Pharmacogenomics Can Help in the Administration of Drugs; Also Has Its Challenges

Pharmacogenomics can be useful in the selection and administration of drugs, and may also help reduce adverse reactions in patients; however, there are still some challenges facing the field. These were some of the findings from a review of genomic medicine and its advances that was recently published in the New England Journal of Medicine [2011;364(12):1144-1153].

Pharmacogenomics investigates the role that inherited and acquired genetic variations have in drug responses and can be used by medical professionals to identify biomarkers to determine drug selection, dose, treatment duration, and possible adverse reactions for patients based on the genetic variations they display.

This review examines the latest advances and research in the field of genomics and its clinical implications. According to the article’s authors, there has recently been a switch from the study of individual candidate genes to genomewide association studies.

Cardiovascular drugs are just one area where pharmacogenomics can be used. These types of drugs, including warfarin and clopidogrel, typically have narrow therapeutic indices that may be influenced by genetic variation.

Patients who are prescribed warfarin can be given an international normalized ratio (INR)—a laboratory test that is used to measure the anticoagulant effect of the drug; however, there are still serious adverse effects for some patients. According to the review’s authors, nearly a decade ago research found that those patients who required a low final dose of warfarin based on INR values often carried 1 or 2 CYP2C9 variant alleles, which made them metabolize the drug more slowly. However, this finding did not account for most of the variation in final warfarin dose.

In 2004, it was discovered that single-nucleotide polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) were associated with the dose of warfarin required to achieve a targeted INR value, and a genomewide association study in 2009 found that people carrying a variant CYP4F2 allozyme may require an increased dose of warfarin.

Research has also shown that including genotype information about patients has led to enhanced patient outcomes, and the US Food and Drug Administration (FDA) has revised warfarin’s label to suggest genotypes be considered when prescribing the medication.

The FDA also added a boxed warning for clopidogrel, which stated that those patients with a CYP2C19 variant may require dose adjustment or a different medication. However, there has been conflicting research about whether genotyping for the CYP2C19 variant to determine treatment response has been helpful.

Pharmacogenomics is also valuable in identifying patients who may be susceptible to severe adverse reactions in medication. For example, a multicenter genomewide association study analyzing the genotypes of 51 persons with floxacillin-induced hepatic injury and 282 matched controls found that there was an association between the presence of HLAB* 5701 and hepatic injury. One challenge facing pharmacogenomics is that often it can be difficult to collect enough data to replicate associations found in studies for rare adverse drug reactions. The FDA tends to include pharmacogenetic information regardless of whether the response has been replicated, and clinicians need to use their own judgment when prescribing these medications.

Research into antineoplastic drugs has shown that pharmacogenomic variations in both the tumor genome and patient’s germline can affect a patient’s response to therapy.

Clinical context also plays a role in pharmacogenomics. For example, a large clinical trial of aromatase inhibitors used to treat breast cancer patients found that there was an association between patients with variants in the T-cell leukemia-lymphoma proteins and musculoskeletal pain from the medication. Tamoxifen could be an alternative treatment option for these patients, and a genetic test to predict whether patients will experience problems with aromatase inhibitors could be useful.

The authors concluded that there have been advances in genomic medicine, and this type of research can be helpful in selecting drugs and their administration. There are still challenges associated with the field, including little consensus on the level of data required to establish clinical utility. If pharmacogenomic tests are expected to become a routine part of clinical practice, the authors said that a blend of scientific, regulatory, and psychological factors should be examined.