Pharmacogenomics & Precision Medicine

August 15, 2013

Transplant drug added to PREDICT program

Tacrolimus is essential for patients receiving new hearts, kidneys and other organ transplants. The drug suppresses the body’s immune system, helping to prevent rejection.

Tacrolimus is essential for patients receiving new hearts, kidneys and other organ transplants. The drug suppresses the body’s immune system, thereby preventing rejection.

Marketed as Prograf, tacrolimus has a narrow “therapeutic window.” If too little of the drug gets into the circulation, acute transplant rejection may occur. Too much of it can cause serious side effects, including a form of diabetes and squamous cell skin cancer.

Patients also differ in how much drug they need to block rejection. Last year, Kelly Birdwell, M.D., MSCI, and colleagues at Vanderbilt University Medical Center confirmed that a single genetic variation largely impacted different dose requirements.

Kelly Birdwell, M.D., MSCI

In March 2013, that finding was adopted by Vanderbilt’s pharmacogenomics testing program, PREDICT. Since then, more than 2,800 Vanderbilt patients have been found to carry this genetic variation. More than 600 of them are adults who have received or are awaiting heart or kidney transplants.

“This is an example of a striking variation in genetics by ancestry,” said Dan Roden, M.D., assistant vice chancellor for Personalized Medicine. For example, African Americans are more likely to require the higher dose requirement.

This information is now included routinely in the electronic health record. Doctors who prescribe tacrolimus receive notifications that they may need to adjust the dose if their patients carry the genetic variation.

Will genetic testing lower rates of rejection and side effects long-term? “We’re collecting those data (now),” said Birdwell, an assistant professor of Medicine who also is helping draw up national guidelines for improving tacrolimus dosing in transplant patients.

Tacrolimus is the fifth drug for which pharmacogenomic information is included in the electronic health record. The others are the anti-platelet drug clopidogrel (Plavix), the anti-coagulant warfarin, the cholesterol-lowering drug simvastatin (Zocor), and thiopurine therapies, which are used to treat certain cancers and autoimmune disorders.

Since it was launched in August 2010, PREDICT has genotyped more than 14,000 Vanderbilt patients for 184 different genetic variations that affect the body’s response to various drugs.

More than 12,000 of the patients, 88 percent, have genetic variations that increase their risk of adverse effects from one or more of the five drugs currently included in the electronic health record, said Julie Field, Ph.D., PREDICT project manager.

As the value of genetic testing becomes established for other drugs, that information will be added, Field said.

Birdwell is first author of a paper published last year that used Vanderbilt’s DNA databank, BioVU, to confirm that a genetic variation in a subfamily of cytochrome P450 enzymes called CYP3A altered the tacrolimus dose requirement.

The late Vanderbilt pharmacologist Grant Wilkinson, Ph.D., D.Sc., helped identify the importance of these enzymes, found in the liver and intestines, in drug response.

Birdwell also is principal investigator of a National Institutes of Health grant (GM100183) to study the genetics of a common tacrolimus side effect, abnormal glucose metabolism and new-onset diabetes after transplant.