PERSONALISING DRUG PRESCRIPTION BASED ON OUR GENETICS? It may not be too far away. What is “pharmacogenomics” and how does it work?   In today’s modern society, drug prescription has become one of the most common areas of concern for health practitioners due to the increasing diversity within the growing population. Currently, a “one size fits all” method is used when it comes to prescribing drugs. In many cases individuals will experience the positive benefits of drugs, however, unfortunately others do not. Sizeable minorities of the population carry genetic called polymorphisms that affect their response to various drugs. These effected negative responses however can be more than just a “bad fit”, if a patient does not response well to their prescribed drug they can have serious side effects known as adverse drug reactions. In many patients, certain drugs do not work as well as expected, causing toxic effects, even at lower doses. This is where Pharmacogenomics changes the game. Pharmacogenomics or the more commonly used term, Pharmacogenetics looks at the parallel analysis between individual genetics and the ability for drugs to interact with them. Put simply, scientists are able to look at the genetic profiling of individuals that obtain unwanted side effects from drugs to see how other drugs may interact with them if taken. Pharmacogenomics is in turn, able to tailor drugs to individuals based on their genetic makeup and molecular profile to warrant only the positive effects of the drug. Pharmacogenomics in society is currently still a while off as it is in the transitional phase from bench research to clinical applications however, as prescriptions continue to grow and physicians gets a better knowledge of patients genetic status, predictions of responses to certain drugs can be more accurately made leading to better efficacy, fewer adverse drug reactions and a better cost-benefit ratio. The Evolution of Pharmacogenomics   Pharmacogenetics first started to evolve in 510 B.C. when Pythagoras, a Greek philosopher, noted that ingestion of fava beans resulted in potentially fatal reaction in some, but not all, individuals. Even though this research is now the basis of pharmacogenomics, it took until the 1900s for pharmacogenomics to come back into the science research field. The term wasn’t even coined until 1959 by Friedrich Vogel. In the early 1900s, British scientist Archibald Garrod made the first major advance in human genetics by identifying errors in metabolism in individuals that carry recessive traits in their DNA. However, it wasn’t until the landmark paper in 1949 by the Linus Pauling’s group, where understanding of pharmacogenomics interactions started to take place. They linked sickle cell anaemia to a specific protein imbalance, the first proof that genetic changes could produce human disease. Arno Motulsky followed the findings in 1957, observing a deficiency in the enzyme NAT2 which is used to breakdown the antituberculosis medication Isoniazid. Due to the increasing amount of findings throughout the 1900s, this lead to the first established publication on pharmacogenomics in 1962 by Werner Kalow, one of the world’s most renowned scientists contributing more than 300 papers to the field of pharmacogenomics. Current Pharmacogenomics testings Clopidogrel An example of pharmacogenomics testing currently used in today’s society is the use of Clopidogrel, a prodrug used to block platelets from sticking together and prevents them from forming blood clots in individuals suffering from chest pain, peripheral arterial disease, heart attacks or strokes. The effectiveness of clopidogrel depends on its conversion to an active metabolite by CYP2C19. In healthy patients, the drug gets rapidly absorbed from the intestine and extensively metabolised in the liver through two pathways by the CYP2C19 enzyme.

However, due to genetic variation in some patients, with studies showing that about 30% of the patients taking clopidogrel do not respond effectively, with this being able to be broken down into two sub-populations. Individuals who carry 2 non-functional copies of CYP2C19 gene are classified as CYP2C19 poor metabolisers. This means that there is no enzyme activity and cannot activate clopidogrel resulting in the drug having no effect on the patient and another platelet inhibitor medication should be used. The second population are those that carry 1 non-functional copy of CYP2C19 gene who are referred to as intermediate metabolisers. However, researchers have found that either choosing an alternative drug, or doubling the dose of clopidogrel to 150 mg daily dose, 600 mg loading dose will be able to give the patient the positive effects. Therefore, for this drug to be helpful patients need to take a CYP2C19 genetic test to see what copy of CYP2C19 they have and in turn make those necessary changes to their medication regime.   Tamoxifen Tamoxifen is a drug prescribed to prevent the recurrence of estrogen-receptor-positive breast cancer, to treat metastatic breast cancer, to prevent cancer in high-risk populations, and to treat ductal carcinoma in situ. Tamoxifen is metabolized by CYP2D6 and CYP3A4/5 to form endoxifen which has much higher potency and higher systemic levels than tamoxifen. Very much like Clopidogrel, discussed above, about 7% of the population are unable to respond to Tamoxifen due to genetic variation. This group are classified as poor-metabolisers meaning that they have an impaired ability to metabolize the CYP2D6 substrates. CYP2D6 testing is available however, has been considered insufficient at this current time. What direction is pharmacogenomics taking?   Even though the field of pharmacogenomics is still in its infancy, the future of pharmacogenomics looks bright. As more research is being undertaken in the field of pharmacogenomics so too is the amount of information that is being derived from DNA. As DNA holds the key to the limitless possibilities of pharmacogenomics, more and more knowledge will be able to be unlocked. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDs and asthma. However, there is always room for improvement. Currently, there are still many limitations of pharmacogenomics testing that are needed to be looked at in order for this field to really have an impact on the future of drug prescription. At the minute, one single pharmacogenomics test cannot be used to determine how you will respond to all medications meaning that you may need more than one test if you are taking numerous medications. Pharmacogenomics tests are also not available for all medications including aspiring and many over-the-counter pain relievers. But the era of truly individualised medicine is not here yet. Adverse drug reactions remain a significant detriment to public health, having a substantial impact on rates of morbidity and death and on health-care costs. Ethical boundaries will always been a conscious concern for researchers as DNA contains such private information, not everyone will be willing to share their genetic profiles. For most drugs, pharmacogenomics testing has not been endorsed by expert committees since we still lack evidence that clinical outcomes improve. However, it is a field where extensive funding is required to obtain accurate and substantial results. If this is able to be achieved, the possibilities are endless.