It is common knowledge that genetic influences are often significant in predicting how patients will respond to drugs. As a result, companies are now beginning to integrate the genetic component into drug discovery and development to improve safety profiles.
The terms pharmacogenetics and pharmacogenomics are often used loosely and even interchangeabley. According to Dan Burns, Ph.D., senior vp for pharmacogenetics at GlaxoSmithKline, pharmacogenetics can be seen as variation in a patient’s inherited genome, while pharmacogenomics is a broader term, covering anything to do with gene expression that might include, for instance, the genome of a patient’s tumor.
“It is accepted that genetics plays a role in adverse events for all kind of drugs,” Dr. Burns reported at the recent European Science Foundation and University of Barcelona’s “Conference on Pharmacogenetics and Pharmacogenomics.”
Dr. Burns presented research pertaining to GSK’s abacavir, a nucleoside reverse-transcriptase inhibitor with activity against HIV that is typically used in combination with other antiretroviral drugs. The most significant adverse effect of abacavir is a hypersensitivity reaction, affecting between 5 to 8% of patients during the first six weeks of treatment. The hypersensitivity reaction includes gastrointestinal, skin, or respiratory symptoms. It can be hard to distinguish from concomitant infection, reaction to other drugs, or inflammatory disease. Withdrawal of abacavir results in rapid resolution of the hypersensitivity reaction, but rechallenge with the drug can result in a renewed reaction that may be more rapid and severe.
There is a known association between a diagnosis of hypersensitivity reaction to abacavir and carriage of the major histocompatibility complex allele HLA-B*5701. In the Predict-1 study, a group of HIV positive patients was screened for HLA-B*5701 and not given abacavir if they tested positive. In a control group, no screening was performed, and all patients were given the drug.
Screening eliminated immunologically confirmed hypersensitivity reactions, which were found in 2.7% of the control group. The hypersensitivity reaction was clinically diagnosed in 3.4% of the prospectively screened group, compared to 7.8% of the control group. The findings show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug.
“This is one of the first examples where a genetic marker has been used prospectively to demonstrate its ability in predicting adverse events,” commented Dr. Burns.
Following discussions with regulatory agencies, changes were made in the labeling of abacavir to reflect the utility of pharmacogenetic testing for HLA-B*5701. Currently the test is available through clinical labs rather than at point of care. “Physicians will use their clinical judgement over whether to offer a patient a pharmacogenetic test,” he noted.