Capecitabine and DPYD

 

Ashley Raffay, Pharm.D. Candidate; Sean Bennett, Pharm.D. Candidate; Isabel Cwikla, Pharm.D. Candidate; Denys Ivasechko, Pharm.D. Candidate

About the Drug

Capecitabine is a drug that is used to treat several different cancers including breast and colorectal (a cancer that starts in either the colon or the rectum). Researchers are also looking into whether it can be used in other cancers such as gastric (in the stomach) or ovarian.

Capecitabine is converted in the body into 5-fluorouracil which is the active form (or version) of the drug. This drug is converted by enzymes known as cytidine deaminase and thymidine phosphorylase. Thymidine phosphorylase in particular is found in high concentrations in the cancer cells themselves. This is why capecitabine is considered to be “tumor activated” since the drug is activated by the tumor itself. 5-fluorouracil then binds to cancer cells which ultimately stops them from dividing and stops the formation of new cancer cells.

Capecitabine is available in tablet form and is absorbed very well in the small intestine. This drug should not be used by any patient with kidney damage and its safety has not yet been evaluated in children or babies. Capecitabine has a long list of potential side effects; however, it is still recommended as a first-line treatment for both breast and colorectal cancers.

About the Gene

The dihydropyrimidine dehydrogenase (DPYD) gene provides instructions for making an enzyme of the same name. This enzyme is responsible for breaking down bases known as uracil and thymine, which are the building blocks of DNA. This breakdown of DNA bases is important in DNA’s ability to edit itself for copying mistakes.

About the Drug-Gene Interaction

Depending on the variability in the DPYD gene, capecitabine can cause severe or even fatal drug toxicity. The chemical that capecitabine breaks down into, 5-fluorouracil, has a similar structure to the uracil and thymine DNA bases that DPYD is normally responsible for breaking down. If there is a mutation in the DPYD gene, this means that capecitabine will not be broken down properly, which could lead to potential drug toxicity.

Patients that have a “normal” DPYD pair of genes (or a genotype) of *1/*1 (two normal alleles) should not have any problems breaking down capecitabine. However, if a patient has a heterozygous genotype (one normal allele and one nonfunctional allele) such as *1/*13, the patient will have a decreased ability to break down capecitabine and should be started on a dose that is 50% of what a normal dose would be. If the patient has two nonfunctional alleles (such as *2A/*2A), a different therapy should be recommended altogether.

Drug-Gene Interaction Example

Jasmine is a 55-year-old African American female who has been prescribed capecitabine for treatment of colorectal cancer. While visiting a doctor, she was told that she wouldn’t receive full treatment benefits and might even experience potential side-effects, in case she has a DPYD genotype deficiency. She decided she doesn’t want another test being done on her and leaves the hospital on capecitabine. A week later, Jasmine is admitted to the emergency room and was found to have mouth sores, grade 2 oral mucositis, grade 3 neutropenia (ANC of 650/mm³) and grade 3 diarrhea. Doctors decided to order the genetic test for DPYD deficiency after realizing she was on capecitabine. Reports showed presence of Y186C variant and low DPYD function, which decreased effectiveness of treatment and evoked the present side effects. Jasmine was treated and prescribed a different chemotherapy regimen which accounted for her genotypic deficiency. No severe side effects were further observed.

Later on in the year, the same doctor is treating Angelika, a French-Caucasian female, who recently was diagnosed with breast cancer. After telling Angelika about the risks of the DPYD genotypic deficiency and its possible side effects with capecitabine, she agreed to have a genetic test. Results show the presence of the non-functional allele (rs67376798), which leads to low levels of DPYD. This means that she is more likely to have severe side effects from this chemotherapy due to a drug build up if the dose is not adjusted. Two options become available: either adjusting of the dose or switching to non-fluoropyrimidine containing regimen. Doctors choose the former and Angelika’s dose is reduced by 50%. She avoids the severe side effects she would have experienced if genetic testing was not done.

DPD genetic testing does not completely rule out the risks of taking capecitabine, 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 capecitabine. The links are to external websites and will be checked regularly for consistency.

Sources of Information

Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Capecitabine; [updated 2014 Oct 24; cited 2015 Dec 3]; [about 3 screens]. Available from: http://0-www.clinicalpharmacology-ip.com.polar.onu.edu/Forms/drugoptions.aspx?cpnum=2279&n=Capecitabine&t=0&enh=1

Genetics Home Reference [Internet]. US National Library of Medicine; c2011-2016. DPYD; [cited 2015 Dec 4]; [about 3 screens]. Available from: http://ghr.nlm.nih.gov/gene/DPYD.

Mattison LK, Fourie J, Desmond RA, Modak A, Saif MW, Diasio RB. Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians. Clin Cancer Res. 2006 Sep 15;12(18):5491-5.

Munshi HG and Montgomery RB. Severe neutropenia: a diagnostic approach. West J Med. 2000 Apr;172(4):248-52.

Offer SM, Lee AM, Mattison LK, Fossum C, Wegner NJ, Diasio RB. A DPYD variant (Y186C) in individuals of African Ancestry associated with reduced DPD enzyme activity. Clin Pharmacol Ther. 2013 Jul;94(1):158-66.

PharmGKB [Internet]. PharmGKB; c2001-2016. Capecitabine; [updated 2016 Jan 27; cited 2015 Dec 4]; [about 3 screens]. Available from: https://www.pharmgkb.org/chemical/PA448771.