Irinotecan and UGT1A

Austin Pifher, Pharm.D. Candidate; Catherine Oby, Pharm.D. Candidate; Taylor Beale, Pharm.D. Candi

 

About the Drug

Irinotecan (Camptosar® and generic products) is used in patients with cancer of the colon or rectum that has spread to other parts of the body (often the liver or lungs). Treatments for this type of cancer typically aim to control cancer growth and relieve symptoms.

Irinotecan works by blocking the action of an molecule called topoisomerase I. This molecule is an enzyme, and it is important when cells are dividing and multiplying. Blocking the enzyme often leads to cell death, and because cancer cells divide faster than most normal cells, they are more likely to be affected by irinotecan.

About the Gene

The gene of interest is UGT1A, which is responsible for producing an enzyme that metabolizes, or inactivates, irinotecan.

About the Drug-Gene Interaction

Changes in the UGT1A gene may lead to serious side effects when a patient is given irinotecan. Irinotecan is more likely to cause more serious side effects in patients who have two altered copies (one from each parent) of UGT1A (called UGT1A1*28/*28). This is because less drug is converted to an inactive form, meaning there is more active drug in the body at any given time. These higher active drug concentrations put patients at risk for serious or life-threatening side effects such as weakening of the immune system. This puts patients at a higher risk of infection. Patients that have one normal and one abnormal UGT1A gene will most likely be able to take a normal starting dose of irinotecan.

About 10% of the people in North America have two altered UGT1A genes. This means that one out of every ten people is at risk for life-threatening side effects with a normal dose of irinotecan. Patients with two altered UGT1A genes (UGT1A1*28/*28) should be given a lower starting dose of irinotecan compared to patients with only one altered UGT1A gene or two normal genes. Genetic testing can help identify these patients and help to start them of a correct dose of irinotecan.

Drug-Gene Interaction Example

Jennifer, a 68 year-old white female, was recently diagnosed with advanced colon cancer. Her doctor decided that treating her with irinotecan may slow the cancer’s growth. Because her cancer was progressive, the doctor decided to start irinotecan at a high dose. Jennifer’s doctor explained that genetic testing is recommended for patients before starting irinotecan to help select an optimal dose. This genetic test will tell the doctor if Jennifer had a defective UGT1A1 gene, meaning that she would be more sensitive to a drug-induced decrease in immune function at higher irinotecan doses. She declines to have the test done because she does not understand genetic testing and doubts that it would help. After Jennifer starts her chemotherapy, a routine blood test shows her white blood cell count is dangerously low. This means her immune system is not functioning well, leaving her at an in increased risk for infections. Her doctor stops Jennifer’s irinotecan immediately. She must now be admitted to the hospital for monitoring until her immune function improves. Once her immune function recovers, her doctor can restart her irinotecan, but this time at a lower dose.

If Jennifer had chosen to have the genetic test for UGT1A1 before starting irinotecan, her doctor could have seen that she has a variant form of this gene which puts her at increased her risk of having serious immune system dysfunction from irinotecan. In addition to being costly and dangerous, these reactions can also delay treatment with other cancer therapies.

UGT1A1 testing does not completely rule out the risks of taking irinotecan, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

Provider Information

The links below provide access to important articles and information relative to warfarin. The links are to external websites and will be checked regularly for consistency.

Sources of Information

American Cancer Society [Internet]. Atlanta (GA): American Cancer Society; c2017. More information on cancer drugs; [cited 2012 Oct 2]; [about 3 screens]. Available from: https://www.cancer.org/treatment/treatments-and- side-effects/cancer- drugs.html.

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2012. Irinotecan; [cited 2012 Oct 2]; [about 4 screens]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=80f3b79c-a399- 45b3-b755- 8535457719af.

Facts and Comparisons [Internet]. St. Louis (MO): Wolters Kluwer Health, Inc. 2005 March [cited 2012 Oct 02]. Available from: http://online.factsandcomparisons.com/index.aspx

Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. Journal of the National Cancer Institute. 2007;99:1290-5.

Perera MA, Innocenti F, Ratain MJ. Pharmacogenetic testing for Uridine Diphosphate Glucuronosyltransferase 1A1 polymorphisms: are we there yet? Pharmacotherapy. 2008;28(6):755-68.

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2017. Irinotecan; [cited 2012 Oct 04]; [about 4 screens]. Available from: https://www.pharmgkb.org/chemical/PA450085/.