The role of pharmacogenomics in drug development
By - 05/24/2007
Vikas Kumar
Pharmacogenomics is a biotechnological science that combines the techniques of medicine, pharmacology, and genomics and is concerned with developing drug therapies to compensate for genetic differences in patients which cause varied responses to a single therapeutic regimen. Patient-drug interaction is a complex trait influenced by many genes.
Without a comprehensive knowledge of all the genes that influence drug response, it is difficult to develop genetic tests that could predict a person's response to a particular drug. Pharmacogenomics is a science that examines the inherited variations in genes that dictate drug response and explores the ways these variations can be used to predict the kind of response a patient would have to a drug 1.
Pharmacogenomics refers to the entire spectrum of genes that determine drug behavior and sensitivity, whereas pharmacogenetics is often used to define the more narrow spectrum of inherited differences in drug metabolism and disposition, although this distinction is arbitrary and the two terms are now commonly used interchangeably 2. As summarized clearly by World Health Organization (WHO) Drug Information,
pharmacogenetics refers to the study of DNA sequence variation as it relates to differential drug response in individuals, i.e. the use of genomics to determine an individual’s response and pharmacogenomics refers to the use of DNA-based genotyping in order to target pharmaceutical agents to specific patient populations in the design of drugs.
The benefits of pharmacogenomics are numerous. Pharmaceutical companies could exclude those people who are known to have a negative response to the drug, from the clinical trials. This, of course, increases the probability that the drug might be a success with a particular population. Pre-screening clinical trial subjects also helps in reducing the drug costs by allowing the clinical trials to be smaller, faster and more inexpensive 1.
Also, the ability to assess an individual's reaction to a drug before prescribing it will increase the physician's confidence in prescribing and the patient's confidence in taking the drug 1.
However, while pharmacogenomics does offer an appealing alternative to medications that have side effects, personalizing medicine in this way is not as simplistic as it appears. Individual variation supports the heterogeneity of disease and the individual response to drugs and so it should be expected that with all therapeutics some patients respond and some do not. The source of individual variation in response to drugs may be single nucleotide polymorphisms (SNPs) or mutations. SNPs are abundant in the human genome and may affect the pharmacokinetics and pharmacodynamics of a drug. Studies on gene expression are vital to understanding the state and function of a cell, tissue, organ or patient. The challenges of such research are in determining which genes make the best targets, which genes should be used for diagnostic or prognostic markers and which genes are markers for drug toxicity.
Allelic variations in the drug-metabolizing cytochrome P450s, for example, have significant effects on drug metabolism, and their expression may be regulated by several factors, including hormones, xenobiotics, nuclear factors and DNA modifications 3.It is now obvious that the role of pharmacogenomics in drug development is just the beginning and not an end within itself.
Need For Pharmacogenomics
Pharmacogenetics offers a wide area for research. The knowledge of the effects of polymorphism of genes for the enzymes involved in drug metabolism, like those belonging to the family of cytochrome P450 can be applied in drug delivery, development and the clinical use of drugs. Cost effective methods of genotyping are being developed and this, when included in the patient's record can be used for the guidance of the physician in individualizing the treatment 4. Along with pharmacogenetics and pharmacoproteomics, pharmacogenomics represents the advent of personalized medicine designed to match a treatment for a patient according to his genotype. Although genotyping is not a clinically accepted technique currently, this status is expected to change by 2010 4. While pharmacogenomics and personalized treatment promise increased efficacy and safety of treatment, ethical issues, social issues and considerations of race are important issues which need to be analyzed, in adherence to the FDA guidelines on pharmacogenomics. This segmentation of the market would not sell the conventional blockbusters, but smaller and exclusive markets for personalized medicines would be profitable 4. Current results in the field of pharmacogenomics have not been fast, but with more recent high-throughput screening methods and data-mining approaches, drug development in the future promises more.
To achieve individualized drug therapy, a high level of accuracy and precision is required of any clinical test proposed in human patients. Perhaps, metabonomics, in combination with proteomics, might complement genomics in achieving individualized drug therapy 5.
What Recent Research Promises
Recent research areas involving pharmacogenomics have dealt with how alliances with niche technology providers can boost the commercial potential of the abundance of targets available in the post-genomic era. Various technologies have been integrated to develop personalized therapy in the case of genotyping for drug resistance in HIV infection, personalized therapy for cancer, antipsychotics for schizophrenia, antidepressant therapy, antihypertensive therapy and personalized approach to neurological disorders 4. The recent trend concerning methods to maximize sales of pharmacogenomics-derived products reflect pharma’s need to develop portfolios of best-in-segment or ‘multi-buster’ drugs and application of proprietary cost-effectiveness framework to assess the therapy areas that are best suited to pharmacogenomics, the benefits of positioning pharmacogenomics-derived drugs to patients, physicians and healthcare payers, evaluation of the impact of key niche genomic-based technologies on the pharmacogenomics industry until 2012, analysis of the revenue opportunities associated with the ‘new generation’ of blockbuster products offered by post-genomic science and a neat assessment of the ability of pharmacogenomics to solve the pharmaceutical industry’s current R&D productivity crisis 6.
Pharmacogenomics In Drug Development
There was an initial enthusiasm that the Human Genome Project would reveal many novel targets against which new medications could be developed. Although this promise has yet to be realized, there remains great potential for the human genome to yield new insights into the pathogenesis of human diseases and to reveal new strategies for their prevention or treatment. Pharmacogenomics may enhance drug discovery and development in two ways: by the identification of drug targets and by subpopulation-specific drug development. For example, genomics can be used to identify new targets through the discovery of genes that are under- or over- expressed in cancer cells that are sensitive to anticancer agents compared with those that are resistant. The products of such over-expressed genes represent plausible targets for inhibitors that could reverse the drug resistance phenotype. Another application is the use of gene expression in target tissues (for example, cancer cells) to ascertain the effects of chemotherapy and how cells respond to treatment with single drugs or drug combinations. Another use of pharmacogenomics is to identify genetic polymorphisms that predispose patients to adverse drug effects that, although they may occur in only a small subset of the people treated with a new medication, are sufficiently toxic to jeopardize further development of the drug for all patients. One approach is to obtain genomic DNA from patients entered on large Phase III clinical trials of a new agent, and then retrospectively to search for genetic polymorphisms that predispose a small subset to severe toxicities, should they arise. The hope, at the outset, is that no such toxicities would emerge for new agents under development, but should severe toxicity occur in a very small percentage of patients who could be prospectively identified based on genotype, then an otherwise efficacious new drug might be ‘saved’ from abandonment during development, or from withdrawal after approval and widespread use 7.
Pharmacogenetics could be incorporated into clinical development programs so that efficacy of medicine response profiles (MRPs) could be developed. By collecting DNA samples in Phase II clinical trials and identifying DNA markers that correlate with defined efficacy parameters, it might be possible to further focus Phase III clinical trials by recruiting only those patients likely to respond. This will make these studies more efficient. In addition, information collected that identifies ‘non-responders’ in Phase II studies could be used in drug discovery to find new drugs to meet current unmet need in real time, rather than many years after trial-and-error post marketing. In fact, using genetic and genomic technologies to improve our understanding of variations in a drug candidate’s metabolic profile or target before it enters phase II clinical trials will decrease attrition rates overall. Interestingly, one of the major points of failure in drug development is preclinical toxicology. Regulatory toxicology studies add at least two years to the drug development programs. Designing experiments that provide predictive toxicology information in 1–2 months rather than 1–2 years could increase the efficiency by better utilizing those resources that are currently used for longer toxicology studies. A greater throughput of candidates that are less likely to fail regulated toxicology studies could lower the overall cost of drug development. This greater efficiency will provide opportunities to target diseases that are currently thought to be providing a low level of return on research and development investment 8.
Some companies are trying to introduce pharmacogenetic evaluations from the very early stages of drug development, that is from phase I and phase II studies. The aim is to develop pharmacogenetic tests, when this is desirable and feasible, alongside drug development to reduce attrition in the pipeline and then guide clinical practice. Pharmacogenomics can provide new targets from the study of genes involved in diseases. From the knowledge of gene function and of their role in the disease pathway, new targets can be derived, that might be innovative and not accessible with non-genomic approaches 9.
Challenges Posed By Pharmacogenomics
The challenges to the industry created by pharmacogenetics and pharmacogenomics are significant and include the following:
• Genotyping will identify many new disease-related genes and provide an explosion of new targets to pursue; and
• Pharmacogenomics profiling will lead to patient stratification, and these new targets, as well as existing targets, will be divided into subsets.
It is estimated that genotyping will identify new disease related genes that will lead to between 5,000 and 10,000 new potential targets. Because the current amount of targets is approximately 503 and is comprised of mainly four target classes, such as G-protein-coupled receptors (GPCRs), ion channels, nuclear hormone receptors and enzymes, these new targets will add genomic and medicinal diversity 9, 10.
Pharmaceutical industries must urgently overcome these key hurdles if they are to integrate pharmacogenomics successfully.
Scientific hurdles-
Post-genomic science guarantees a 10-fold increase in the number of drug targets but target validation bottlenecks must be overcome 4. Pharmacogenomic processes remain difficult owing to population-specific sources of error, limits of experimental approaches, and the challenges of investigating the many potential regulatory modes, including accounting for epistasis and epigenetics. In some cases, if well-characterized genes are indicative, a few common polymorphisms within a population will cover the bulk of the genetic variation while many, less frequent polymorphisms will explain the rest 11.Consider, for instance, using pharmacogenomic approaches to cardiovascular diseases. The everyday reality of scientific research brings in several problems: first, the definitions of cardiovascular diseases, which allow the distinction between normal and pathologic, are founded on heterogeneous clinical and biologic bases. Second, the transcription analysis techniques are not standardized and the studies of reproducibility limit the generalizations of the conclusions drawn. Thirdly, multiple differences are normally observed and isolation of several transcribed sequences is not an easy task 12.
Commercial hurdles -
Pharmacogenomics encounters several hurdles at the developmental stage and during the marketing stage of drug development.
In the developmental stage -
Micro-segmented markets do not necessarily mean reduced revenue streams for pharmacogenomics-derived products because genotype screening identifies areas of high unmet need. In fact, the application of pharmacogenomics in cancer significantly increases the revenue potential of drugs with narrow therapeutic indices.
One more important factor to consider is that despite the promise of more efficient markets, and smaller stage trials which cost less, thereby reducing cost of late-stage clinical development, pre-clinical and early- stage development costs may increase as a result of the cost of designing gene-base assays and then using these assays to screen and select patients for inclusion in later clinical trials. Essentially, this represents a shift in the stages of drug development which might prove to be a problem for smaller companies. Also, market segmentation would result in the decrease in the revenue. However, some pharmacogenomics-based drugs still become blockbuster drugs, as the breast cancer therapy trastuzumab aptly demonstrates 13.
In the marketing stage -
Traditional mass marketing is ineffective at positioning pharmacogenomic interventions and to achieve this, radical new approaches are required. By 2010, regulatory bodies would require a diagnostic test before pharmacogenomics-derived products are approved 4. Maximizing the commercial potential of pharmacogenomics-derived products through effective targeting of patients, physicians and identifying the clinical trial stages that benefit most from integrating pharmacogenomics, targeting therapeutic markets effectively by applying a proprietary pharmacogenomics cost-effectiveness framework, minimizing the investment risk in accessing niche genomic-based technologies to improve pipeline quality, reducing time and costs by learning from the industry’s leaders when optimizing the commercial potential of genomics-based development strategies.
The impact of genomic technology on clinical trials and medical practices assesses the challenges and future prospects for incorporating genomics technologies into standard clinical practice. In 2003, the Human Genome Project completed the sequence of all human genetic material, in addition to an essentially complete catalogue of all human genes 14. Since the practice of genomics relies on large-scale, comprehensive analyses of genes, this information will prove very valuable in speeding the implementation of genomics in clinical settings. The F.D.A. has also issued draft guidelines for the submission of genomic data in drug applications, signifying a potentially pivotal change in the use of genomics in drug development 14. The clinical genomics environment is ripe with opportunities for all players in the field, especially the pharmaceutical companies.
Ethical hurdles-
While the potential for the development of customized, genotype-based therapies is scientifically and clinically attractive, it raises ethical concerns for the conduct of research with human subjects, particularly with respect to confidentiality, risk–benefit analysis, DNA-banking and pharmacoeconomic issues. There are serious potential risks for discrimination and loss-of-privacy, which need to be addressed to formulate a policy to prevent such possible harm. Thus, despite the obvious scientific value of using families in pharmacogenomic trials, such studies raise serious ethical concerns that ensue from the dynamics and social significance of the family 15. The six ethical issues of most concern are: (1) regulatory oversight, (2) confidentiality and privacy, (3) informed consent, (4) availability of drugs, (5) access, and (6) clinicians’ changing responsibilities 16. Also, pharmacogenomics evokes the concept of consumer satisfaction, and acts at the borderline of the realm of health, in areas such as the use of medication for improving social and working skills, physical appearance, etc. For instance, many sports scientists warn that current performance-enhancing drugs may be a thing of the past once pharmacogenomics are introduced 17.
Ethical, Legal And Social Implications Of Human Genomics
The pharmaceutical industry is showing increasing interest in pharmacogenomics; similarly, governments, regulatory and advisory bodies in some countries are demonstrating a greater attention to this promising area of research. Simultaneously there is a similar growth in the understanding and ability to appropriately address the ethical, legal and social implications of pharmacogenomics. It is a field in its infancy; while evidence to data suggests reason for optimism, so far there are few applications in practice. In particular there is a lack of evidence on its impact in the context of developing countries. The complexity of human responses to medicines makes it cautious not to overestimate the probable impact of pharmacogenomics.
It is important to consider the extent to which pharmacogenomics might contribute to the further marginalization of individuals’ whose conditions and genetic peculiarities put them in the minority of patient populations. On the basis of genetic criteria, some conditions may be neglected as drug manufacturers focus on developing those therapies that impact on the greatest proportion of the population. Broad pharmacogenomics programmes may require obtaining extensive genetic information, which raises concerns about the appropriate protection of patients’ privacy and confidentiality. Moreover, the targeting of specific populations may result in the unfair discrimination against some groups. For instance, pharmacogenomic knowledge could be linked with specific racial or ethnic indicators, making it tempting to assume a biological linkage between race and responsiveness to particular medications, which could lead to inappropriate decisions about treatment.
Pharmacogenomics will need to be carefully evaluated by countries to determine its effectiveness, including its cost-effectiveness, compared to existing public health measures. It will also be important, if pharmacogenomics is to be effectively integrated into clinical practice, to educate both the public and health professionals about its basic principles, its benefits and limitations. Because much of the information provided by pharmacogenomic tests will be probabilistic, effective communication between physicians and patients about risk will be crucial to ensure informed discussion about appropriate treatment decisions. Its integration into clinical medicine needs to take into account questions of equity and fairness, and should be accompanied by appropriate regulatory structures that ensure that patients’ privacy and confidentiality is protected 18.
Success So Far
It is well known that genetic variability may alter drug catabolism (i.e. dihydropyrimidine dehydrogenase for 5-fluorouracil, thiopurine-S-methyl transferase for thiopurines, aldehyde dehydrogenase for cyclophosphamide) and anabolism (i.e. thymidine phosphorylase for capecitabine, deoxycitidine kinase for gemcitabine). Moreover, increased expression of transporter systems (i.e. the ATP binding cassette (ABC) superfamily) is associated with reduction of the cytoplasmic levels of drugs which may be unable to exert a cytotoxic effect. Additional systems could protect tumor cells from drug cytotoxicity, including the DNA repair machinery (nucleotide excision repair (NER) and DNA alkyltransferases) and antiapoptotic systems (i.e. bcl-2). Finally, alterations of drug targets may be associated with a decrease in the effectiveness of chemotherapy (i.e. mutations affecting tubulin and topoisomerase I for taxanes and irinotecan, respectively, and increased expression of thymidilate synthase for 5-fluorouracil). Therefore, genetic analysis has the potential to predict treatment efficacy and tolerability. The current research in pharmacogenomics provides a very interesting area of study.
1. Oncogenomics
There are promising areas of cancer investigation which may represent the future scenario for therapeutic intervention, increasing treatment efficacy and/or reducing drug toxicity on the basis of genetic profile of cancer and patient, respectively. The identification of candidate genes on which pharmacogenetic analysis has to be focused is a complex process, mainly because the majority of anticancer drugs need to undergo an activating metabolism or are substrates of inactivating enzymes or excretion systems. Moreover, some factors which were considered to be predictors of cancer susceptibility to the therapy have gained a particular role in pharmacogenetics because of their role as indirect determinants of drug effects (i.e. p53 as a factor which triggers the apoptosis cascade in response to DNA damage). Finally, the existence of enzymatic systems which are involved in the repair of drug-induced damage (i.e. the activity of ERCC1 against alkylating agents) increases the number of genes which have to be investigated in order to predict the clinical outcome of chemotherapy. Therefore, the pharmacogenetic analysis should take into consideration both the molecular targets of anti-neoplastic agents and factors involved in drug disposition 19. Numerous gene variants frequently found in human populations may influence different stages of the neoplastic growth. These variants act through their products involved in various regulatory systems and metabolic chains at different levels of biological organization. Proliferation, differentiation and death of transformed and even malignant cells can be affected by pre-existing polymorphisms in genes exerting regulation of these basic processes 20.
Colorectal cancer (CRC) is the second most common cause of cancer death in Europe and the United States.5-Fluorouracil (5-FU)-based chemotherapeutic regimens are the standard treatment for the patients suffering from colorectal cancer. However, response rates for 5-FU as a single first-line treatment in advanced CRC are very poor. Combining 5-FU with the newer chemotherapies irinotecan (CPT-11) and oxaliplatin has improved response rates for advanced CRC 21. In the treatment of advanced colorectal cancer, irinotecan has become one of the most important drugs, despite its adverse effects (diarrhea and neutropenia) in some patients. Individual variation in response to irinotecan can be analyzed by using the data pharmacogenetics and pharmacogenomics would provide regarding the role of genetic polymorphisms in the main enzyme-systems in the metabolic pathways of irinotecan 22.
Resistance to chemotherapy limits the effectiveness of current cancer therapies, including those used to treat colorectal cancer. Drug resistance can be intrinsic or acquired during treatment and is believed to cause treatment failure in a large percentage of patients with metastatic cancer. Furthermore, drug resistant micrometastic tumour cells are also likely to reduce the effectiveness of adjuvant chemotherapy following surgery. Overcoming drug resistance is one of the main challenges of current cancer. Pharmacogenomics research could, however, .identify patients most likely to benefit from chemotherapy and to identify which chemotherapy regimen to use 21.
Pharmacogenomics, especially, with increased number of the biomarkers used in the study, would enable tumour samples to be profiled on a global scale. Pre-clinical and clinical studies have already shown that combining information from more than one molecular biomarker increases our ability to predict tumour drug response. As well as analyzing the molecular phenotype of the tumour, pharmacogenomic and pharmacogenetic profiling of normal tissue may also be useful in predicting systemic toxicity. Individualization of therapy according to the molecular phenotype of tumour and patient should dramatically increase the effectiveness of chemotherapy.21 Investigation of common gene polymorphisms with regard to cancer progression and prognosis is still going through its initial stages. Its ultimate goal is, however, to reach a much higher level of understanding the forces driving the process of malignant growth. This understanding would allow predicting its future course in each individual case and developing individually adopted means of its elimination or containment 20.
Genomic abnormalities in lung cancer suggest that the application of a pharmacogenomic approach has the potential to greatly improve survival in certain subpopulations of patients with non-small cell lung cancer (NSCLC). The studies further led to the conclusion that ribonucleotide reductase M1 polypeptide (RRM1) is a biologically and clinically important determinant of malignant behaviour in non-small cell lung cancer NSCLC and represents a strong predictor of outcome in patients with resectable disease 22. Subgroups of NSCLC patients that might have different responses to treatment are primarily defined on the basis of clinical parameters such as performance status, personal preference, convenience, central nervous system metastases, histology, bleeding disorders, gender and smoking status. However, pharmacogenomics has the potential to allow the selection of specific patients on a genetic basis. It is hypothesized that this specific tailoring of therapy, guided by individual patient genetics, could lead to unequivocally superior responses following chemotherapy treatment 23.
Functions of single genes are typically studied by creating a mutation or deletion in a rodent model and the pathophysiology of cancer is learned through this approach. However, forward genetics is too time consuming and cost inefficient to be applied to every gene responsible for the characteristics of a single cancer, and it is unknown whether the results would be applicable to human cancer. Recently, DNA micro arrays have been used to profile and compare the global gene expression patterns of different cancers in human patients 24. Much work remains before micro array technology can be applied to the general population. Although several groups have successfully narrowed the number of genes needed to determine the subgroup or prognosis of a tumor, the list is still too extensive to screen in every patient and pharmacogenetic analysis has the potential to predict treatment efficacy and tolerability 24. Another major problem encountered in pharmacogenetic and pharmacogenomic studies is the need for extensive validation of available technology. There is also considerable difficulty in obtaining a suitable amount of tissue from patients during the course of their disease and the extremely complex regulation of gene function. From this perspective, the evaluation of the cellular effect of drugs in relation to protein expression and function (pharmacoproteomics) may be able to overcome these obstacles, and allow the optimization of cancer chemotherapy in association with a pharmacogenetic approach 25.
2. Cardiovascular Therapy
Pharmacogenomics is markedly influencing the management of essential hypertension. While the final phenotype of elevated blood pressure may be similar in different patients, the underlying hereditary determinants of the increase in blood pressure levels are likely to be polygenic and heterogeneous 26. The identification of genetic markers of drug response will help to achieve a better control of blood pressure in the population, by allowing a better tailor of antihypertensive therapy to individual patients 27. Several polymorphisms in blood pressure-regulating drug receptors [e.g., beta-adrenergic receptors (ADBR)] and receptor response pathways [G-protein beta3 subunit (GNB3), Renin-Angiotensin-Aldosterone System (RAAS)] have been predictive of responses to blood pressure lowering treatment. Genomic studies on the Renin-Angiotensin-Aldosterone System constitute the most information among the different antihypertensive drug classes 28.
Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease (CAD). Data from pharmacogenetic studies are expected to have great impact in statin therapy. The characteristics of the drugs and the pathophysiological mechanisms of adverse effects are understood from the results of pharmacogenetic and pharmacogenomic studies related to statin therapy 12. Also, exploring genetic variation related to susceptibility to serious adverse events such as myositis, as well as the cost-effectiveness of statin therapy potentially would be of great value. It may be easier to elucidate the genetic variability responsible for variations in drug response than the genetic variabilities responsible for common chronic diseases such as CAD. Data from pharmacogenetic studies are expected to have great impact in the clinical arena in the future and will allow for the identification of persons likely to get the greatest and least benefit from a given intervention 29.
The prevention of cardiovascular disease is critically dependent on lipid-lowering therapy and although, these drugs are generally well tolerated, severe adverse effects can occur in a minority of patients. Furthermore, a subset of patients does not respond to cholesterol-lowering therapy with a reduction in coronary heart disease progression.30The influence of ethnicity on pharmacogenetic responses must be taken into account by performing and comparing clinical trials in various ethnic groups. In the near future, pharmacogenomics may allow the identification of patient subgroups which most likely profit from lipid-lowering therapy. Furthermore, genotyping of high-risk patients may prevent adverse effects in individuals with genetic predisposition 30.
In cardiovascular disease, oral anticoagulants, non-steroidal anti-inflammatory drugs, oral hypoglycemic drugs and other drugs are affected by genetic polymorphisms of the cytochrome P450 drug metabolizing enzyme. Pharmacogenomic studies in patients or healthy volunteers reveal up to 10-fold differences in pharmacokinetic parameters due to genetic polymorphisms. Pharmacogenetics based dose adjustments are one tool to individualize drug treatment according to genetic factors 31.
Warfarin is a commonly prescribed oral anticoagulant for the treatment and prevention of thrombotic diseases. However, warfarin has a narrow therapeutic range and there is greater than 10-fold inter-individual variability in the dose required to attain a therapeutic response. An insufficient dose may fail to prevent thromboembolism, while an overdose increases the risk of bleeding. Warfarin therapy management is challenging for several reasons including the need to determine a safe and effective maintenance dose during the early phase of therapy and the fact that maintenance doses must be adjusted to compensate for changes in patients’ weight, diet, disease state, concomitant use of other medications, and genetic factors. It takes several weeks to achieve a stable warfarin control, thought the risks of overdose and increasing the warfarin induction period still remains. However, recent research has suggested that genetic variation in cytochrome enzymes greatly influences effective warfarin dose. Pharmacogenetic and pharmacogenomic algorithms could potentially minimize the risk of over dose during warfarin induction 32.
3. Central Nervous System (CNS) related conditions
There are ample evidences to suggest that genetic changes in neurotransmitter systems may be important in the pathogenesis of variety of CNS disorders like Alzheimer’s disease, Schizophrenia and Epilepsy. Pharmacotherapy of Alzheimer’s disease (AD) has attracted the interest of both the public and scientific world. The more the enigma of AD unravels, the clearer it seems that a mechanism-based approach to therapy may be a more practical way to disease-modifying discoveries to manage this devastating disease. Pharmacogenomics has a potential to contribute invaluably to the proposed mechanism-based approach (i.e. genotype-based approach) by providing answers not only for familial AD but also for non-familial (sporadic) AD 33.
Although antipsychotic drugs are effective in alleviating schizophrenic symptoms, individual differences in patient response suggest that genetic components play a major role, and pharmacogenetic studies have indicated the possibility for a more individually based pharmacotherapy. Pharmacogenomics aids in understanding how genetics influence disease development and drug response, and contribute to discovery of new treatments. Prospective genotyping of schizophrenic patients for the many genes at the level of the drug target, drug metabolism, and disease pathways will contribute to individualized therapy matching the patient’s unique genetic make-up with an optimally effective drug 34.
There has been very little change in the incidence of pharmacoresistant epilepsy despite the introduction of several new drugs in the last decade. It is becoming increasingly clear that genetic polymorphisms play an integral role in variability in both antiepileptic drug pharmacokinetics and pharmacodynamics. The publication of the human genome and increasing sophisticated and powerful genetic tools offers new methods for screening drugs and predicting deadly idiosyncratic side effects 35. Studies of genetic variation that relate to proteins involved in antiepileptic drug kinetics and dynamics will identify key polymorphisms in the endogenous molecules that determine degrees of drug efficacy and toxicity. Delineation of these effects in the coming years will promote enhanced success in the treatment of epilepsy 36.
4. Respiratory conditions
Pharmacogenetic studies of drugs used in the treatment of asthma have produced a few examples of reduced response in patients carrying specific genotypes in genes. Genotyping for individual pharmacogenetic responses may be useful in establishing an anti-asthmatic therapy. Future objectives include expanded gene knowledge from asthma genetic and genomic studies, the development of new preventive and curative treatments and the construction of asthma functional pharmacogenomic profiles 37. It is likely that in the near future, information regarding individual genetic polymorphisms will allow us to identify those patients most likely to respond, those likely to experience adverse effects from therapeutic interventions in asthma 25.
5. Pharmacogenomics in diagnosis
Single nucleotide polymorphisms (SNPs) within genes affect drug disposition or drug targets. One of the well-characterized examples is highly relevant to inflammatory bowel disease therapeutics, that of thiopurine methyltransferase pharmacogenetics. By using high-throughput SNP genotyping, combined with careful phenotypic characterization of disease, previous term pharmacogenomic next term research carries the potential of identifying individual biomarkers that predict the relative likelihood of benefit or risk from a therapeutic intervention.
6. Miscellaneous
Pharmacogenomics shows promising result in various other areas of therapeutics viz. Immunosuppressive therapy for organ transplant and autoimmune diseases 17, genetic polymorphism of CYP 450 enzymes 38 and recently in the pharmacotherapy of HIV-infection 39.
Pharmacogenomics holds many promises for improved treatment of a large variety of medical conditions, including immunosuppression for organ transplantation and autoimmune disease. The enormous potential of the human genome, if deciphered, can be successfully used within the pharmacogenomic framework for individualizing immunosuppressive therapy based on the patient’s genomic profile 17.
Pharmacogenomics in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors has made it clear that some patients benefit from EGFR therapies and these differential responses are mostly due to the genetic nature 40.
Conclusion
Pharmacogenomics unequivocally have an increasingly important role in drug discovery and development. Pharmacogenomics can potentially lead to better clinical candidates, fewer clinical failures, faster drug development and breakthrough medicine. While it is believed that pharmacogenomics is already delivering these promises, there is still a long way to go and genomics should not be thought of in isolation, it should be used alongside other disciplines by different types of institutions to tackle drug discovery as a multidisciplinary enterprise. However, although pharmacogenetics and pharmacogenomics offer new approaches to an improved healthcare and to targeted care, the cost of the technology is currently very high and it remains to be seen how the pharmaceutical industry will assess the risk–benefit of such technologies.
References
1.One size does not fit all: the promise of Pharmacogenomics. Just the Facts: A Basic Introduction to the Science Underlying NCBI Resources, National center for Biotechnology Information. Available online at: http://www.ncbi.nlm.nih.gov/About/primer/pharm.html
2.Grant, S.F.A. Pharmacogenetics and pharmacogenomics: tailored drug therapy for the 21st century. TRENDS in Pharmacological Sciences, 22, 1, 2001, 3-4.
3.Hughes, J.E. Genomic technologies in drug discovery and development. DDT, 4, 1, 1999, 6.
4.Personalized Medicine - Scientific and Commercial Aspects, Jain PharmaBiotech, Feb. 2007.
5.Daniel W. Nebert, Elliot S. Vesell, Advances in pharmacogenomics and individualized drug therapy: exciting challenges that lie ahead, European Journal of Pharmacology, 500 (2004) 267–280.
6.Personalized Medicine: The Impact of Pharmacogenomics on Pharmaceutical R&D and Sales, Datamonitor, Aug 2002.
7.W.E.Evans & M.V. Relling, Moving towards individualized medicine with pharmacogenomics. Nature, 429, 2004, 464-468.
8.A.D.Roses, How will pharmacogenetics impact the future of research and development? DDT, 6, 2, 2001, 59, 60.
9.A.Pirazzoli & G. Recchia, Pharmacogenetics and pharmacogenomics: are they still promising? Pharmacological Research, 49, 2004, 357–361.
10.N.P.Peet, and P. Bey, Pharmacogenomics: challenges and Opportunities. DDT, 6, 10, 2001, 495-498.
11.A. D. Johnson, D. Wang, W. Sadee et al, Polymorphisms affecting gene regulation and mRNA processing: Broad implications for pharmacogenetics, Pharmacology & Therapeutics 106, 2005, 19–38.
12.P. Amouyel, A critical assessment of the role of pharmacogenomics and pharmacogenetics approaches to cardiovascular diseases, The Pharmacogenomics Journal, 2001, 1, (2), 95-97.
13.The Role of Pharmacogenomics in Personalized Medicine, Decision Resources, Inc., June 2006.
14.Clinical Genomics: The Impact of Genomic Technology on Clinical Trials and Medical Practice, CHA Advances Reports, Jan 2004.
15.Amalia M. Issa, Ethical considerations in clinical pharmacogenomics research, TIPS, 2000, 21.
16.A.Buchanan, Califano A, Kahn J, McPherson E, Robertson J, Brody B. et al, Pharmacogenetics: ethical issues and policy options, Kennedy Institute of Ethics J, 2002,12 (1), 1–15.
17.Y. Yagil, C. Yagil, Insights into pharmacogenomics and its impact upon immunosuppressive therapy, Transplant Immunology 9, 2002, 203–209.
18.World Health Organization. Genomic resource centre; Ethical, legal and social implications (ELSI) of human genomics. Available at: http://www.who.int/genomics/elsi/en/
19.A. Di Paolo, R. Danesi, M. Del Tacca et al, Pharmacogenetics of neoplastic diseases: new trends, Pharmacological Research, 49, 2004, 331–342.
20.A. Loktionov, Common gene polymorphisms, cancer progression and prognosis, Cancer Letters, 208, 2004, 1–33.
21.D. Longley, W. Allen, P. Johnston et al ,Drug resistance, predictive markers and pharmacogenomics in colorectal cancer, Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1766, 2, 184-196.
22.Floris A. de Jong, Maja J.A. de Jonge,Jaap Verweij, Ron H.J. Mathijssen et al. Role of pharmacogenetics in irinotecan therapy, Cancer Letters, 2006, 234, 90–106.
23.G. Bepler, Pharmacogenomics: A reality or still a promise? Lung Cancer, 54, S3-S7.
24.John R. Scheel and Michael D. Kuo, Exploring the Human Genome in Cancer with Genomic Approaches, Journal of Vascular and Interventional Radiology, 2006, 17, 1225-1233.
25.E. Israel, Genetics and the variability of treatment response in asthma, Journal of Allergy and Clinical Immunology, 115, 4 (1), 2005, S532-S538.
26.Sharma P, Fatibene J, Ferraro F, Jia H, Monteith S, Brown C et al, A genome-wide search for susceptibility loci to human essential hypertension, Hypertension 2000, 35, 1291–1296.
27.R. Trotta, M. Benedetta Donati, L. Iacoviello et al, Trends in pharmacogenomics of drugs acting on hypertension, harmacological Research, 49, 2004, 351–356.
28.Donna K. Arnett, Steven A. Claas, Stephen P. Glasser et al, Pharmacogenetics of antihypertensive treatment, Vascular Pharmacology, 44, 2006, 107 – 118.
29.K. Kajinami, H. Akao, E. Polisecki, E. Schaefer, Pharmacogenomics of Statin Responsiveness, The American Journal of Cardiology, 96, 9, 65-70.
30.G. Schmitz, T. Langmann, Pharmacogenomics of cholesterol-lowering therapy, Vascular Pharmacology, 44, 2, 75-89.
31.J. Kirchheiner, A. Seeringer, Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes, Biochimica et Biophysica Acta, 1770, 2007, 489–494.
32. T. Yin, T. Miyata, Warfarin dose and the pharmacogenomics next term of CYP2C9 and VKORC1 — Rationale and perspectives, Thromb Res. , 120 (1), 2007, 1-10.
33.V. Crentsil, The pharmacogenomics of Alzheimer’s disease, Ageing Research Reviews, 3, 2004, 153–169.
34.Kawanishi, H. Tachikawa, T. Suzuki et al, Pharmacogenomics and schizophrenia, European Journal of Pharmacology, 410, 2000, 227–241.
35.Gregory L. Holmes, The interface of preclinical evaluation with clinical testing of antiepileptic drugs: role of pharmacogenomics and pharmacogenetics, Epilepsy Research, 50, 2002, 41–54.
36.Thomas N. Ferraro, Russell J. Buono, The relationship between the pharmacology of antiepileptic drugs and human gene variation: An overview, Epilepsy & Behavior, 7, 2005, 18–36.
37.P. Franco Pignatti, Trends in pharmacogenomics of drugs used in the treatment of asthma, Pharmacological Research, 49, 2004, 343–349.
38.T. Ishizaki, CYP2C pharmacogenetics and tailor-made therapeutic implications, International Congress Series, 1244, 2002, 1–9.
39.Tim R. Cressey, M. Lallemant, Pharmacogenetics of antiretroviral drugs for the treatment of HIV-infected patients: An update, Infection, Genetics and Evolution, 7, 2007, 333–342.
40.A. Jimeno, M. Hidalgo, Pharmacogenomics of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1766, 2, 217-229.
About Authors:
Dr. Vikas Kumar
Dr. Vikas Kumar is native to Faridabad, Haryana and currently serving as Reader in Pharmacology at Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi, U.P. India. Prior to joining BHU, Dr. Kumar was employed as Post Doctoral Research Associate at Texas Tech School of Pharmacy's Pharmaceutical Sciences Department. Dr. Kumar received Ph.D. (Pharmacology) from the IT, BHU, India in year 2001 after obtaining basic degrees in Pharmacy viz. M.Pharm., B.Pharm. and D.Pharm. Dr. Kumar have also worked at R&D Centre of Indian Herbs Ltd., Saharanpur as Scientist-C where he was instrumental in setting up of laboratory devoted to behaviour and other neuropharmacological studies in rodents. After working with India Herbs, Dr. Kumar joined Lupin Research Park, as Research Associate-II based at Pune. There he was one of active team members responsible for performing efficacy studies and documenting the reports for filing Investigational New Drug Application on LL-4218 (an isolated herbal fraction for the treatment of Psoriasis). Dr. Kumar has published more that 40 papers in peer reviewed national and international journals. Dr. Vikas has also published one chapter in an international book ‘Hypericum’ under a series ‘Medicinal and Aromatic Plants-Industrial Profile’ published by Taylor & Francis, London; simultaneously published by Taylor & Francis Inc., New York, USA and Canada (ISBN 0415369541). Dr. Vikas is also member of various reputed professional organisations in India and abroad as well. Dr. Kumar is recipient of Semi Khatib Gold Medal and “Servier Young Investigators’ Award” (1999) instituted by Institutet de Researches Internationales Servier, France. Beside USA, Dr. Vikas have also visited Canada, Germany and France to enhance his professional experience at various capacities. Dr. Kumar can be contacted through e-mail at vikask@bhu.ac.in or neuropharmacologist@rediffmail.com
Mr. G.M. Husain
Gulam Mohammed Husain is native to Najibabad, U.P. and currently pursuing M. Pharm. (Final Year) in Pharmacology from Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi, U.P. India. E-mail: gmhusain@gmail.com
Ms. Radha Ganesan
She is native to Chennai, Tamil Nadu and currently pursuing B.Pharm. (Final Year) from Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi, U.P. India. E-mail: radsganesan@gmail.com