- A good example of pharmacogenomics at work is the use of trastuzumab in addition to chemotherapy for breast cancer patients who are positive for the human epidermal growth factor receptor 2 (HER2) oncogene.5
Pharmacogenetics is the branch of pharmacology that examines the relation of genetic factors to variations in response to drugs.
The use of pharmacogenetics to predict individualized responses to medications and to prevent adverse drug reactions through individualized dosing regimens or avoidance of certain medications hinges on our knowledge of genetic polymorphisms, that is, gene-based differences in drug absorption, distribution, metabolism, or excretion.
Polymorphisms of the cytochrome P450 family of drug metabolizing enzymes have been the most extensively studied. The names of these enzymes are abbreviated by using CYP and then a series of letters and numbers to describe individual enzymes. The 4 most extensively studied CYP enzymes are CYP2A6, CYP2C9, CYP2C19, and CYP2D6. These 4 metabolize an estimated 40% of all drugs; the distributions of polymorphisms of each vary considerably by race/ethnicity.6-8
A sampling of medications and classes of medications where polymorphisms play a significant role in drug metabolism is listed in the TABLE. Three with significant potential for prevention of adverse drug reactions are the antipsychotics, because of the severity of a specific drug adverse reaction, tardive dyskinesia;6,9 warfarin, because of the risk of bleeding complications and its narrow therapeutic index;7,10 and chemotherapeutic agents because of the serious nature of the disease and the potential for tailoring individualized therapies to maximize tumor response to medication and to minimize adverse reactions of very toxic drugs.11
TABLE
Polymorphisms to these enzymes affect drug metabolism
| DRUG/CLASS | ENZYMES |
|---|---|
| Antiarrhythmmics7 | CYP2D6 |
| Antidepressants7 | CYP2D6 |
| Antipsychotics6,9 | CYP2D6, CYP1A2, CYP2C19, CYP3A4 |
| Beta-blockers7 | CYP2D6 |
| Cancer chemotherapy11 | Varies by the agent |
| HMG-CoA reductase inhibitors (statins)29 | CYP2D6, CYP2C9, CYP2C19 |
| Losartan7 | CYP2C9 |
| Neuroleptics7 | CYP2D6 |
| NSAIDs29 | CYP2C9 |
| Phenytoin7 | CYP2C9, CYP2C19 |
| Proton pump inhibitors29 | CYP2C19 |
| Tolbutamide7 | CYP2C9 |
| Warfarin7,10 | CYP2C9 |
Clinical resources reflect an information gap
In spite of the potential for improved patient care, there remains very little clinical application of pharmacogenetic information in primary care practice. Zineh and colleagues reviewed prescribing information in the electronic version of the Physicians’ Desk Reference (PDR) in 2004 and found that only 76 package inserts out of 3382 contained pharmacogenetic information.12 In only 25 was there enough information to affect treatment decisions. Just 5 inserts mentioned that the chance of successful response to treatment could be predicted by genetic testing, and only one insert mentioned that a specific genetic subgroup should not take a drug.
The authors concluded that, generally, the pharmacogenetic information was inadequate to guide drug therapy and the majority of information was available for drugs that are not commonly prescribed. The FDA is addressing this issue by requiring the inclusion of pharmacogenetic information in package inserts more frequently.
Consider, too, the 2005 edition of Applied Therapeutics, a commonly used medical textbook.13 In it there is no mention of the use of pharmacogenetics in managing pharmacological therapies, which tells us that very little teaching on this topic is going on in medical schools and residencies.
But why? Why are clinicians and the tools we rely on so out of sync with the recommendations and expectations of personalized medicine advocates?
Will litigation be the tipping point?
Certain conditions will need to exist before testing for CYP polymorphisms will become the standard of care in dosing certain drugs, such as warfarin. (see “Warfarin: An ideal, but far from ready, candidate”.) The most important is that this clinical approach needs to be proven superior to existing methods, such as INR monitoring. Should this occur, guidelines that are evidence-based will include it as a recommendation, physician continuing education courses will cover it, and it will enter into the curricula of medical schools and residency programs. But the process of adopting new, evidence-based best practices has historically been slow.32-36
One variable that may play a part in facilitating more rapid acceptance of genetic testing before warfarin use is litigation. Marchant and colleagues describe potential legal pressures that may drive medicine to adopt more personalized medicine.37 If genetic testing before warfarin use results in better outcomes (fewer catastrophic events or very bad outcomes) and there is plausible evidence that a catastrophic outcome (massive bleeding) could have been avoided with genetic information, then litigation will surely be close behind.
As news of successful litigation spreads, one of two results will likely occur: Either the use of the CYP polymorphism testing will increase, or the movement to use alternative medications, such as fractionated heparin, will accelerate.