Pharmacogenomics-The Promise of Personalized Medicine

Introduction: Pharmacogenomics (PGx) is the study of the genetic basis of variability among individuals in response to drugs. It is the newest discipline of medicine and is becoming a very active area of research, with the pharmaceutical industry gaining experience applying it, integrating it into the drug development process, and also learning to better manage the expectations of the medical community. Methodology: A comprehensive review of the literature on the principles, applications, challenges and prospects of pharmacogenomics was performed. Results: Pharmacogenomics tailors therapies to the genetic makeup of an individual and can therefore offer treatments that are more efficacious and have fewer side effects. Despite these benefits, personalized medicine has not been embraced by large pharmaceutical companies. It is expected that the first wave of successful pharmacogenomics products will be used in acute treatments for which current therapies have and severe side effects. These products should also be good candidates for premium pricing. Personalized medicine (PM), based on the genetic makeup of a patient, may result in not only an improved therapeutic response but also a clinically important reduction in adverse drug reactions. The experience to date is mixed, with a few successes but many frustrations. Conclusion: However, for pharmacogenomics to be truly embraced, the benefits of this technology must become more widely accepted in terms of economic, public, regulatory and ethical issues. DOI: http://dx.doi.org/10.3329/bjms.v12i4.11041 Bangladesh Journal of Medical Science Vol. 12 No. 04 October ’13 Page 346-356


Introduction
There is an imperative need for the pharmaceutical industry to discover and market drugs that will allow patients to live longer and healthier lives.However, the pharmaceutical industry is facing a huge problem and some key challenges 1 .The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects.Many environmental factors including genetic variation of human affects the delivery, distribution, persistence and activity of the drugs 2 .Thus the pharmaceutical industry is in desperate need of innovation, increased productivity, ways to better differentiate compounds from competitive compounds, and ways to bring better, safer, more efficient drugs to the market with lower costs of development 3 .Pharmacogenomics possess solution of all these quests.Pharmacogenomics is the art of analyzing various genomic information (e.g.polymorphisms, gene expression, copy number, methylation and protein profiles) in assessing differential response to drugs 4 .The objective of such analyses is to detect evidence of variation in response to drug action and factors influencing the absorption, distribution, metabolism, and excretion of these chemical agents 5 .Pharmacogenomics, which is considered as an outgrowth of the Human Genome Project is the next research frontier and significant industrial investment is anticipated in this field 6 .

What Is Pharmacogenomics?
Pharmacogenomics is an umbrella term that includes the use of genetics to optimize drug discovery and development.This term broadly refers to tailor-made drugs or personalized medicine-that is developing the right drug for the right people.Personalized medicine is the marriage of functional genomics and molecular pharmacology 7 .
Pharmacogenomics seeks to find and decipher correlations between patient's genotypes (genetic profile) and their therapeutic responses.Pharmacogenomics uses these correlations to discover new and highly effective therapies tailored to specific genetic makeups 8 .The process involves identifying genes and their protein offspring as potential drug targets and then understanding the variations of the genes.Interest and funding in pharmacogenomics is largely fueled by growing evidence that an individual's genetic profile is and will continue to be the key predictor of how effective particular therapies are 9 .
Pharmacogenomics focuses on large clinical effects of single gene variants in small numbers of patients.However, the concept of pharmacogenomics examines many genomic loci, including large biological pathways and the whole genome, to identify variants that together determine variability in response to drug therapy (Fig 1) 10 .

Personalized Medicine
Personalized medicine is the use of new methods of molecular analysis to better manage a patient's disease or predisposition toward a disease.It aims to achieve optimal medical outcomes by helping physicians and patients choose the disease management approaches likely to work best in the context of the patient's unique genetic and environmental profile 4 .Variations in human genome can influence how well a patient might respond to a particular drug.Personalized medicine hopes to use these variations to develop new safe and effective treatments for genetically defined sub-groups of patients.Treatments may include administration of drug therapy as well as recommendations for lifestyle changes that can delay onset of a disease or reduce its impact 1 .Personalized medicine also offers the possibility of improved health outcomes and has the potential to make healthcare more cost-effective.The natural variations (DNA polymorphisms) found in our genes play a role in our risk of getting or not getting certain diseases 7 .Understanding these genetic variations and their interactions with environmental factors will help researchers produce better diagnostics and drugs, and will help physicians better select treatments and dosing based on individual need 9 .

Pharmacogenomics In Use
Pharmacogenomics is in use today to a limited degree.The cytochrome P450 (CYP) family of liver enzymes is responsible for breaking down more than 30 different classes of drugs.DNA variations in genes that code for these enzymes can influence their ability to metabolize certain drugs.Less active or inactive forms of CYP enzymes that are unable to break down and efficiently eliminate drugs from the body can cause drug overdose in patients 11,12 .Today, clinical trials researchers use genetic tests for variations in cytochrome P450 genes to screen and monitor patients.In addition, many pharmaceutical companies screen their chemical compounds to see how well they are broken down by variant forms of CYP enzymes 13 .
Another enzyme called TPMT (thiopurine methyltransferase) plays an important role in the chemotherapy treatment of common childhood leukemia by breaking down a class of therapeutic compounds called thiopurines.A small percentage of Caucasians have genetic variants that prevent them from producing an active form of this protein.As a result, thiopurines elevate to toxic levels in the patient because the inactive form of TMPT is unable to break down the drug.Today, doctors can use a genetic test to screen patients for this deficiency, and the TMPT activity is monitored to determine appropriate thiopurine dosage levels 14 .

Market Justification
The pharmacogenomics vision includes three key goals: to increase efficacy and reduce risk to patients, to develop diagnostics that impact therapeutic decisions and improve patient care, and to improve clinical development outcomes 25 .These goals must all be accomplished while allowing for attractive economic returns.Pharmacogenomics products will remain unattractive to Big Pharma unless the economic impact of having a smaller target market is offset by either decreased development costs or premium pricing 26 .Specifically, the attractiveness of pharmacogenomics to pharmaceutical companies relies on the following factors: Pharmacogenomics is raising new issues in the hotbed of biotechnology.Although the toxicity model tries to maximize the population with the inclusion of as many genotypes as possible, the efficacy model of personalized medicine involves targeting patients with specific genotypes, which raises important ethical challenges.For example, in 2005, Nitro Med (Lexington, Massachusetts) launched the first "Black" drug, Bidil, specifically targeted to treat heart failure in African Americans 27 .Beyond the clear concerns of using skin color as a therapeutic category, the introduction of this drug also involves issues of fairness.
Both models (toxicity model and efficacy model) may also arouse fears about racism because, by nature, pharmacogenomics highlights the differences in genotype among individuals and populations.Certain types of genetic variations that are of importance in the metabolism of drugs are known to be more common in some ethnic groups than in others.If adverse responses are associated with a partic-Fakruddin M, Chowdhury A ular ethnic group, members of the group might suffer from stigmatization.Similarly, if one treatment serving an ethnic group comes to market more quickly than another, issues will certainly surface about placing greater "value" along racial lines.In adverse countries, it will be difficult to ensure that therapies for all ethnic groups are fairly addressed 28 .
Personalized medicine also prompts concerns about the security and privacy of a patient's pharmacogenomics information.Among those concerns, issues relating to informed consent and secondary information are key 29 .
Patients will more readily accept pharmacogenomics testing if their rights to consent to the testing are fully protected.First, the information gathered in pharmacogenomics tests, like that in many diagnostic or clinical lab tests that are now routinely administered with at most minimal informed consent, should theoretically carry no major risk of psychological harm.Second, in determining what information should be collected from patients, the benefits of diagnostic information and the costs to privacy should be balanced 30,31 .

Ethical Issues
The most important ethical issue that concerns pharmacogenomics is privacy of the study subjects 32 .
Participants should be adequately informed about how their genetic material will be handled, what all tests may be done, how the data will be utilized, where the genetic material be stored and how secure the DNA banks are.They should have knowledge about the persons who will have access to their genetic material.They should also be told that their DNA may be required for future use and how that data will be maintained.Informed consent for future use should also be taken before hand.Privacy issues of family: A genomic study may need some information about subject's family, which may not be acceptable.Some critics are of the opinion that even the patient subjects should not be disclosed with their own genetic material to avoid the fear of future harm that may be predicted 33 .
Better pharmacological care means better life expectancy.It may not be affordable for a common man.It is possible that only those who have money to afford the high expenses may benefit.Ethics demand equality, the cost of these pharmacogenom-ic techniques should be thus subsidised by the government.In countries like India where potable food is more important a public issue, is it worth allocating funds to learn how genes indicate a predisposition to disease and developing cures for the same?On the other hand in countries like USA, where adverse drug reactions account for major morbidity and hospitalisation (the fact that medicines are "a one-size fits-all", leading to adverse drug reactions can be avoided), a lot of which can be avoided if genetic profile is known and drugs given accordingly 34 .Initial high cost of technology development for genome analysis along with threat of losing one's autonomy needs to be reviewed.The interest of pharmaceutical companies in financial gains that they may have if treatment is highly specific with minimal adverse effects, could threat the valid research or threaten protection of the rights and wellbeing of individuals may become need of the hour.Genes are not the only thing, environment has its own role in pharmacokinetics and pharmacodynamics of drug response.Thus implicating everything on genetics and promoting drugs may not be ethically acceptable 35 .

Legal Issues
With pharmacogenomics in future, some legal issues need to be discussed before full implementations occur.The person should know who owns the genetic data once he has given consent to analyse that.What is the legal liability if that data is stolen or lost or made public?Who is responsible for the damages?What is the compensation?Besides this, if he has not given consent for future use of his genomic data, and that is breached, what is the legality in such a situation?Can a person refuse for using his data without payment at any stage of drug development and use?How much is the doctor or hospital obliged to inform the person?One viewpoint is that the study subject should be informed only about the particular condition being tested and the rest should not be disclosed.i.e. person should not be told the future.What is the legal issue if discrimination is made by job providers or insurance firms 36 .In case the job providers know the person's gene data and avoids job (good for company as only best fitted individuals will be there to improve success but a loss for person who may have to face unemployement and switch over to malpractices) or insurance cover is avoided 37 .These issues need to be answered.

Social Issues
Pharmacogenomics & Personalized Medicine The economic burden of a new therapeutic science will be borne by the society.Knowing the genotype of the person will open the genotype of whole community of that person.Family tree can be constructed.Alot can be deduced from this family tree.This leads to breach in privacy of whole community whose consent is not taken 38 .This may also lead to formation of a group susceptible to a particular drug, having a possibility of a particular disease in future or having a predisposition to something not curable as per current standards.In one way it is good: the lifestyle modifications can be initiated early, the effective therapy can be started for prevention and treatment at the earliest and longevity can be expected.But other side is, if the person knows that sometime in future he will develop some cancer for which no treatment exists, he will die hundred deaths before that.Pharmacogenomic variations may lead to opening up of some constitutional issues like those of getting some special incentives or minority status 35 .

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

Limitations
Many genes are likely to be involved in how someone reacts to a drug.It means that targeting different drugs may be very complex.Everyone has small variations in their genes that do not cause any problem with the way that the gene works.Since these differences may influence drug metabolism or how the condition develops, the variations would need to be identified 40 .This process is very difficult and time consuming.In addition other factors may influence a specific drug reaction such as interactions with other drugs and environmental factors.The influence of these factors will need to be determined before any conclusions are made about the genetic influence on how the drug is working 41 .
Fakruddin M, Chowdhury A Anticipated Benefits Of Pharmacogenomics (a) More Powerful Medicines Pharmaceutical companies will be able to create drugs based on the proteins, enzymes, and RNA molecules associated with genes and diseases.This will facilitate drug discovery and allow drug makers to produce a therapy more targeted to specific diseases.This accuracy not only will maximize therapeutic effects but also decrease damage to nearby healthy cells 42 .
(b) Better, Safer Drugs Instead of the standard trial-and-error method of matching patients with the right drugs, doctors will be able to analyze a patient's genetic profile and prescribe the best available drug therapy from the beginning.Not only will this take the guesswork out of finding the right drug, it will speed recovery time and increase safety as the likelihood of adverse reactions is eliminated.Pharmacogenomics has the potential to dramatically reduce the the estimated 100,000 deaths and 2 million hospitalizations that occur each year in the United States as the result of adverse drug response 43 .
(c) More Accurate Methods of Determining Appropriate Drug Dosages Current methods of basing dosages on weight and age will be replaced with dosages based on a person's genetics--how well the body processes the medicine and the time it takes to metabolize it.This will maximize the therapy's value and decrease the likelihood of overdose 44 .
(d) Advanced Screening for Disease Knowing one's genetic code will allow a person to make adequate lifestyle and environmental changes at an early age so as to avoid or lessen the severity of a genetic disease.Likewise, advance knowledge of a particular disease susceptibility will allow careful monitoring, and treatments can be introduced at the most appropriate stage to maximize their therapy 45 .
(e) Better Vaccines Vaccines made of genetic material, either DNA or RNA, promise all the benefits of existing vaccines without all the risks.They will activate the immune system but will be unable to cause infections.They will be inexpensive, stable, easy to store, and capable of being engineered to carry several strains of a pathogen at once 46 .
(f) Improvements in the Drug Discovery and Approval Process Pharmaceutical companies will be able to discover potential therapies more easily using genome targets.Previously failed drug candidates may be revived as they are matched with the niche population they serve.The drug approval process should be facilitated as trials are targeted for specific genetic population groups--providing greater degrees of success.The cost and risk of clinical trials will be reduced by targeting only those persons capable of responding to a drug 47 .
(g) Decrease in the Overall Cost of Health Care Decreases in the number of adverse drug reactions, the number of failed drug trials, the time it takes to get a drug approved, the length of time patients are on medication, the number of medications patients must take to find an effective therapy, the effects of a disease on the body (through early detection), and an increase in the range of possible drug targets will promote a net decrease in the cost of health care 48 .

Expectations And Future Possibilities
Resurrecting Previously Failed Drugs It has been reported that 10% of drugs are withdrawn in the years following FDA approval 49 .This statistic provides a great deal of motivation for resurrecting such drugs using pharmacogenomic knowledge.Most of these drugs are expected to be the ones that failed during clinical trials due to toxicity or lack of efficacy.Since the level of toxicity of a drug is confounded by the level of drug metabolism, there is a chance that by matching the drug dose to the genetic information, one can control the bounds on the toxicity and thus use such drugs for genetically selected responders.Therefore, for drugs that failed during clinical trial or at the discovery stage because of ADRs, pharmacogenomics provides hope for gaining a balance between the generality of a drug and its efficacy 50 .In other words, one could obtain an effective drug (i.e., less prone to causing ADR) by narrowing the scope of a drug to certain genetic groups 49 .

Balancing Efficacy and Toxicity of Drugs
For a drug to be effective, it must be exposed to the tissue of interest at a critical concentration for a given period of time.Below this critical concentration, the drug is not expected to be effective.Above this critical concentration, there is a margin above which the drug could be toxic 51.This critical con-Pharmacogenomics & Personalized Medicine centration and the associated margin (for effectiveness vs. toxicity) are functions of the drug dose and drug metabolism.Drug metabolism has been linked to genetic variation (e.g., the polymorphic cytochrome P450 enzyme).Pharmacogenomics could use such information on such polymorphisms to predict the correct dose for effectiveness of a drug 52 .In fact, many of the large companies are already considering pharmacokinetic variations 53 with the particular interest of drug effectiveness and toxicity 54 .In summary, there is great interest in fine-tuning the effective drug concentration to obtain a maximal effect and minimal toxicity.Cancer is considered to be an ideal condition for which to apply this approach, as subtle differences could account for notable differences between a particular dose of chemotherapy being toxic or effective 55 .

Improved Generalization
Japanese pharmaceutical authorities require clinical trials on the Japanese population 13 .This bias toward a certain population could create a gap in the applicability of such products for other populations.Such biases are not always evident and overtly stated.For instance, similar biases do exist in drug development in the United States, where a majority of the drugs are tested on the Caucasian population.Such biases provide the basis for inefficacy of the drugs on other populations (e.g., the untested groups).Pharmacogenomics can provide guidance to those drugs being of use to other populations in two ways.
The most obvious way would be to design drugs for different ethnic groups based on their genetic composition.However, this method has serious flaws.The more elegant way would be to bypass the dependency of the drug to population composition by screening for compounds that bind to all expressed variants of a target (if possible), thus eliminating the need for such a genetic test 56 .

Strategic And Commercial Considerations
There are concerns in the pharmaceutical industry about generating potentially uninterpretable PGx results in a regulated environment.This has led sometimes to a "let's not generate data that we do not fully understand" attitude in relation to PGx research on pharmaceutical compounds.This attitude is gradually going away in view of the recognition that many of the PGx data generated are exploratory and probabilistic in nature, extremely difficult to replicate and to translate into clinical practice, and that in the long term more information, particularly about drug safety, is better.When thinking about the commercial attractiveness of PGx, critics often suggest that a more targeted approach to the identification of patients who might respond to therapy would "niche" those drugs, leading to a reluctance to embark on a given PGx study.In fact, utilizing a stratified approach (to identify the group of patients who might benefit from a particular therapy) may reduce new patient trials for some therapies 57.But this initial sales reduction may be offset by better compliance rates, ultimately higher product use, and pricing strategies that consider market size.One key variable is ensuring that PGx work is initiated sufficiently early to optimize a proactive approach to integration into development.Generally, the establishment of biomarker-driven endpoints within early phase clinical development may enable more efficient clinical trial design.Additionally, prospective introduction of PGx clinical endpoints can enhance the prospects for expedited drug approval, reduce development costs, and improve attractiveness to payers and prescribing physicians58.Therefore, in the short term, a PGx approach may provide a competitive advantage for pharmaceutical compounds and support better treatment practices through druglinked diagnostics.But commercial viability may not be a question of what is gained or lost by moving forward with the development of biomarkers; rather, it may center around what is at stake by not moving forward with these approaches.While pipelines for many therapeutic areas are shrinking, a landscape review highlights the increasing infrastructure development in PGx and the initiation of product-specific work across a variety of therapeutic areas, indicating the awakening of the pharmaceutical industry 59 .So in the longer term, the utilization of biomarkers may improve prospects for significant new product development, in a time when there are fewer novel compounds in the pharmaceutical pipelines.Finally, as external groups apply more pressure on pharmaceutical companies to develop valuable new offerings, it may become a requirement to provide information that helps the regulatory agencies to ascertain which patient populations might benefit from the availability of a new drug.PGx is one means for providing such information to regulators and payers 60 .

Conclusion
Pharmacogenomics is emerging as a boon for medical fraternity.Although many believe in the scientific value of pharmacogenomics, the industry still has Fakruddin M, Chowdhury A many skeptics.Some argue pharmacogenomics to be too complex.Other argues that although pharmacogenomics has incredible potential, people are too impatient in our desire to realize its promise.Pharmacogenomics will be an important factor in the future of medicine but cautions that the long discovery and development times in the industry means we must be patient before the benefits of pharmacogenomics are realized.There are numerous controversies concerning the utility of pharmacogenomics.While at a small scale and for a limited number of drugs, it may be possible to use genomic information to provide drugs that are more potent and have fewer side effects for certain individuals, generalizing this idea to the whole genre of medicine and treating pharmacogenomics as a panacea is the subject of much speculation and debate.However, before the full application of this branch, the higher authorities should frame and address the various social, legal, ethical issues along with incentives to overcome technical difficulties.