The incorporation of genetic testing to faciliate a more efficient drug treatment for individuals is a relatively new field with advancements being made every day. Many of the statistics found here can be corroborated with the American Medical Association, who routinely issues guidelines for practicing physicians.

Pharmacogenomics

One of the most important components of personalized medicine is pharmacogenomics, the study of genetic variations that influence individual response to drugs. Enzymes responsible for drug metabolism and proteins that determine the cellular response to drugs (receptors) are encoded by genes, and can therefore be variable in expression, activity level and function when genetic variations are present. Knowing whether a patient carries any of these variations may help health care professionals individualize drug therapy, decrease the number of adverse drug reactions and increase the effectiveness of drugs. Pharmacogenomics has been characterized as “getting the right dose of the right drug to the right patient at the right time.”

Genes Commonly Involved

There are several genes responsible for differences in drug metabolism and response. Among the most common are the Cytochrome P450 (CYP) genes, encoding enzymes that control the metabolism of more than 70 percent of prescription drugs. People who carry variations in certain CYP genes often do not metabolize drugs at the same rate or extent as in most people, and this can influence response in many ways. Other genes known to affect drug response encode the receptors for regulatory molecules such as neurotransmitters, hormones, cytokines and growth factors, and cellular proteins such as enzymes, transporters, carriers, ion channels, structural proteins and transcription factors. Variations in these genes can lead to poor response and adverse drug reactions by disabling, inactivating, interfering with, or inaccurately inducing the signaling mechanisms or cellular machinery that must function for the body to respond properly to the drug; or by causing side effects that prevent continued use of the drug.

Particular drugs whose safety and efficacy are affected by gene variations

The table below is a partial list of drugs that exhibit reduced therapeutic effectiveness and/or safety concerns in patients carrying certain genetic variations. These variations often make the drug unsafe or unsuitable for patients who carry the variations. This list contains examples of drugs that are affected by inherited genetic variations and by variations that are acquired and present in tumor tissue.

Drug	Gene(s)	Drug	Gene(s)
Clopidogrel (Plavix®)	CYP2C19	Azathiopurine (Imuran®)	TPMT
Atomoxetine (Strattera®)	CYP2D6	Irinotecan (Camptosar®)	UGT1A1
Codeine	CYP2D6	Cetuximab (Erbitux®)*	EGFR
Tamoxifen (Nolvadex®)	CYP2D6	Erlotinib (Tarceva®)*	EGFR
Warfarin (Coumadin®)	CYP2C9, VKORC1	Imatinib mesylate (Gleevec®)*	C-KIT
Abacavir (Ziagen®)	HLA-B*5701	Panitumumab (Vectibix®)*	KRAS
Carbamazepine (Tegretol®)	HLA-B*1502	Trastuzumab (Herceptin®)*	Her2/neu

* Response to these drugs is dependent on genetic variations that are present in tumor tissue.
Data can be found at the U.S. Food and Drug Administration website.

Metabolizer phenotype

The metabolizer phenotype describes the patient’s ability to metabolize certain drugs and is based on the number and type of functional alleles of certain genes that a patient carries. For example, poor metabolizers are unable to metabolize certain drugsefficiently, resulting in a potentially toxic build-up of an active drug or the lack of conversion of a prodrug into an active metabolite. In contrast, in ultra-rapid metabolizers, an active drug is inactivated quickly, leading to a subtherapeutic response, while a prodrug is quickly metabolized, leading to rapid onset of therapeutic effect.

Using pharmacogenomics to prevent Adverse Drug Reactions, Effectiveness, and Optimal Doses.

Knowing about patients’ genetic variations can help physicians select drug therapies that will be most effective for individual patients. Below are some drug treatment examples.

Abacavir - A Hypersensitivity reaction occurs in 5–8 percent of patients taking abacavir, usually during the first six weeks after initiation of therapy. The hypersensitivity symptoms include a combination of fever, rash, gastrointestinal tract symptoms and respiratory symptoms that become more severe with continued dosing.

Codeine - Variations that decrease the metabolic activity of CYP2D6 result in a poor analgesic response due to the reduced conversion of codeine into morphine, and patients carrying such a variation receive little therapeutic benefit from codeine. On the other hand, variatons that increase the metabolic activity of CYP2D6 result in an enhanced analgesic response due to the rapid conversion of codeine into morphine. Patients who carry such variations are at risk for opioid toxicity, which includes moderate to severe central nervous system depression.

Clopidogrel - Clopidogrel (Plavix®) is a platelet inhibitor used in the treatment of a number of cardiovascular diseases. Patients who carry certain variations in CYP2C19 are considered poor metabolizers and show reduced ability to convert clopidogrel into its active metabolite, resulting in a diminished antiplatelet effect.

Warfarin - Warfarin (Coumadin®) is the most widely-prescribed anticoagulant used to treat and prevent thromboembolic diseases. Variation in the CYP2C9 gene causes some patients to have slow metabolism of warfarin and a longer half-life of the drug, resulting in higher than usual blood concentrations of warfarin and greater anticoagulant effect. Certain variations in the VKORC1 gene result in reduced activity of the enzyme and subsequently reduced synthesis of coagulation factors.

The Future of Pharmacogenomics

It is important to note that the field of pharmacogenomics is still developing, with new findings being rapidly reported. Clinical trials and other studies focusing on the benefits, risks and cost-effectiveness of using genetic information to inform drug therapy are underway. In the meantime, physicians and health care providers should be familiar with the concept that genetic variations can cause their patients to respond unexpectedly to drug therapy, and that in some cases, it may be appropriate to use genetic testing to guide therapeutic decisions.