The Study Of Pharmacogenetics Biology Essay

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Personalized medicine refers to the tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not." [1] 

The study of Pharmacogenetics is an important field in personalised medicine, due to the differences in response to drugs taken by individuals. Such differences includes slow metabolism of the drug in some individuals to fast response or adverse drug reactions and drug -drug reaction when taken with other drugs. [2] This results in unwanted side effects in patient and even fatal in some cases. The purpose of drug therapy is to give the appropriate drug in the right dose to produce a desired effect with minimum side effects [3] .

Factors influencing variations in drug response in individual patients includes environment factors, ethnic variation, and genetic variation. Other important factors are dose of the prescribed medicine, patient compliance to the prescribed dose, underlying diseases, other drugs the patient is taking, and the age, weight, sex and diet of the patient. Ethnic variations in drug response occur as a result of variation in enzymes metabolising the drug, receptors and transporters. It is also noted that there is a lot of variation within an ethnic group than between different ethnic groups.

Diseases especially in the liver or in the kidney can affect the metabolism of drugs. There is a relationship between the dose prescribed to a patient and the response, sometimes an increase in dose can produce a very large increase in effect, be it beneficial or not, and sometimes it might not produce an increase in effect [4] . Therefore it is important to note that, the dose response relationship for a beneficial or adverse effect is not always the same. For example the drug thiazide used to decrease blood pressure, when its dose is increased it doesn't produce a notable decrease in blood pressure but leads to potential adverse side effects such as decrease in potassium and increase in uric acid in the blood.

Patient compliance is a major variation in drug response, studies has shown that its frequency can be as low as 10% and as high as 90% in some drugs [5] . The adverse effect of the drugs and the complex regime involved in taking the drugs can affect the patients compliance especially when the patient fails to see that the beneficial effects is more than the adverse side effect. While in some cases the cost of the drugs or even simple forgetfulness can affect the patient's compliance.

Genetic factors can influence drug response through the pharmacokinetic and pharmacodynamic processes [6] . Variations in individuals DNA occur during DNA replication, sometimes mutation occurs as a result of substitution of a particular base resulting in a defective gene, which can cause harm by making the body more susceptible to a disease or change the body's response to a drug. However in most cases mutation have no effect on the function of a gene or can improve survival by giving resistant to a disease or environmental hazards. For example polymorphisms in cytochrome P450 genes for the enzyme cytochrome P450 causes individual variations in response to drugs. Polymorphisms of beta receptors and protein kinase receptor can cause both beneficial and adverse drug effects. Therefore it is know that Individuality in drug response is inherited.

 In the course of the essay I would discuss how important the field of pharmacogenetics is in the promise of a personalised medicine. The potential application of pharmacogenetics to improve the efficacy and safety of drug prescribing the advantages, different obstacles and implications to personalized medicine would also be analysed.

Pharmacogenetics is the study of genetically determined variations in drug metabolism and the response of the individual [7] . Pharmacogenetics research is increasing advancing with the recent advances in molecular genetics and genome sequencing as a result of emergence of technologies that allows rapid screening for specific polymorphisms. The knowledge of the genetic sequences of target genes such as those coding for enzymes, ion channels, and other types of receptors involved in drug response also helps [8] .

Research in pharmacogenetics is focused on identifying specific genes and gene products associated with various diseases, so as to act as targets for new drugs, and, identifying genes and allelic variants of genes that affect response to current drugs [9] .

Identifying a gene that affects the action of drugs is found by examining the whole genome or by making an educated guess and examining the gene which has a high probability of being involved that is a candidate gene. Tools and techniques involved in pharmacogenetics include DNA cloning, Polymerase chain reaction, DNA sequencing, fluorescence in situ, (FISH) and DNA microarrays.

Benefits of Personalised Medicine

Listed below are the potential benefits derived from personalised medicine

identify the disease at an early stage and be able to treat it effectively,

Reduce the incidence of adverse drug effects

More Concentration on prevention of diseases rather than treatment

Reduction in time, cost, and failure of clinical trials

Allows selection of most advantageous therapy and Reduction in trial and error prescribing

Reduction in cost of total healthcare.

Increase patient compliance with treatment

Personalised medicine offers the opportunity for disease to be identified at an early stage prevented and treated effectively. For example by undergoing genetic test p16 for melanoma, those who are positive will be made available preventive options, such as treatments and preventive surgery before the signs and symptoms persist, and they can also change their lifestyle by reducing their exposure to sun so as to reduce the Incidence [10] . Another test been made available is the test for BRCA1 and BRCA2 genetic variants that indicates genetic tendency for Ovarian and breast cancer. Women with BRCA1 or BRCA2 genetic risk factors have a 36 to 85 percent lifetime chance of developing breast cancer, compared with a 13 percent chance amongst the general female population [11] . For ovarian cancer, women with certain BRCA1 or BRCA2 gene variants have a 16 to 60 percent chance of having the disease, compared with a 1.7 percent chance among the general public [12] . Therefore having genetic tests for the BRCA1 and BRCA2 will make preventive options available such as chemoprevention, prophylactic surgery and increased frequency of mammography to individuals available.

UK study has proposed that about  1 in 15 hospital admissions are due to adverse drug reactions [13] ,  and a recent US study estimated that 106 000 patients die and 2.2 million are injured each year by adverse reactions to prescribed  drugs. [14] This could have been prevented by testing individuals for genetic variations indicating their susceptibility to adverse reactions. Many adverse drug reactions are caused by variations in genes coding for enzymes. Most drugs are metabolized by the cytochrome P450 family of enzymes, there are over 30 different forms of these enzymes, each coded for by a different gene [15] . Variations in these genes can lead to decreased or increased metabolism of certain drugs. For example people with polymorphism of the CYP2D6 gene have complications with codeine. This can result in the increase production or decrease of the CYP2D6 enzyme that metabolises codeine into the active form morphine. People with the increased enzyme production are fast metabolisers and develop side effect such as impaired breathing and sedation when a standard dose of codeine is taken. While those with decreased enzyme production are slow metabolisers and will not experience any pain relief. It is estimated that as many as 7% of Caucasians may have a defective CYP2D6 gene resulting in reduced pain relief [16] .

Warfarin, used to prevent blood clot formation, is complicated by genetic variations in the drug metabolizing enzyme (CYP2C9) and enzyme (VKORC1). The dose is normally adjusted for the individual patient through multiple rounds of trial and error, during which the patient may be at risk of excessive bleeding or further blood clots [17] . The need to get Warfarin dosing right the first time to avoid adverse effects led an FDA advisory committee to recommend genotyping for all patients receiving Warfarin. [18] 

Personalized medicine has the ability to use molecular markers that indicate the risk of disease or its presence before clinical signs and symptoms appear. This help would help to reduce the incidence of the disease. Molecular markers now being used include C reactive protein, which indicates the risk of cardiovascular disease, and LDL and HDL cholesterol indicating risk atherosclerosis. Identifying abnormal levels of these markers allows for preventive options for future disease.

Personalised medicine will help to reduce the time, failure and cost of clinical trial. Drug discovery is a very long and costly process. Recent studies have shown that

The average time from project inception to new drug launch is approximately 13-14years and can coast about £555million [19] . And sometimes the project can fail during different stages of the development process. With personalised medicine the pharmacogenetic data is considered during drug discovery and this reduces the time and cost of drug development

For example Using genetic tests, patients are selected on most likely to respond or least likely to suffer side effects thereby enriching the clinical trial pool. According to a report by the Boston Consulting Group, drug companies could save as much as $335 million per drug by incorporating this type of data into certain drug development programs [20] . Subjective evidence suggests that pharmacogenetics can reduce the length of clinical trials. For example, a phase III clinical trial for the drug Tykerb (lapatinib) was terminated early due to the drug's remarkable success in treating a genetically distinct group of patients with breast cancer [21] . The development, time and cost were reduced when a diagnostic test was used to pre-select patients in an essential clinical study in the case of Herceptin.

Personalised medicine allows selection of most advantageous therapy and Reduction in trial and error prescribing. The growth factor receptor 2 (HER2 ) promotes normal cell growth but as a result of genetic mutation it can be over expressed causing some breast cells to multiply uncontrollable and invade surrounding tissues. About 25-30% of breast tumours have high levels of HER2. Women with this condition don't respond well to standard therapies, but the discovery of Herceptin that blocks the HER2 receptors has increased the survival rate of women with this type of cancer. Genetic tests can now be done to measure the HER2 protein levels so as to help patients that have the relevant gene to benefit from Herceptin.

A study found out that giving Vectibix (panitumumab) or Erbitux (cetuximab) to only patients with metastatic colorectal cancer whose KRAS gene is not mutated could save $604 million annually because they are the only ones that benefit from the drug. If the 2 million people that start taking Warfarin each year were to be tested at a cost of $125 to $500 per patient, the overall cost savings to the healthcare system would be $1.1 billion annually. Similarly, researchers showed in a 2006 article published in Cancer that adjusting dosage of the colon cancer drug irinotecan based on UGT1A1 testing, results in about $1,000 in savings per patient tested by reducing adverse events. [22] 

Inherited forms of hypercholesterolemia (high cholesterol) can increase the risk of myocardial infarction before the age of 40. Genetic testing causes detecting

Condition before there are observable signs of disease, knowledge of a genetic tendency for hypercholesterolemia provides patients with an incentive to make lifestyle changes and to treat their condition seriously. Patients with a genetic diagnosis have shown more than 86 percent compliance to their treatment after two years compared to 38 percent prior to testing.

Obstacles that will need to be overcome in order to achieve personalised medicine

Listed below are the obstacles in achieving personalised medicine.

Education and Training

Ethical issues and social issues

Health Economics, Health structures and Information Technology

Problems in investigation and application of pharmacogenetics

For personalised medicine to be achieved and introduced in clinical practice in the nearby future, Education in pharmacogenetics, clinical genetics and clinical pharmacology has to be continuously taught at different levels of education. Doctor, nurses and pharmacists will require more training in the fundamental of human genetics. More centres should be built up for training and research for clinical pharmacology. Training would also be spread out to non clinical and basic scientists in areas such as IT, about clinical pharmacology biostatistics and population genetics because of the large amount of genetic, prescribing and clinical data that will become available. Education of medical students, both undergraduate and postgraduate should focus on education in genetics so as to have a greater understanding in human diversity and clinical pharmacology.

There is still so much work to be done before clinical application of pharmacogenetics. The technology is available but pharmacogenetic has to prove to be able to improve patient's treatment compared with current practice. Pharmacogenetic tests are made hard because diseases are caused from multiple genes. For example arthritis, high blood pressure and heart disease are disease caused by variations in many different genes. The fact that drug use might be targeted to a particular population groups posses concerns, For example the drug BiDil has been licensed in the treatment in only African -Americans.

Some Developing countries have not yet reached the stage at which proper drugs are made available to them, due to poverty in this regions let alone being exposed to the application of pharmacogenetics or genetic tests, and even if they where they would be too expensive. For pharmacogenetic investigation patient compliance to drug regimes, genetic variation, age, weight, diet and other drugs taken play a vital role in drug efficacy and safety, although it is still not clear how this causes improvement in clinical care.

The major Ethical and social issues arise as a result of the consent, privacy and confidentiality of the information that is obtained and stored. Mistakes can arise as from the anonymity for genetic data, someone's genetic data might be mistaken for someone else's and this can result in serious adverse effect when the right dose is given to an individual with different genetic information.

Doctors would also be faced with issues when a patient refuses to undergo a genetic test as a result of privacy issues and as a result the doctors can hold back treatment from patients. Doctors are also faced with the situation by which they have to tell family members of patients about their pharmacogenetic information against the wishes of their patients

Other obstacles raised up by the public are health care and trust, drug companies can't be trusted to give impartial advice about drugs, genetic tests can also cause complex issues when it comes to making a family and can lead to changes in lifestyle. The fact that a lot of genetic information would have to be collected raises issues of how it would be stored, who should be allowed access to such information and miss use.

Pharmacogenetic testing has the potential to reduce costs through reduced adverse drug effects, greater efficacy, and less inappropriate prescribing. Although it is still not clear if the tests will increase or decrease overall health costs of training, developing, implementing and evaluating genetic testing as well as the clinical time needed to interpret tests effectively. [23] 

In conclusion pharmacogenetics is an important approach towards achieving a personalised medicine. Personalised medicine has the ability to help maximize the efficacy and safety of drugs. Personalised medicine has its benefits such as reduction in adverse drug reactions in the case of codeine and Warfarin and reduction in costs and hospital admissions resulting from the adverse effects. It has the ability to use molecular markers that indicate the risk of disease or its presence before clinical signs and symptoms appear. This help would help to reduce the incidence of the disease, and is also seen to help in optimal therapy treatment for some forms of cancer. However potential obstacles to personalised medicine are Ethical issues, the health economic cost, training and education.

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