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Genomics - Page 2


Pharmacogenomics is generally regarded as the study or clinical testing of genetic variation that explains why some people respond to certain drugs while others do not. The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably. We will always use the term pharmacogenomics for consistency throughout our explanation.

Pharmacogenomics uses information about a person's genetic makeup, or genome, to choose the drugs and drug doses that are likely to work best for that particular person. This new field combines the science of how drugs work, called pharmacology, with the science of the human genome, called genomics.

Much of current clinical interest is at the level involving variation in genes involved in drug metabolism, with a particular emphasis on improving drug safety in people. We now know that there are not only rapid or slow metabolizers but also responders and non-responders to a certain drug treatment.

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The wider use of pharmacogenomic testing is viewed by many as an outstanding opportunity to improve drug prescribing safety and efficacy.

Driving this trend are the 106,000 deaths and 2.2 million serious events caused by adverse drug reactions in the US each year (Lazarou 1998).

What Pharmacogenomics Means For People?

Until recently, drugs have been developed with the idea that each drug works pretty much the same in everybody. But genomic research has changed that 'one size fits all' approach and opened the door to more personalized approaches to using and developing drugs.

Depending on your genetic makeup, some drugs may work more or less effectively for you than they do in other people. Likewise, some drugs may produce more or fewer side effects in you than in someone else.

It is hoped that in the near future, doctors will be able to routinely use information about your genetic makeup to choose those drugs and drug doses that offer the greatest chance of helping you. Pharmacogenomics may also help to save you money.

By using information about your genetic makeup, doctors soon may be able to avoid giving you drugs that are likely to be ineffective or cause bad side effects. Most people today are given a drug dose determined by their BMI (body mass index).

This results in some people being:

  • Under treated if they metabolize the prescribed drug quickly and it does not have enough time to interact and kill the cancer cells.
  • Over treated if they metabolize the drug very slowly or not at all and are subjected to the drug for too long a period of time leading to toxic levels in their bodies.
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Examples in use today:
  • 5-FU metabolism - 1 in 4 individuals carries variations in either the DPYD or TYMS genes that will increase their risk of dose-limiting toxicity. These variations confer up to a 60% risk of toxicity to 5-FU-related therapies.
    • "...given the large number of patients treated each year with 5-FU...and the human and economical cost of grade 3 and 4 toxic side effects, pretherapeutic detection of DPD deficiency should be considered."1 Reference: 1. Morel A, Boisdron- Celle M, Fey L, et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther. 2006;5:2895-2904.
  • The breast cancer drug trastuzumab (Herceptin) is a therapy that works only for women whose tumors have a particular genetic profile that leads to overproduction of a protein called HER2.

  • The U.S. Food and Drug Administration (FDA) recommends genetic testing before giving the chemotherapy drug mercaptopurine (Purinethol) to patients with acute lymphoblastic leukemia. Some people have a genetic variant that interferes with their ability to process the drug. This processing problem can cause severe side effects.

  • The FDA also advises doctors to test colon cancer patients for certain genetic variants before administering irinotecan (Camptosar). The reasoning is that patients with one particular variant in the UGT gene may not be able to clear the drug from their bodies as quickly as others, resulting in severe diarrhea and increased infection risk. Such patients may need to receive lower doses of the drug.

  • Patients with variant forms of the gene CYP2D6 may not receive full benefit from tamoxifen because it is metabolized too slowly. On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.

  • Recent studies suggest that taking antidepressants such as Paxil, Prozac, etc., can decrease the effectiveness of tamoxifen, because these drugs compete for the CYP2D6 enzyme. This enzyme is needed to metabolize tamoxifen into its active form endoxifen.

  • Chemicals in grapefruit juice and grapefruit pulp interfere with the enzymes that break down (metabolize) various drugs in the digestive system. The result can be excessively high levels of these drugs in the blood and an increased risk of potentially serious side effects. Tell your doctor if you drink/eat a lot of grapefruit products.
Can Pharmacogenomics Be Used To Develop New Drugs?

Besides improving the ways in which existing drugs are used, genome research could lead to the development of better drugs. The goal is to produce new drugs that are highly effective without causing serious side effects. SNP screenings will benefit drug development and testing because pharmaceutical companies could:

  • Exclude from clinical trials those people whose pharmacogenomic screening showed that the drug being tested would be harmful or ineffective for them.
    • Excluding these people will increase the chance that a drug will show evidence of effectiveness in a particular population thus increasing the chance that the same drug will make it into the marketplace.
  • Pre-screening clinical trial subjects could also allow the clinical trials to use fewer subjects, proceed faster, and therefore be less expensive, resulting in consumer benefit from reduced drug costs.
  • Assess an individual's reaction to a drug before it is prescribed will increase a physician's confidence when prescribing the drug and the patient's confidence when taking the drug. This in turn should encourage the development of new drugs tested in a similar manner.
  • Breathe new life into some drugs that were shelved during the development process.
What Are Some Of The Barriers To Pharmacogenomic Progress?

Pharmacogenomics is a developing research field that is still in its infancy. Several of the following barriers will have to be overcome before many pharmacogenomics benefits can be realized.

  • SNPs - Single nucleotide polymorphisms (SNPs) are DNA sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered.

    SNPs occur every 100 to 300 bases along the 3-billion-base human genome therefore millions of SNPs must be identified and analyzed to determine their involvement (if any) in drug response.

Further complicating the process is our limited knowledge of which genes are involved with each drug response. Since many genes are likely to influence responses, uncovering the big picture on the impact of gene variations is highly time-consuming and complicated.

  • Limited drug alternatives - Only one or two approved drugs may be available for treatment of a particular condition. If patients have gene variations that prevent them from using these drugs, they may be left without any alternatives for treatment.
  • Disincentives for drug companies to make multiple pharmacogenomic products - Most pharmaceutical companies have been successful with their "one size fits all" approach to drug development. Since it costs hundreds of millions of dollars to bring a drug to market, will these companies be willing to develop alternative drugs that serve only a small portion of the population?
  • Healthcare provider education - Introducing multiple pharmacogenomic products to treat the same condition for different population subsets undoubtedly will complicate the process of prescribing and dispensing drugs.

    Physicians must execute an extra diagnostic step to determine which drug is best suited to each patient. To interpret the diagnostic accurately and recommend the best course of treatment for each patient, all prescribing physicians, regardless of specialty, will need a better understanding of genetics.



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