Indo American Journal of Pharmaceutical Research, 2013

ISSN NO: 2231-6876

PHARMACOGENOMICS-NEW ERA OF DRUG DISCOVERY AND

DEVELOPMENTS
Praveen khirwadkar*, Viny Dave, Kamlesh Dashora
Institute of pharmacy, Vikarm university, Ujjain
ARTICLE INFO
Article history
Received 10/09/2014
Available online
13/12/2014

Keywords
Pharmacogenomics,
Pharmacogenetics,
Multigenic based,
Healthcare industry

ABSTRACT
Pharmacogenomics is already making an impact in a wide array of disease states and drug
therapy; it will eventually become part of standard patient management in selecting and
monitoring drug therapy. Pharmacogenomics will definitely help us to sharpen our medical
and pharmaceuticals tools. Drugs will become more precise and efficient and the risk of
toxic side effects will be reduced. But at the same time increasing amounts of information
will be collected, which may be put to a variety of uses. Furthermore, current advancement
of pharmacogenetics that are mainly based on single nucleotide polymorphism will not be
sufficient as most of the common disease in aging like heart failure, hypertension are more
likely to be multigenic based. Pharmacists will not be ready for the implementation of it if
they do not acquire relevant knowledge about human genetics. They will need to access to
appropriate education regarding pharmacogenetics to keep pace with the ongoing
development and prepare for its implementation in near future that will revolutionize
healthcare industry.

Corresponding author

Copy right 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Page

Please cite this article in press as Viny Dave et.al. Ppharmacogenomics-new era of Drug discovery and developments. Indo
American Journal of Pharm Research.2014:4(12).

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Viny Dave
Institute of pharmacy, vikarm university, Ujjain
Email-Email-praveen.pharmaresearch@gmail.com

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INTRODUCTION
Pharmacogenomics is the technology that analyses how genetic makeup affects an individual's response to drugs. It deals with the
influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with
adrug's efficacy or toxicity. By doing so, pharmacogenomics aims to develop rational means to optimize drug therapy, with respect to
the patients' genotype, to ensure maximum efficacy with minimal adverse effects.[3] Such approaches promise the advent of
"personalized medicine"; in which drugs and drug combinations are optimized for each individual's unique genetic makeup.Postgenomic biomarkers are now playing a critical role in making a prediction of transfer from preclinical to clinical development of drugs
in terms of both safety and efficacy.[6] This trend is revolutionizing diagnostics and drug development. For example, single nucleotide
polymorphisms (SNPs) screenings will help target discovery and drug development since pharmaceutical and biotech companies can
exclude patients whose drug screenings show that a drug being tested would yield adverse drug-related serious toxicities and
ineffective efficacy to them. Drug development currently takes too long and costs too much. The main reason that drug development is
so expensive is that it is so unproductive.[7] Estimated the average cost of bringing a new drug from the time of investment to
marketing is $802 million in year 2000 US dollars. Pharmaceutical Research and Manufacturers Association responded that the
estimate of US$ 802 million was likely to be conservative. [8] At the 2006 Drug Discovery Technology conference, the cost of the new
medical entity is currently $1.2 billion, and warned that the cost of producing a successful drug could reach $2 billion by 2010 unless
the pharmaceutical industry can identify new and better ways to improve efficiency and effectiveness of drug discovery and clinical
trials. Pharmaceutical companies can no longer afford to continue allocating the resources in cost-intensive later stages of clinical
trials with drugs that are unlikely to have therapeutic effectiveness or are not better than the existing treatments. That is, the model for
blockbuster drug development with large-scale markets is increasingly less viable. Pharmaceutical companies should be more careful
in the selection of drug candidates at an earlier stage so that the only promising drug candidates get the full development resources.[9]
Bringing a new drug to the market currently costs approximately $1.2 billion, which makes it economically impossible to target small
patient populations. However, targeting well-defined small patient populations will reduce the risk of failure and increase the
likelihood of success of new drugs. Pharmacogenomics will allow us to identify genes with the highest likelihood of predicting
efficacy for novel therapeutics and permit clinical trials to be substantially reduced in size. The ability to classify diseases into distinct
molecular subcategories challenges traditional pharmaceutical business economic models of one-size- fits-all drugs, i.e., blockbuster
drugs, by aiding in identifying patients for whom the drugs will be both safe and effective. Pharmacogenomics could enhance the
value of currently approved drugs with limited market share due to significant side effects or limited efficacy, Thus, the economic
rationale for personalized medicine-driven healthcare decisions will be based increasingly on the cost savings realized through
preventive interventions. The blockbuster drugs that have been pursued by pharmaceutical companies carry high risks and high costs.
New tools and technologies such as pharmacogeno- mics can be used to improve the quality of decisions in target discovery and drug
developments.[10] Pharmacogenomics promises to usher in an era of personalized medicine. The use of pharmacogenomics to identify
biomarkers that have true predictive value would shorten development time and cost. Personalized medicine will help to achieve
optimal medical outcomes by helping patients and clinicians select the disease management approaches that are likely to work best in
the context of a patients genetic and environmental profile. The US Food and Drug Administration launched the Critical Path
Initiative with the release of a report entitled Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical
Products. The report indicated concern on the rising difficulty and unpredictability of drug development and called for a concerted
effort to modernize the scientific tools and exploit the potential of bioinformatics for the evaluation and prediction of safety,
effectiveness, and manufacturability of candidate drugs. Projections on the future of Pharmacogenomics are markedly different. For
example, projections range from pessimistic opinions to optimistic opinions. In this article, we investigate the use of
pharmacogenomics in drug development.
NEED AND CONCEPT

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Therapists of necessity make decisions about the choice of drug and appropriate dosage based on information derived from population
averages. This "one drug fits all" approach could, with the fruits of pharmacogenomic research, evolve into an individualized approach
to therapy where optimally effective drugs are matched to a patient's unique genetic profile. This involves classifying patients with the
same phenotypic disease profile into smaller subpopulations, defined by genetic variations associated with disease, drug response, or
both. The concept underlying pharmacogenomics is that response to drug therapy is variable, in part because of genetic variation.
Genetic variations that are common (occurring in at least 1% of the population) are known as polymorphisms, and mutations of a
single nucleotide are known as single nucleotide polymorphisms (SNPs) More than one-third of human genes have been found to be
polymorphic.[22] A change in the nucleotide sequence of a gene can lead to a change in the amino acid sequence of the protein and

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Pharmacogenomics (or toxicogenomics) as recently emerged discipline stems from the fusion of pharmacogenetics (or
toxicogenomics) with genomics. Enabled by high-throughput technologies in DNA analysis, genomics introduces a further dimension
to individualized predictive medicine. Determining an individual's unique genetic profile in respect to disease risk and drug response
will have a profound impact on understanding the pathogenesis of disease, and it may enable truly personalized therapy. This concept
can be highlighted as "therapy with the right drug at the right dose in the right patient." Its urgency emerged in a recent survey of
studies on adverse drug effects in hospitalized patients: adverse drug reactions may rank as the fifth leading cause of death in the
United States.[19] Thus, it is anticipated that pharmacogenomics will play an integral role in disease assessment, drug discovery and
development, and selection of the type of drug. Moreover, it may provide information useful to the selection of dosage regimen for an
individual patient.

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altered enzymatic activity, protein stability, and binding affinities. Genetic variation can thus affect drug efficacy and safety when the
mutations occur in proteins that are drug targets (e.g., receptors), are involved in drug transport mechanisms (e.g., ion channels), or are
drug-metabolizing enzymes.
HISTORY OF PHARMACOGENOMICS
The history of pharmacogenetics stretches as far back as 510 B.C. when Pythagoras noted that ingestion of fava beans resulted in a
potentially fatal reaction in some, but not all, individuals . Since then there have been numerous landmarks that have shaped this field
of research, and have led to the current wave of interest. Variation within the human genome is seen about every 5001000 bases .
Although there are a number of different types of polymorphic markers, most attention recently has focused on single nucleotide
polymorphisms (SNPs, pronounced snips), and the potential for using these to determine the individual drug response profile. SNPs
occur at a frequency of 1% or greater in the populationPharmacogenomics first started with Archibald Garrod in 1902, who developed
the theory that ingesting chemical substances alters the biological functioning of genes. He also hypothesized that enzymes were
responsible for detoxifying substances and therefore individuals who did not have the particular enzyme would contain poisonous
substances in their bodies.In 1932, the first pharmacogenomics study took place with a chemical compound known as
phenylthiocarbamide. This study served to confirm that chemicals react differently according to the genetic make-up of an
individual. In the 1940s and 1950s however, further research led scientists to appreciate variable drug responses . This basically
means that the genetic composition of an individual not only leads to adverse effects from drugs but it also determines whether the
drug will actually work or not. This phenomenon was observed due to the peculiar finding that during World War II soldiers who
were given the anti-malarialThe first observations of genetic variation in drug response date from the 1950s, involving the muscle
relaxant suxamethonium chloride, and drugs metabolized by N-acetyltransferase. One in 3500Caucasians has less efficient variant of
the enzyme (butyrylcholinesterase) that metabolizes suxamethonium chloride. As a consequence, the drugs effect is prolonged, with
slower recovery from surgical paralysis. It is clear that the field of pharmacogenomics is still developing and hopefully it will have an
even larger impact in the medical world in the near future.
PHARMAGENOMICS DRUG DEVELOPMENTS
Pharmacogenomics can be used to improve drug discovery and drug development in at least two ways: development of new drugs to
overcome drug resistance or target new drug targets, and optimization of drug metabolism and pharmacokinetics (DMPK) to minimize
variations in drug levels.
A major challenge in targeted cancer therapy is the rapid development of resistance to targeted anticancer agents as a result of frequent
mutations of drug targets in cancer cells. The anticancer drug imatinib inhibits BCR-ABL tyrosine kinase and receptor kinases
mast/stem cell growth factor receptor and platelet-derived growth factor receptor. BCR-ABL is required for CML cancer cell growth,
whereas, oncogenic mutations of SCFR and PDGFR are over-represented in gastrointestinal stromal tumors. Clinical studies showed
that more than 90% of patients with CML and 75 to 90% of patients with GIST responded to imatinib anticancer therapy. However, a
small number of the patients suffered relapse because of the development of resistance to imatinib through mutations of BCR-ABL
kinase in patients with CML or SCFR kinase in patients with GIST [53][54] . In the case of BCR-ABL, at least 40 mutations were found
in the ABL kinase domain. Mutations such as T315I and F359V directly affect the contact between imatinib and the ABL kinase
domain, whereas others, such as those in the P-loop that bridges the ATP-binding pocket of the kinase domain, affect the
conformation required for imatinib binding[53]. Genetic and crystal structural information on mutated BCR-ABL facilitated
modification of imatinib to improve drug binding to ABL mutants. As a result, nilotinib showed 10- to 30-fold higher potency over
imatinib against the major resistant mutants but retained the kinase specificity profile with inhibition confined to ABL, SCFR, and
PDGFR. Because nilotinib and several other second-generation-kinase-inhibitor-anticancer drugs, such as nasatinib, bind to the kinase
domain in a fashion similar to that of imatinib, resistance due to the emergence of the T315I mutation that directly affects drug
binding remains an issue for these drugs. New drugs that inhibit the T315I mutant are now being developed.

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The development of antiplatelet and factor Xa inhibitor drugs illustrates the feasibility of DMPK optimization to reduce variability in
drug levels. Clopidogrel exhibits perhaps the most complex pharmacokinetics and most variable drug response among marketed
antiplatelet drugs. As a prodrug, clopidogrel requires two sequential P450-mediated oxidations to generate its active metabolite:
formation of 2-oxo by CYP2C19, -1A2, and -2B6, followed by formation of active thiol metabolite by CYP3A4, -2B6, -2C19, and 2C9. Contributions by CYP2C19 and -3A4 are more important than those by other P450s for bioactivation of clopidogrel. The hepatic
carboxyl esterase 1 inactivates 90% of the administered drug and esterase inactivates 40% of the intermediate thiolactone metabolite.
Therefore, generation of active metabolite from clopidogrel depends on the enzymatic balance between bioactivation by P450s and

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Antithrombotic medications are frequently used for the treatment and prevention of heart attack, stroke, and peripheral vascular
diseases. Warfarin has been the first-line anticoagulant drug for many years because of the lack of alternatives. Inhibition of VKORC1
by warfarin is limited by a narrow therapeutic index, potentially lethal side effects, and many genetic variations of VKORC1 that
confer either hypersensitization or true resistance. Moreover, warfarin has complex pharmacokinetics that is influenced by
polymorphisms of CYP2C9. The emergence of new oral anticoagulants that inhibit blood coagulation by blocking ADP-dependent
platelet aggregation [i.e., clopidogrel (Plavix) and prasugrel] or the function of clotting factor Xa (i.e., apixaban) provides alternatives
to warfarin. New anticoagulants are characterized by simpler, more predictable pharmacodynamics and pharmacokinetic and by
reduced need for monitoring. It is noteworthy that clopidogrel is now the second-highest selling drug in revenue, surpassed only by
atorvastatin. Moreover, the use of combination of drugs that inhibit different targets of blood coagulation allows reduced doses and,
consequently, reduced on-target side effects of individual anticoagulants.

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bioinactivation by hepatic carboxyl esterase 1 and esterase, which is influenced by genetic polymorphisms of the P450s and drug-drug
interactions. Individual variability in the response to clopidogrel is well recognized. Patients having coronary artery disease but with
lesser degrees of platelet inhibition by clopidogrel are at increased risk of cardiovascular events.
The incorporation of genomic biomarkers into the drug development and clinical trial continuum allows biopharma to select the
optimal group of patients to be enrolled into trials and reduce the number of adverse events. This will lead to more successful clinical
trials and decrease the time to market for compounds. Whether genomic biomarkers are incorporated into early phase development to
selectively enroll patients or assessed for severe adverse events in post market monitoring, the intrinsic value ultimately lies in
matching a patients genetic information to the appropriate treatment.
Deliver more predictable responses to drug therapy
Minimize the occurrence and severity of adverse drug reactions (ADRs)
Accelerate the drug discovery and development process
Conduct more cost-effective clinical trials
Government regulators continue to encourage companies to evaluate and incorporate genomic biomarkers in clinical trials, releasing
an updated draft guidance for Clinical Pharmacogenomics in February 2011. Gentris, in compliance with the FDA, EMEA, ICH,
Laboratory Standards Committee, and other regulatory bodies, has implemented company-wide policies and procedures that meet and
exceed regulatory guidelines.
Gentris has 10 years of experience in designing, implementing, and interpreting pharmacogenomics to improve clinical trials.
Examples include genotyping patients for oncogene mutations that affect the efficacy and/or safety of specific drugs and measuring
gene expression markers of drug metabolizing enzymes to identify variations associated with drug response.
PHARMACOGENOMICS DRIVEN MEDICINES CYP2C19 AND CLOPIDOGREL
CYP2C19 is a drug-metabolizing enzyme that catalyzes the biotransformation of many clinically useful drugs including
antidepressants, barbiturates, proton pump inhibitors, antimalarial, and antitumor drugs. Clopidogrel, or Plavix, is an antiplatelet
prodrug for prevention of strokes and heart attacks and is metabolized by CYP2C19 into an active form. Several landmark studies
have proven the importance of 2C19 genotyping in treatment using clopidogrel. These studies have demonstrated that CYP2C19 poor
metabolizers, up to 14% of patients, are at high risk of treatment failure due to a lack of conversion of the prodrug into its active form.
The findings led to an FDA black box warning on clopidogrel in 2010 to communicate the importance of genotyping patients before
prescribing clopidogrel.
CYP2D6 AND TAMOXIFEN
CYP2D6 is another drug-metabolizing enzyme that is responsible for the biotransformation of the prodrug tamoxifen into its active
form. Patients with variant forms of the gene CYP2D6 may not receive full benefit from tamoxifen because the prodrug is converted
to the active form too slowly. Clinical studies have shown that CYP2D6 variations in breast cancer patients can lead to worse clinical
outcomes for tamoxifen treatment. In 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to
include information about genotyping for CYP2D6 in the package insert.

BRAF AND VEMURAFENIB

Vemurafenib is the first and only FDA-approved personalized medicine shown to improve survival in people with BRAF V600E
mutation-positive metastatic melanoma. It is designed to target and inhibit some mutated forms of the BRAF protein found in about
half of all cases of melanoma, the deadliest and most aggressive form of skin cancer. The BRAF protein is a key component of the
RAS-RAF pathway involved in normal cell growth and survival. Mutations that keep the BRAF protein in an active state may cause

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KRAS AND CETUXIMAB

Cetuximab is an EGFR inhibitor that has been shown to be ineffective in treating metastatic colon cancer patients with specific
mutations in the KRAS gene. KRAS encodes a small G protein in the EGFR signaling pathway. Studies have demonstrated that
characterizing mutations in the KRAS gene can assist physicians in determining the appropriate treatment for patients. In 2009, the
FDA added label information to both cetuximab and panitumumab regarding the association between certain KRAS mutations and
efficacy in treating metastatic colon cancer. As such, genetic testing to confirm the absence of KRAS mutations is now clinically
routine before the start of treatment with EGFR inhibitors.

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CYP2C9 AND WARFARIN

Warfarin, a commonly prescribed anticoagulant, has a very narrow therapeutic index and wide inter-individual variation in dose
requirements. A number of studies suggest that genetic variation in two genes is partially responsible for the observed differences in
dose requirements between patients. CYP2C9 is the primary metabolizer of warfarin. Polymorphisms in CYP2C9 significantly slow
the metabolism of warfarin, which leads to longer circulation times of the drug and thus lowering the dose needed to achieve
therapeutic efficacy. VKORC1 encodes the protein subunit targeted by warfarin to exert its anticoagulant effect. Individuals with a
particular mutation in VKORC1 produce less of the protein and require less drug to achieve the necessary anticoagulant effect. The
FDA has now suggested that healthcare providers can use genetic tests to improve their initial estimate of what is a reasonable
warfarin dose for individual patients.

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excessive signaling in the pathway, leading to uncontrolled cell growth and survival. The FDA approval of Zelboraf is based on results
from two clinical studies (BRIM3 and BRIM2) in people with BRAF V600E mutation-positive, inoperable or metastatic melanoma as
determined by the cobas BRAF Mutation Test.[55]
PROMISE OF PHARMACOGENOMICS
Right now, in doctors' offices all over the world, patients are given medications that either don't work or have bad side effects. Often, a
patient must return to his doctor over and over again until the doctor can find a drug that is right for him. Pharmacogenomics offers a
very appealing alternative. The day is not far when you go into your doctor's office and, after a simple and rapid test of your DNA,
your doctor changes her/his mind about a drug considered for you because your genetic test indicates that you could suffer a severe
adverse reaction to the medication. However, upon further examination of your test results, your doctor finds that you would benefit
greatly from a new drug on the market, and that there would be little likelihood that you would react adversely to it. Yes can do this to
mankind.
Pharmaceutical companies, physicians and the public are anticipating the promise of significant advancements in medicine brought by
the genomics revolution. where drugs are chosen for patients based on their individual genetic make-up. Pharmacogenomics should
allow pharmaceutical companies to develop safer and more effective drugs. In addition, understanding how individuals are genetically
predisposed to risk of disease may result in new drug targets. This will lead to new classes of drugs designed to delay or prevent
disease onset. Pharmaceutical industry has made significant investments in pharmacogenomics with the hope that it will help eliminate
the unpredictable nature of drug development, bring new products to market aimed at preventing common diseases and create
premium pricing for their products. [56]
Perhaps a gene chip that establishes a single nucleotide polymorphism signature involving multiple genes relevant to therapeutic
outcome for each individual will be developed. This signature could offer insights into an individual's susceptibility to disease and
responsiveness to drugs, enabling optimal drug selection by genetic criteria. while the remainder of the patients experience little gain
or even severe toxicity from chemotherapy. If we could predict which patients respond best to a particular drugor better, which drug
will yield optimal effects for a given patientmuch will be gained. The success of this approach will depend critically on the selection
of single nucleotide polymorphisms tested by the gene chip. Single nucleotide polymorphisms must be informative and many must be
tested to scan the entire genome. This task is by no means complete and constitutes a major goal of those companies which are
focusing on genomics.

Better, Safer starting 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 from the beginning. This will
take the guesswork out of finding the right drug, but it will also speed recovery and increase safety as the likelihood of
adverse reactions is eliminated. Pharmacogenomics has the potential to dramatically reduce the estimated 100,000 deaths and
2 million hospitalizations that occur each year in the United States and other countries as the result of adverse drug response.
More Accurate Methods of Determining Drug Dosages - Current methods of prescribing dosages on weight and age will
be replaced with dosages based on a person's geneticsThe way 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.
Advanced Screening for Diseases - 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 particular disease susceptibility will allow careful monitoring, and treatments can be introduced at the most appropriate
stage to maximize their therapy.
Availability of 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.
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. Targeting only those persons capable of responding to a drug will
reduce the cost and risk of clinical trials.
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

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BENEFITS OF PHARMACOGENOMICS
The potential benefits of pharmacogenomics are many. Pharmacogenomics holds the promise that drugs may one day be tailor-made
to each persons genetic makeup The products of this "rational drug design" technology would replace current drugs that are intended
to serve the entire patient population. These traditional blockbuster, one- formula-fits-all, drugs, typically work for only 60 percent of
the population at best. Some of the benefits are listed below Improved Medicines - Pharmaceutical companies will be able to
research for 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.

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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 [56]

Fig.1.toxicity level differ in different patient

TECHNOLOGICAL ADVANCES IN PHARMACOGENOMICS
As the cost per genetic test decreases, the development of personalized drug therapies will increase. [57] However, as of now, we only
have access to single-gene test and which is currently quite expensive. In the future, more advanced sequencing will be able to test for
multiple genes in a short amount of time. A disposable DNA sequencing device, which will retail for under $900 has recently been
announced. The device was made to be the size of a USB memory drive to make it portable and easy to use Likewise, companies like
DeCode Genetics, Navigenetics and 23andMe offer genome scans. The companies use the same genotyping chips that are used in
GWAS studies and provide customers with a write-up of individual risk for various traits and diseases and testing for 500,000 known
SNPs. Costs range from $995 to $2500 and include updates with new data from studies as they become available. The more expensive
packages even included a telephone session with a genetics counselor to discuss the results.[58]
The transition from genetics to genomics marks the evolution from an understanding of single genes and their individual functions to
an understanding of the actions of multiple genes and their control of biologic systems. Whereas the tools of the Human Genome
Project initially advanced research on single genes, they are now forming the basis for genomic-scale analysis of the human organism.
The so-called DNA chip currently provides one promising approach to genome-scale studies of genetic variation, detection of
heterogeneous gene mutations, and gene expression. The result of an adaptation of dot blot hybridization techniques, DNA chips, also
called microarrays, generally consist of a thin slice of glass or silicon about the size of a postage stamp on which threads of synthetic
nucleic acids are arrayed. Sample probes are added to the chip, and matches are read by an electronic scanner. As with
semiconductors, the capacity of DNA chips has doubled about every two years, so chips that held a few hundred arrays not so long
ago now hold hundreds of thousands.
Microarray technology has been applied to the detection of DNA variations as well as expression of messenger RNA in individual
cells and tissues. Microarrays are used clinically to detect human immunodeficiency virus sequence variations, p53 gene mutations in
breast tissue, and expression of cytochrome P450 genes. In the laboratory, microarray technology has also been applied to genomic
comparisons across species, genetic recombination, and large-scale analysis of gene copy number and expression, as well as protein
expression, in cancerous tissues.

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Microarray gene chips

Novel technology in the form of microarray chips enables us to scan the entire human genome for relevant polymorphisms. We can
determine simultaneously many thousands of polymorphisms in a patient. At present, these single nucleotide polymorphisms are
selected merely as markers evenly distributed throughout the genome, in the hope that functionally relevant polymorphisms can be
associated with specific markers by virtue of their proximity on the chromosome. Such genome-wide association studies are already
being used in the discovery of susceptibility genes for diseases such as asthma and prostate cancer, but they are equally suitable for
determining the genes involved in drug response. Genome-wide scanning can identify these genes even if we do not know the
mechanisms by which the drug acts in the body. The French genomics company, Genset, currently uses gene chips with 60 000 single
nucleotide polymorphism markerssufficient for a complete genomic scanapplied to clinical drug trials in partnership with major
pharmaceutical companies.. Stratifying patient populations in relation to genetic criteria emerges as a major challenge to the

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Use of microarrays and other new technologies to detect DNA variations holds promise, along with family histories and data from
large population studies, for establishing a person's risk of contracting common, adult-onset disorders. A base-line genome scan could
provide helpful information about a person's risk profile and point to the prevention strategies if available that should be used.

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pharmaceutical industry. Undoubtedly, the insights expected to emerge from such an approach are staggering, but they cannot be
gauged accurately at present.
Chip technology
Microarrays can further serve to determine the expression pattern of genes in a target tissue. This shows the mechanisms of drug
action in a genomic context. It can also clarify interindividual differences in drug response that are downstream of immediate drug
effects in the body by shear force of the massive amount of information emanating from chip technology. Analysing the entire
transcriptional programme of a tissuefor example, fibroblasts in response to serum stimulation14provides unprecedented details of
a complex system and leads to new insights in pathophysiology and biological drug response. Tissue transcript profiling is especially
appropriate in cancers because mRNA can be extracted from biopsy specimens or surgical samples. genes encoding transporters. [59]

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Genomic or personalized medicine seeks to exploit an individuals genetic or genomic information in the context of guiding the
clinical decision-making process. Examination of a patients genome sequence can allow physicians to estimate disease risk and to
individualize treatment modalities. At the same time, the molecular basis of a growing number of disease states has been elucidated
and can now be readily identified by reference to specific genotypes and/or gene expression patterns. This has potentiated the risk
stratification of patients for a wide variety of genetic disorders on a genome-wide basis. We are now entering an age in which
individualized health care is fast becoming a reality through consideration of each persons unique genomic profile alongside their
clinical profile. This should give rise to unprecedented opportunities in the context of inherited disease, not only in terms of
optimizing preventive medicine strategies and customizing patient care but also with a view to personalizing conventional therapeutic
interventions. Such interventions could potentially be made at an early stage in the onset of a genetic disorder or even presymptomatically. Mutation-specific targeted intervention is already a reality in some cancer treatments.At the same time, molecular
genetic testing technology has evolved such that low- and medium-throughput methods have been largely replaced by high-throughput
genome-wide microarray-based assays, an important advance which has allowed the genetic testing industry to grow at a very rapid
pace. Indeed, a considerable number of different private diagnostic testing laboratories now provide a wide variety of genetic testing
services and over 2,000 specific genetic tests, often employing a direct-to-consumer (DTC) business model. Genetic laboratories
currently offer DTC antenatal carrier testing and/or pre-pregnancy family planning tests, which have been designed to identify
mutations underlying common Mendelian disorders such as cystic fibrosis and -thalassemia. However, in parallel, tests that purport
to assess a persons risk of a multitude of complex (multifactorial) diseases including heart/cardiovascular disease, hypertension,
diabetes, osteoporosis, and lung and breast cancer are also available. In practice, despite the extravagant claims often made on behalf
of the tests being offered, our current level of scientific understanding is usually insufficient to accurately assess the risk of common
diseases such as cancer, diabetes, and heart/cardiovascular disease; even though data on genetic markers can be readily obtained and
accurately ascertained, we are as yet unable to interpret them with any degree of accuracy or reliability .Recently, we have noted a
novel trend in the provision of private molecular genetic testing services, namely saliva and buccal swab collection kits (for DNA
isolation) sold over the counter through pharmacies. These tests are very different from the standard pregnancy or blood sugar test kits
that have long been sold over the counter in pharmacies since these latter kits do not involve DNA isolation or genetic analysis.
Several genetic testing laboratories in Europe and the USA appear to have entered into partnerships with pharmacies to provide their
services to the public. These private genetic laboratories offer the following types of genetic test:
(a) genetic tests for the detection of single-gene (Mendelian) disorders;

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PHARMACOGENETICS TESTS
Pharmacogenetics test is the assay of an individual genetic to detect the variation, or single nucleotide polymorphism in the genetic
code in order to predict their responses to drug. The genetic variation will determine the efficacy of a drug or the likelihood to sustain
adverse drug reaction by the patient. The test can be done by direct analysis of the patients DNA or indirect analysis of the DNA
influenced molecules, like RNA or proteins. Pharmacogenetics test can be done on blood samples, cheek swabs or in cancers biopsy
tissue.Genetic tests obtainable through pharmaciesGenomic medicine seeks to exploit an individuals genomic information in the
context of guiding the clinical decision-making process. In the post-genomic era, a range of novel molecular genetic testing
methodologies have emerged, allowing the genetic testing industry to grow at a very rapid pace. As a consequence, a considerable
number of different private diagnostic testing laboratories now provide a wide variety of genetic testing services, often employing a
direct-to-consumer (DTC) business model to identify mutations underlying (or associated with) common Mendelian disorders, to
individualize drug response, to attempt to determine an individuals risk of a multitude of complex (multi factorial) diseases, or even
to determine a persons identity. Recently, we have noted a novel trend in the provision of private molecular genetic testing services,
namely saliva and buccal swab collection kits (for deoxyribonucleic acid (DNA) isolation) being offered for sale over the counter by
pharmacies. This situation is somewhat different from the standard DTC genetic testing model, since pharmacists are healthcare
professionals who are supposedly qualified to give appropriate advice to their clients. There are, however, a number of issues to be
addressed in relation to the marketing of DNA collection kits for genetic testing through pharmacies, namely a requirement for
regulatory clearance, the comparative lack of appropriate genetics education of the healthcare professionals involved, and most
importantly, the lack of awareness on the part of both the patients and the general public with respect to the potential benefits or
otherwise of the various types of genetic test offered, which may result in confusion as to which test could be beneficial in their own
particular case. We believe that some form of genetic counseling should ideally be integrated into, and made inseparable from, the
genetic testing process, while pharmacists should be obliged to receive some basic training about the genetic tests that they offer for
sale.

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(b) pharmacogenomic tests to individualize drug (including cancer) treatment, e.g., to guide specific mutation-targeted treatment
decisions;
(c) predictive genomic testing for complex disorders and traits, e.g., heart/cardiovascular disease, osteoporosis, diabetes, athletic
performance, etc.;
(d) nutrigenomic tests, to individualize diet choices with the aim of bringing about weight loss; and (e) identity DNA testing.
These tests may be organized into three main categories:
1. Genetic tests designed to diagnose inherited disorders and conditions that can be unambiguously assigned to specific genomic
variants, namely
(a) single-gene disorders and
(b) drug-treatment efficacy or toxicity. For many of these tests, there is strong scientific evidence to support genotype-phenotype
correlations, especially in the case of common genetic/genomic disorders. For a number of anticoagulant, psychiatric, and anti-cancer
drugs, several pharmacogenomic markers have been identified in genes encoding drug-metabolizing enzymes and transporters that can
predict drug efficacy or toxicity with a high degree of reliability, and many of them (including tests for variants
in CY2D6, CYP2C9, VKORC1, and other pharmacogenes) have been cleared for use in clinical practice.
2. Genetic tests designed to diagnose complex health states and/or conditions characterized by a very poor or incomplete knowledge of
genotype-phenotype correlations, e.g., cardiovascular disorders, diabetes, osteoporosis, etc., and/or with a very powerful geneenvironment interaction, e.g., nutrient uptake, athletic performance, etc., that does not allow accurate estimation of disease risk based
on an individuals genetic profile. This situation is similar to attempting to solve a jigsaw puzzle that is missing several key pieces. In
these genetic tests, risk profiles are calculated on the basis of risk markers with the aid of certain algorithms. When different genetic
risk markers or algorithms are employed, different risk profiles may be generated, even for the same individual. In this case, there is
an omnipresent danger of obtaining a false-positive or false-negative result, which may either cause unnecessary alarm or alternatively
provide inappropriate reassurance. Such misinterpretation of test results may in turn lead to the requisitioning of unwarranted,
expensive, and potentially risky invasive diagnostic procedures or, conversely, could result in the individual concerned becoming less
vigilant about their health.
3. Genetic tests that are ethically and/or legally questionable, despite being scientifically sound and accurate. This category of test is
perhaps best exemplified by several well-publicized paternity cases in which the person whose DNA has been isolated and
subsequently tested, has not provided the necessary consent (the so-called infidelity DNA testing). In these cases, the parties
involved would be guilty of a misdemeanor punishable by law, at least in European countries and several US states.
This situation is somewhat different from the standard DTC genetic testing model since pharmacists are healthcare professionals who
are in principle qualified to give appropriate advice to their clients, with the proviso of course that they have the necessary basic
genetics training. In all these cases, and in several different countries, pharmacies are in effect acting as middlemen between the
genetic testing providers and their customers.
There are certainly many benefits for the customers to be derived from the genetic tests which have been designed for the diagnosis of
single-gene disorders and pharmacogenomics. First of all, by raising awareness of genetic issues, they can empower the individual to
make decisions that could improve their health, including the adoption of better lifestyle choices. Moreover, the availability of this
type of genetic test may contribute to a general decrease in the cost of genetic testing as a result of commercial competition. There are
nevertheless a number of issues to be addressed in relation to selling DNA collection kits for genetic testing in pharmacies to ensure
that the process is indeed beneficial to the patients involved and does not mislead the general public.

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Another major area of concern is the comparative lack of appropriate genetics education on the part of the healthcare professionals
involved, namely pharmacists and physicians. The genetic tests in question do not come with detailed pre- or post-test counseling, and
so, the consumer is unlikely on their own to be able to interpret the test results satisfactorily or even appropriately. Further, most
genetic test results come with a range of caveats and, if this is not fully appreciated by the user, misunderstanding of the clinical
implications of these results is likely to be the rule rather than the exception. When physicians and pharmacists have been surveyed in
the USA and in some European countries, many have readily admitted that they lack the formal genetics education that would allow
them to fully exploit the wealth of information that can now be obtained from genetic tests so as to deliver better healthcare to their
patients. Further, they have acknowledged that even if the genetic test were potentially beneficial, they would not necessarily
understand it well enough to be able to relay the appropriate diagnostic information to their patients. Unsurprisingly, both patients and
the general public at large are often either unaware of the benefits of genetic testing or cannot easily distinguish between valid and
informative genetic tests and those that will yield uninformative, unhelpful, or even potentially harmful results. As such, members of
the public can easily be misled or end up being confused as to which test could be beneficial in their own particular case, and how

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In the USA, regulatory clearance is required before a DNA collection kit (saliva, urine, or buccal swab tabs) can be commercially
distributed. In 2010, the US Food and Drug Administration banned a commercial partnership between Walgreens, a retail pharmacy
chain, and Pathway Genomics, a private genetic laboratory, from offering a variety of over-the-counter genetic tests since the
company had not previously obtained regulatory clearance for the saliva collection kit to be sold as a medical device. In contrast to the
USA, such legislation is currently lacking in many European countries, even at a central level as a directive of the European
Medicines Agency, as is the case for DTC genetic testing, where the environment is still not properly regulated.

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effective that test could be at improving their long-term clinical outlook and/or decreasing their health costs. In addition, the general
public could put themselves at risk if they:
(a) place undue reliance upon tests that have not been scientifically validated or approved by regulatory agencies and/or have intrinsic
limitations based on existing scientific knowledge or
(b) make important medical and lifestyle decisions based on these test results without first consulting an informed healthcare
professional.
For all the reasons discussed above, we believe that some form of genetic counseling should ideally be integrated into, and made
inseparable from, the genetic testing process. To this end, we believe that genetic counseling should be made available to guide the
patient through the entire genetic testing process (perhaps as a test-related single-session service) to determine what information an
individual wishes to acquire from the test in question and what should be done with that information in terms of any post-test
modification of their treatment regimen or lifestyle. Moreover, pharmacists should be obliged to receive some basic training about the
genetic tests that they sell in their practices, at a bare minimum from the genetic laboratories that provide the tests, so that they are
able to advise their clients accordingly and guide them to (and through) the test that is most appropriate to their needs. Pharmacists
(and physicians) should also be encouraged to pursue continuous genetics education, in the form of, e.g., medical education-accredited
seminars organized in concert with local universities and/or international organizations. This is particularly germane for those
pharmacists who did not acquire the necessary level of genetics expertise during their undergraduate training. This notwithstanding, it
should be pointed out that a recent survey in the USA indicated that very few participants utilized a genetic counseling service after
direct-to-consumer personal genomic testing. Ultimately, however, the decision as to whether or not have themselves avail of a
genetic counseling service, offered at the point of sale of the genetic test, has to be the participants prerogative. Despite having some
very real concerns as to how this might work in practice, we believe that with appropriate safeguards agreed and with the necessary
legislation in place, it is likely that the current trend toward unregulated DTC testing will gradually decline of its own accord, and the
partnerships between genetic testing laboratories and pharmacies will become better organized as they become better regulated.
Patients and the general public alike should come to appreciate the fact that a genetic test is never going to be all enlightening, and that
there will remain many limitations pertaining both to genetic testing and to the interpretation of genetic test results.
Finally, we must all understand that our knowledge of the genome remains at a fairly rudimentary stage which can, metaphorically
speaking, be likened to the Phaestos disc, where one can just about understand the individual characters but certainly not the full
meaning of the text.
PHARMACIST EDUCATION IN THE ERA OF GENOMICS MEDICINES
Pharmacists are increasingly expected to incorporate an understanding of the genomic contributions to medication management in
their daily practice, and a general consensus exists that many pharmacists are not adequately prepared to effectively make use of
genomic information. In November 2011, the National Human Genome Research Institute of the National Institutes of Health
convened a meeting to discuss the status of genomics education for pharmacists. A variety of pharmacist organizations and other
stakeholder groups attended the 2-day event and explored the current status of pharmacist genomic education, barriers and facilitators
to enhanced education, and important next steps to ensure that pharmacists are prepared for the coming decades. This report
summarizes the background, content, and outcomes from this meeting. Pharmacists focus on education in genomics at meeting with
NHGRI Meeting participants contributed to the conversation, sharing perspectives about individual and organizational efforts, and
identifying potential opportunities for focused action. [64]

Whether we will see broad use of gene chips in clinical practice within 10 years is questionable, but the mere knowledge of the
principles underlying genetic variability will prove valuable in optimising drug therapy. Pharmacogenomics will lead us towards
individualised therapy, but it will also help us understand limitations inherent in treating disease in a broad patient populationPresently

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IMPACT OF PHARMACOGENOMICS ON PHARMACY PROFESSION

Pharmacogenomics will have a profound impact on the way drug treatment is conducted. We can include here bioengineered proteins
as drugs, or even gene therapy designed to deliver proteins to target tissues. These treatments are also subject to constraints and
complexities engendered by individual variability. A case in point is the treatment of breast cancer with trastuzumab[65]) a humanised
monoclonal antibody against the HER2 receptor. Overexpression of HER2 may occur as a somatic genetic change in breast cancer and
other tumours. This correlates with poor clinical prognosis and serves as a marker for effective therapy with trastuzumab, either alone
or in combination with chemotherapy.

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ROLES OF PHARMACISTS
Currently, only a small amount of pharmacists that are involved in pharmacogenetics, particularly those who are specialist like in the
field of HIV service or oncology. The increase involvement of pharmacists in clinical areas will eventually expose pharmacists to
pharmacogenetics. Pharmacists will need to, for example, interpret the test result from pharmacogenetic test and determine the
appropriateness of the drug prescribed. In the same time, pharmacists will be counselling patients about the implication of the result
and advice them on medication intake base on the result. Last but not least, pharmacists can keep the pharmacogenetics test result
together with the patients medical record for future referencing while monitoring and reviewing the treatment.

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the doctor diagnoses a disease [which is based on the symptoms] & prescribes a drug on the trial & error basis, which suits, for the
average patient. Pharmacist currently advises about side effects & drug-drug interaction.But a day will come when one may visit a
doctor & have ones blood drawn for a genotype to be done which would indicate what genes one has for drug transporters, drug
targets or drug elimination enzymes. This is to say one will take a gene report instead of blood reports.Thus after you are diagnosed by
a doctor, pharmacist would interpret the panels of genetic results & advise you which drug would be best for your particular gene so
that you have fast recovery.From all these pharmacists will learn more about the patient genetic information; issue of privacy arises
which should be maintained by pharmacist. Protective measures & standards will be required to control the misuse of personal data &
malpractice in testing procedures. Thus it will lead to teamwork between genetic counselor, doctor & a pharmacist.
By incorporating Pharmacogenomics in scientific, academic and clinical settings, pharmacists will have three distinct roles:
researchers, educators, and clinicians.

As researchers - Pharmacists will play a critical role in developing novel drugs with highly specific mechanistic targets, new
study methodologies for studying drug therapy and criteria that are tailored to pharmacogenomic discovery. Consistent with
the standards of evidence-based medicine, pharmacists will incorporate these new study designs and subsequent outcomes
into effective clinical decision-making.
As educators - The translation of pharmacogenomic advances into clinical practice will require the appropriate training of
current and future pharmacists in the interpretation, management, application, and delivery of pharmacogenomic information.
In addition to the science, however, pharmacists will need advanced training in the ethical, legal and social implications of its
application in healthcare. Schools of pharmacy, professional organizations and clinical practice centers should begin to
implement such a pedagogical framework.
As clinicians - Through the expansion of the pharmaceutical care practice model, pharmacist clinicians will be key players in
recommending and facilitating successfully individualized therapies based on genetic characteristics.
Although the science of Pharmacogenomics will provide an increased level of accuracy in selecting specific drug therapy for
individual patients, it will not replace the art of clinical judgment in practice because of the confluence of social, behavioral,
economic and environmental factors.[56]

APPLICATIONS
Pharmacogenomics has applications in illnesses like cancer, cardiovascular disorders, depression, bipolar disorder, attention deficit
disorders, HIV, tuberculosis, asthma, and diabetes
Individualized Medicine
TABLE.1 provides the prevalence as well as the genes or chromosomes associated with some human genetic disorders.
DISORDER
Cancers
Breast/Ovarian Cancer (susceptibility)
FAP (hereditary nonpolyposis coli)
Lynch syndrome
Neurological Conditions
Huntington disease
Alzheimer disease early onset

PREVALENCE

CHROMOSOME OR GENE INVOLVED

~5% of cases of these cancer types

1:3500
510% of all cases of bowel cancer

BRCA1, BRCA2
APC
MLH1, MSH2, MSH6, PMS2

1:20000
1:2500

Huntingtin
PS1, PS2, APP

CHALLENGES
Genome analysis for all individuals - Rapid, automated methods must be developed to efficiently identify SNPs in the
three-billion-base- pair genome that influence susceptibility to disease and individual drug response & also at an affordable
price.
Studying the genes involved in disease and drug reactions - It takes decades to study a gene's product, function and
association to drug response. New techniques need to prove their worth - SNP analysis and expression profiling are in their
early stage & little success is achieved till date and few success stories used.

CONCLUSION
In the future, pharmacogenetic researchers have the potential to subdivide each disease according to genetics, not symptoms. Specific
diagnoses may be based on the molecular mechanisms involved rather than clinical presentation. Molecular mechanism differences
will subdivide patient groups with common diseases like hypertension, diabetes, and cancer. Health care professionals will use genetic
tests to predict how a disease will progress and the therapeutic response to anticipate.Drug development will be based on
understanding of molecular pathogenesis. The role of genes in determining disease susceptibility, progression, complications and
response to treatment could all be potentially mapped. Pharmacogenomics will yield drugs targeted to act at or near the cause of a

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Complex diseases really are complex! - In reality, disease and drug response to it is a multifunctional process involving
hundreds of genes. Environmental factors such as age, nutrition and lifestyle can influence disease and drug response as
well.[56]

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disease. Genetically defining patient populations will help improve outcomes and genetic prognostics will revolutionize treatment and
improve.
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