8 Dec, 2008 09:38 pm
The concept of pharmacogenomics has been around for decades but only now in the age of the genome is true progress being made in its application. Pharmacogenomics is an understanding of the connections between our genetic make-up and our response to medication. This information can allow tailored dosing of medicines, or personalised pharmacy. This could prevent the "trial and error" dosing that is often used with drugs like the blood thinner warfarin or anti-hypertensives. It could enable the choice of the right drug and right dose first time. This is especially important for anti-cancer medication. There is still much research to be done to understand the multi-factorial processes of our response to medication but, if successful, there are significant therapeutic and economic advantages to be had.
The concept of personalised pharmacy is known as pharmacogenomics. Genomics is the study of genes, which are sections of DNA that carry the instructions for making specific proteins. These proteins make up tissues and organs, control chemical reactions and carry signals between cells. In effect, they are what make us function. Although we all look different, humans are actually genetically very similar and the most common differences are changes in single letters of the DNA code. There are hundreds of thousands of identified changes, and by studying what effect these have on our sensitivity to drugs, therapy can be custom-designed for the individual, or for groups of people with similar genetic characteristics.
Currently, most medicines are given at an average dose, depending on size, age, or gender. Sometimes this is on a “trial and error” basis. Patients treated for high blood pressure, for example, often have to try several drugs, at increasing doses, according to how well their symptoms are controlled. Although the dose is not random and is based on previous experience and clinical trials, there are two main problems with this approach. Firstly, not all patients respond to all drugs. A recent study published in a leading medical journal showed that if a specific chemotherapy regime for breast cancer was targeted to the right patient subgroup using genetic testing, it would improve response rates from 44% up to 70% with that treatment (1). This also means that the patients who are unlikely to respond could be initiated on more appropriate therapies straight away. The second problem is that even if a patient responds to the drug, they do not all require the same dose. Patients on the blood-thinning drug warfarin can take months to become stabilised by adjusting doses and testing their blood. If the dose is too high, bleeding can occur, and if the dose is too low, blood clots might be able to form. Scientists have shown that using pharmacogenomics to better predict the dosing of warfarin could reduce the time for the patients to become stabilised on the correct dose (2).
Most research to date has involved only small studies, and moving away from the “average dose” concept would represent a major shift for the healthcare community. The advantages, however, are obvious. One of the pioneers in the routine use of pharmacogenomics has been the St. Jude Children’s Research Hospital in Memphis, Tennessee, where they treat a type of cancer called acute lymphoblastic leukaemia. They realised that some young patients were unable to make a protein called thiopurine methyltransferase which is needed to break down the anti-cancer drug 6-mercaptopurine. As a result these children were having particularly severe side-effects due to dangerously high levels of drug in their blood. A simple genetic test now regularly identifies these patients; they get a lower drug dose which still treats the cancer but reduces the debilitating side-effects.
Clearly pharmacogenomics has the potential to revolutionise the way patients are treated, but it is still in its infancy. Large clinical trials are needed to fully understand the underlying genetic influences on drugs. It is still not known how external factors, like smoking or diet, might influence the therapeutic outcomes; these could prove to be more significant than genetics in some cases. The pharmaceutical companies are likely to be instrumental in furthering pharmacogenomic research as there are significant therapeutic and economic advantages to be had. Although personalised pharmacy has the potential to narrow the patient base for some products, this could be offset by the possibility of “rescuing” of drug candidates abandoned in development because they didn’t work in all sub-populations. There are also legal and ethical implications; the potential for misuse of genetic information is an increasing concern. These are issues that need to be addressed, but if pharmacogenomics lives up to its promise we can look forward to a future of bespoke pharmacy, because it is clear that when it comes to medication, one size does not fit all.
1. Bonnefoi et al. 2008. Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial. Lancet Oncology; 8: 1071–78
2. Wen et al., 2008. Prospective Study of Warfarin Dosage Requirements Based on CYP2C9 and VKORC1 Genotypes. Molecular Therapy. 84(1):83-9.