexpression of cytochrome P450 3A4, including anticonvulsant medications (such as phenytoin, phenobarbital, and carbamazepine) and rifampin, will cause substantial reduction in exposure to irinotecan and its active metabolite SN-38. The drug labeling should be consulted for changes to the use of other medications.
Herbal supplements that induce the overexpression of cytochrome P450 3A4 such as St. John's Wort, will cause substantial reduction in exposure to irinotecan and its active metabolite SN-38. The drug labeling should be consulted for changes to the use of other medications.
1. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733
2. Goetz MP, Safgren S, Goldberg RM, et al: A phase I dose escalation study of irinotecan (CPT-11), oxaliplatin (Oxal), and capecitabine (Cap) within three UGT1A1 TA promoter cohorts (6/6, 6/7, and 7/7). ASCO 2005; ASCO Annual Meeting Abstract No:2014
3. Package insert: NDA 20-571/S-024/S-027/S-028. Camptosar (Irinotecan HCL) Final Label. Pfizer Inc, NY, rev 7/05