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Role of Pharmacogenomics in Drug Discovery and Development A

Role of Pharmacogenomics in Drug Discovery and Development A

Review Article

Role of in drug discovery and development A. Surendiran, S.C. Pradhan, C. Adithan

ABSTRACT

Pharmacogenetics and pharmacogenomics are two major emerging trends in medical sciences, which influence the success of and therapeutics. In current times, though pharmacogenetic studies are being done extensively for research, its application for drug development needs to get started on a large scale. The major determinants of success of a new drug compound, viz safety and , have become more predictable, with the advent of pharmacogenetic studies. There is a need felt for Department of , pharmacogenomic studies, where the effects of multiple genes are assessed with the study JIPMER, Puducherry, India of entire genome. Pharmacogenetic studies can be used at various stages of drug development. The effect RReceived:eceived: 12.03.2008 of drug target polymorphisms on drug response can be assessed and identified. In RRevised:evised: 13.05.2008 clinical studies, pharmacogenetic tests can be used for stratification of patients based AAccepted:ccepted: 22.08.2008 on their genotype, which corresponds to their metabolizing capacity. This prevents the occurrence of severe adverse drug reactions and helps in better outcome of clinical CCorrespondenceorrespondence to:to: trials. This can also reduce attrition of drug compounds. Further, the variations in Dr. C. Adithan drug response can be better studied with the wider application of pharmacogenomic E-mail: [email protected] methods like genome wide scans, haplotype analysis and candidate gene approaches. The cost of pharmacogenetic testing has become very low, with the advent of newer high throughput genotyping systems. However, the cost of pharmacogenomic methods continues to be very high. As the treatment with several drugs is being more and more pharmacogeneticaly guided (e.g. warfarin and ), the FDA has laid down guidelines for pharmaceutical firms regarding submission of pharmacogenetic data for their drug products in labelling.

KKEYEY WWORDS:ORDS: Drug, genotype, pharmaceuticals, pharmacogenetics, pharmacogenomics

Introduction in therapeutics, can also be utilised in drug discovery and development. In the process of drug discovery, most drug compounds that act on the target during the early phases fail to emerge as Genetic Factors in Drug Effects therapeutic agents. This could be due to unexpected failure of efficacy or occurrence of adverse events. Pharmacogenetics The genetic factors that can affect the drug response involves the study of single gene mutations and their effect include variations in the genes coding for drug metabolizing on drug response. The term pharmacogenomics is much enzymes, receptors and transporters. A classic example of broader and it involves surveying the entire genome to assess genetic polymorphism affecting drug would be several determinants of drug responses.[1] The current status that of the enzyme CYP2C9, which is coded by the polymorphic of pharmacogenomics is restricted to the areas of medical gene CYP2C9. Its variant alleles namely *2 and *3 are poor research and epidemiological studies. metabolizers, with only 12% and 5% respectively of enzyme Many treatment regimens like that of oral anticoagulants and activity, as compared to normal allele *1.[4] Variations in drug cancer chemotherapy are now guided by the pharmacogenetic response due to polymorphism of receptors can be illustrated status of the patient, to avoid as well as treatment with β2 adrenergic receptor polymorphisms, where homozygous failures.[2,3] The traditional method of trial and error in selecting mutants with decreased expression of β2 adrenergic receptors a drug dose is gradually being replaced by pharmacogenetic do not have a predictable response to the use of drugs methods. Pharmacogenetics, which is being utilised currently like salbutamol in asthma.[5,6] Similarly, polymorphisms of

Indian J Pharmacol | Aug 2008 | Vol 40 | Issue 4 | 137-143 137 Surendiran .: Pharmacogenomics and drug development transporters affect drug effects. The promoter region of the or failure of a compound is lack of efficacy, which is followed serotonin transporter gene exists in two forms: short form (sl by safety concerns.[1] This occurs mostly in phase II and phase and ss) and long form (ll). The short form of this polymorphism III of clinical trials. Phase III study, being done on a larger (ss) is associated with decreased clinical response to citalopram scale and on a larger study population, utilises a very large in children or adolescents with depression or anxiety.[7,8] The share of the resources. When a trial is thus ended, the loss variant allele 5HTTLPR-S coexisting with the CYP2C9*3 variant incurred financially as well as in terms of time is unacceptable allele is found to be associated with an even greater risk of major for a pharmaceutical firm. Figure 1 shows the financial losses depressive disorder.[9] incurred by termination of in each phase. Depending upon the nature of the drug being tested, Before the advent of pharmacogenetic studies and these genetic variations can cause either toxicity or failure of proteomics, efficacy and safety concerns were poorly predictable treatment in a clinical trial. Pharmacogenetic methods can in a clinical trial. In current times, the predictability of safety be used to identify these genetic factors.[10,11] When a large and efficacy of a drug has increased to a significant level, as number of patients are to be genotyped, as in a clinical trial, both are influenced by the genetic status of the individual, which high throughput genotyping methods like Amplifluor® and can be assessed by pharmacogenetic studies. TaqMan®[12] can be used at a reasonable cost. Methods like Pharmacogenomics and its Application in Drug haplotype mapping, where more than one genetic variation Development in a single chromosome is studied together, can identify the genetic basis of diseases, as well as newer targets for drug The applications of pharmacogenomics in drug development development.[5] process are briefly given in Table 1. It can be seen that it has a vital role at every key stage of the drug development process. Current Scenario in Drug Discovery and Development Drug target and pharmacogenomics Time factor in drug development The process of drug discovery starts with the identification Drug discovery and development is an elaborate and time of a potential target at which the drug can act. The target can be consuming process. The average time taken from synthesis of an enzyme in a vital pathway, a receptor, a transporter, a a (NCE) to its marketing has increased in signal transduction or any protein produced in a pathological from an average of 7.9 years in 1960 to an average of about 9 condition. After sequencing of the , the number to 12 years in 1990.[13] It includes two major phases, phase I of drug targets was estimated to be around 8000, out of which being the discovery of the drug compound, which is the most 4990 could be actually acted upon - 2329 for antibodies and crucial stage in drug development, and phase II being animal 794 for drug .[15] Based on binding study, 399 and clinical studies followed by marketing. The increase in molecular targets belonging to 130 protein families have time duration can be attributed to the complexity of the clinical been identified.[16] However, currently, the number of targets trials and rigid regulations. Out of five thousand compounds ranges only around 218, though the estimated numbers are evaluated initially during the drug screening process, only five very high.[17] These targets are known to exhibit variations of them enter clinical trials. Of these five drugs, only one gets owing to genetic polymorphisms. Drugs which are based on approved for marketing. targets showing wide polymorphisms can have variations in The process of drug development includes pathway identification and target selection, screening of chemical compounds, drug development, preclinical and clinical studies Figure 1: Potential fi nancial loss with premature termination of a clinical trial and, finally, drug marketing. Cost factor in drug development 70 The total expenditure involved in a drug development and its launch is very high. A study on the 60.6 60 done by DiMasi et al., in 2003, gave an estimate of US $ 802 million in the year 2000, for an NCE development, right up 50 to its marketing. This indicates the resource cost for a firm, and not the effective cost. The capital investment has also been addressed by DiMasi et al. in this study. The estimated 40 capitalised phase cost for an NCE was given as US $ 1.6 million 33.5 30 for animal model testing, 15.2 million for phase I trial, 16.7 27.1 million for phase II and US $ 27.1 million for phase III trials. [14] In a majority of the cases, the termination of a clinical trial 20 16.8 16.7 15.2 occurs during phase II and phase III and the loss of financial Million USD in 2000 dollars resources are high, since millions of dollars have already been 10 utilised. DiMasi has shown that by reducing the clinical phase 1.6 1.6 duration and increasing the success rates, the expenditure for 0 development per NCE is also reduced.[13] P.Cl* Phase I Phase II Phase III

Implications of termination of a clinical trial Cost Invested (DiMasiet al . 2003) Potential loss with termination of trial The most common reason for termination of a clinical trial *Preclinical study

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Table 1

Application of pharmacogenetic/pharmacogenomic methods in various stages of drug development

Stage Application of pharmacogenetics/pharmacogenomics

Drug target Identifi cation Identifi cation and characterisation of the gene coding for the drug target and to assess the variability Phase I clinical trial Patient selection – Inclusion/Exclusion criteria Dose range selection Phase II clinical trial Dose modifi cation Phase III clinical trial Interpretation of trial results based on pharmacogenetic test results Phase IV clinical trial Analysis of reported adverse events with pharmacogenetic tests Regulatory issues Requirements for submission of pharmacogenetic data during development by FDA Patient therapeutics Personalization of drug Pharmacogenetic data in drug labelling Identifi cation of responders and non responders Identifi cation of high risk groups of adverse events

their effect. For example, polymorphism of β2 adrenoceptor drug compound during clinical trials. In current times, the gene, as discussed earlier, has produced responders and non scenario has changed and with the availability of sophisticated responder phenotypes. [7] This can lead to inconsistent results pharmacogenetic tools, the attrition rate can be significantly in the preclinical and clinical studies that would follow if such reduced. This translates into reduction in loss of financial a drug compound is pursued. Such targets can be avoided for resources for drug development. With methods, it can be drug compounds and other suitable targets can be selected. identified during preclinical studies, if the drug is metabolized by Thus, at an early stage, the targets can be characterised based polymorphic enzymes,[19] and a decision regarding continuation on pharmacogenetic studies combined with proteomics and of the trial can be made. Also, this information can help in suitable drug compounds selected for further investment. selecting appropriate patients with normal metabolizing In most cases, variation in drug response in a disease is enzymes in phase I clinical trial; it can also help prevent adverse attributed to many genes rather than a single gene mutation. events.[20] It must be noted that pharmacogenetic principles The results of pharmacogenetic study do not apply when can be used for inclusion or exclusion criteria only when the used clinically, as only single gene mutations are studied metabolic pathway of the drug is known. In cases of exploratory when in fact multiple genes are involved. In such cases, studies, where knowledge regarding the metabolism of the drug more than pharmacogenetic study, it would be appropriate is not known, pharmacogenetic principles cannot be applied for to do pharmacogenomic study comparing single nucleotide selection of subjects in the early phases of studies. However, polymorphism (SNP) maps and gene expression between the acquisition of pharmacogenetic data in the early phases of normal and affected individuals. This can identify the genetic clinical trial can be useful for the later phases. factors associated with the disease and thus provide newer Prediction of efficacy of drug targets to characterise and evaluate, for the purpose of drug In contrast to the conventional methods where . Those that could be potential future drug targets and clinical studies are done with the purpose of determining [1] can be called as “tractable” or “drugable” targets. With the efficacy, drugs designed with pharmacogenomic support availability of advanced human genome sequences, the genes have a predetermined efficacy status. The chance of a drug can now be analyzed for coding regions of the tractable failing in preclinical and clinical studies due to the absence of targets. Polymorphisms of P2Y12 receptors in platelets have efficacy is minimized. The efficacy of a drug, to a great extent, been identified to be associated with increased risk of coronary is determined by appropriate target selection, which can be artery disease by haplotype analysis. In the future, this can guided by pharmacogenomic methods. To cite an example, the be a potential target for a drug compound produced against drug trastuzumab, an anti-HER2 monoclonal antibody against [18] coronary artery disease. Selection of the right target for metastatic breast cancer, was found to be effective only in development of a drug is vital and pharmacogenomics can women who were over expressing the HER2 protein during early play a vital role in it. clinical trials. In the subsequent trials, studies were done only Pharmacogenomics and clinical trials on women found to be over expressing the HER2 protein.[21,22] Pharmacogenomics in clinical trials is a relatively new area The drug got approval for marketing with the requirement of in which considerable hesitation is shown by pharmaceutical testing for HER2 over expression, before starting therapy. Had companies. Incorporation of pharmacogenomic testing with this drug been tested in a whole population without genetic clinical trials has multiple advantages. stratification, the efficacy of the drug would not have been The two most important concerns for new drug development brought out. are efficacy and safety. Before the advent of pharmacogenetic Pharmacogenomics can also be used to identify the target tools, the predictability of both these factors was very low. population that would benefit the most from the drug. A typical This translated into heavy financial loss due to attrition of the example would be association between polymorphisms in the

Indian J Pharmacol | Aug 2008 | Vol 40 | Issue 4 | 137-143 139 Surendiran .: Pharmacogenomics and drug development apolipoprotein E (APOE), cholesteryl ester transfer protein from genetic polymorphism, constitutes only a minor segment, CETP, stromelysin-1 and β-fibrinogen with progression of with very low frequency distribution. In the event of an enzyme atherosclerosis, cardiovascular events and death. It was shown polymorphism occurring in a larger population, the development that people with such polymorphisms derived the maximum of such a drug is avoided by the pharmaceutical firm. benefit from HMG-CoA inhibitors, as compared to those without Another concern would be the cost that the patient would the polymorphisms.[23-26] have to endure for pharmacogenetic testing before starting Prediction of safety of drug therapy, as the drug has been approved for marketing, based The second major concern in a clinical trial is the safety on pharmacogenetic results. The cost of genotyping for single profile of the drug. Data provided by preclinical studies can be nucleotide polymorphisms may not be affordable in many applied to humans only to a certain extent. During a clinical developing and underdeveloped countries. However, with trial, the occurrence of a serious adverse event could jeopardize advancements in technology, this price may come down in the the drug status. Usually, such an event would culminate in the near future. As mentioned earlier, the cost for genotyping 1000 termination of the trial. DNA samples would be at the rate of 0.3 USD per genotype. Drug toxicity occurs mainly due to increased plasma levels of But when the cost is calculated for a single patient sample, it the drug, which may be the result of poor metabolizing capacity amounts to more than 130 USD, as the price for assay marker [27] owing to genetic polymorphisms. Many of the genes (CYP2C9, setup is fixed. Thus it seems, genotyping is cost effective only CYP2C19, CYP2D6, etc) have been intensely studied in various if it is done on a larger scale, which would be the case if it is populations and characterized for various drug groups. The role used for therapeutic testing. of pharmacogenetics in predicting the efficacy of most drugs Pharmacogenetics in patient care is limited, as they are usually dependent on more than one The most commonly applied pharmacogenetic testing for gene. In contrast, the safety of many drugs is, to a great extent, patient care is detection of polymorphisms of genes coding determined by the plasma drug levels, which in turn depends for drug metabolizing enzymes and assisting in dosage upon the drug metabolizing capacity. The drug metabolizing selection or modification. A recent study has shown that enzymes have been identified to exhibit single nucleotide 59% of the drugs that cause adverse effects are metabolized polymorphisms and hence pharmacogenetic approach has a by polymorphic enzymes.[29] There have been reports of better predictability of the safety of a drug. accentuated action of warfarin in patients with increase in The cost of genotyping for SNPs has come down drastically. INR (International Normalized Ratio) at normal doses and on The estimated cost for analyzing 1000 DNA samples for a subsequent pharmacogenetic testing, they were found to be single marker for SNP is 300 USD. This amounts to 0.3 USD per poor metabolizers with *3/*4 and *1/*3 polymorphisms of genotype.[27] With the availability of high throughput genotyping CYP2C9.[2,30,31] As a result of significant association between methods, pharmacogenetic testing can be incorporated into CYP2C9 polymorphisms and warfarin toxicity, the FDA has inclusion criteria for selecting a subject for the trial. Those who approved inclusion of pharmacogenetic data in the product are identified as poor metabolizers of the drug tend to attain a label for warfarin and the warfarin product label now carries higher plasma concentration of the drug, and hence the higher the genetic information.[32] This makes warfarin therapy safer incidence of toxicity. When poor metabolizers are avoided in the during initiation and maintenance of treatment. study, the occurrence of serious adverse events is reduced. For Another potential use of pharmacogenetics is identification example, polymorphisms of UGT1A1 determines the toxicity of population with risk factors not directly related to the response to irinotecan due to its effect on the plasma levels of drug. It has been found that patients with prothrombin gene irinotecan.[28] Thus, the study population can be stratified into mutation have a risk of developing cerebral vein thrombosis groups based on their drug metabolizing capacity and those and when these patients are on oral contraceptive pills, they with diminished capacity can be avoided in the study or given run an even higher risk.[33] This information, when made lower doses of the drug. The drugs can be thus marketed with available, could prevent the occurrence of adverse events pharmacogenetic details along with the product. with oral contraceptives in high risk patients having a genetic Concerns with pharmacogenomics in drug development susceptibility. The reduction in adverse effects reflects upon the protocols safety profile of the drug and in its marketing value. There is When drugs are tested, based on pharmacogenetic profile always a persistent hesitation among pharmaceutical industries of patients and their categorization, it gives the impression to base their drug products on pharmacogenetic testing. This that those with poor metabolizing capacity are being left out. is due to various factors like segmentation of the market based Seen in a broader aspect, it may be noted that this method only on genetic profile and increase in the product and health care brings to light what has not been realized in the pregenomic costs. These factors keep the in a period, where the occurrence of serious adverse events in “wait and see” stance for producing pharmacogenetic data for clinical trials and in clinical practice has been poorly explained. their products. By utilizing pharmacogenetic tools and understanding the Challenges in inclusion of pharmacogenetics in a clinical cause for adverse effects, the drug induced morbidity in poor setting metabolizers can actually be prevented when pharmacogenetics The inclusion of pharmacogenetic data in health care gets linked with clinical practice and drugs are prescribed with delivery poses many more challenges. The knowledge regarding appropriately guided doses. It must also be realized that the the influence of genetics on specific drug response and dose subset of population with poor metabolizing capacity, arising modulation is yet to be imparted to many of the clinicians.

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This is, in fact, a more complicated and challenging issue. approach starts with identification of candidate genes. For a The drug dosage is likely to become complicated with the drug response, candidate genes could be the genes coding for involvement of genetic data. Moreover, the fact that most of the the drug metabolizing enzyme, the proteins involved in the drug patients receive more than one drug for a single disease and transport, the proteins involved in the cellular mechanisms, that many combination exist are likely to make the the receptor proteins etc. The candidate gene is studied for task enormous. Adjustment of drug dosage based on clinical allelic variants. A candidate gene can have more than one parameters like liver and renal function test is well accepted allelic variant or SNP. Candidate gene effects can be studied in and practiced. However, there is hesitation among clinicians case (people with altered drug response) and controls (people to modulate the dose on the basis of the genetic status of the with normal drug response). Candidate gene studies are less individual and they prefer to rely on the clinical parameters. expensive than linkage disequilibrium studies and genome wide This could be due to the hesitation to give up the “trial and scans.[39] A limitation of candidate gene studies is that spurious error” method or unfamiliarity with the genetic principles of association can occur if the case and controls are not adequately drug response.[34] matched. Further, variants in other genes, which are remotely Drug response variability and pharmacogenomics influencing the drug response, cannot be identified. Moreover, a The factors affecting the drug response for a disease level of understanding of the drug response pathway is required are multiple. They can be categorized as unpredictable to identify the candidate genes unlike genome wide scans. (environmental influence, compliance and genetic profile Genome wide scan of the patient) or predictable factors (age, sex, race, body Genome wide scan is a very extensive and elaborate weight, disease state, nutritional status etc). With the advent of study method for effects of various allelic variants occurring pharmacogenetic testing and the human genome breakthrough, throughout the genome and the drug response in a disease the genetic makeup of the patient can now be considered a condition. This method involves identification of all the allelic predictable factor for drug response. However, the predictability variants in the entire human genome and the creation of an based on pharmacogenomic testing may not be absolute, SNP map. This is tested for association with drug response as there are other unpredictable factors also. Yet, with the variation. [40] The advantage of genome wide scan approach, application of pharmacogenomic testing, the drug can be made as compared with the other methods, is that, it can identify relatively more efficacious and safer. The scope of determining the polygenic determinants of drug response. In contrast to drug response variability based on pharmacogenetic testing candidate gene approach, genome wide scan approach does is very limited, as compared to pharmacogenomics. A study not require prior information regarding the drug response done on the polymorphisms of promoter and coding regions pathway in question. This approach increases the translation of β2 adrenoceptors has shown association between the level of genetic testing in clinical response. It is estimated haplotypes and bronchodilator response to salbutamol, whereas that the human genome has approximately three million SNPs no association was seen between individual genotypes of β2 and it is not cost effective to screen all the SNPs. As a result, adrenoceptor and bronchodilator response.[35] Another example only representative SNPs that are distributed evenly across would be the variation in drug response to ACE inhibitors. the genome are selected for testing. This may be in the range Different studies have shown different association between of 200000 to 300000 SNPs per human genome.[41] The SNP the genotypes ACE I/I, ACE I/D and ACE D/D and response maps can be studied for linkage disequilibrium and disease to ACE inhibitors.[36] As per the study done by Cannella et al. or drug response associations. The disadvantages of genome (1998), the genotype of ACE does not predict the effectiveness wide scan approach is that it is very expensive to perform and of ACE inhibitor therapy in reducing the left ventricular mass since a large number of SNPs are mapped, they need to be in chronic uremic patients.[37] Hernandez et al. (2000) have further evaluated, as it is not hypothesis driven like that of the shown a significant reduction in left ventricular mass index in candidate gene approach. renal transplant patients with LVH on treatment with lisinopril Haplotype analysis [38] with ACE D/D genotype. Kohno et al. (1999) have shown Haplotype analysis for drug response variation involves the that patients with ACE D/D genotype are less likely to have study of clusters of SNPs occurring in linkage disequilibrium in a [36] regression of LVH, when treated with ACE inhibitors. Thus, chromosome and their association with the drug response. This is a broader study involving multiple genes or allele variants is different from genome wide scan approach in that only selected needed to understand the intricacies of drug response variability haplotypes are analyzed and not the entire genome. Haplotype and to identify the factors affecting it. The methods which can blocks are created by clustering selective SNPs and their linkage be used for this purpose are candidate gene approach, genome disequilibrium is tested with family studies. The haplotype blocks wide scan approach and haplotypes analysis. are then tested for association with clinical outcomes. Methods of Studying Genetic basis of Drug Response Haplotype analysis provides more information than Variations pharmacogenetic study of single nucleotide polymorphisms and is cost effective. Based on these studies, the various genetic Candidate gene approach determinants of a drug response can be identified and drug Candidate gene approach for identifying genetic determinants development can be customized accordingly. The same methods of drug response variability involves identifying association can be used in clinical trials, to identify high risk groups for between various allelic variants or SNPs within the candidate adverse effects and to derive an explanation for the outliers in gene and the drug response.[39] The method of candidate gene the study group for lack of efficacy.

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Pharmacogenomic data in labeling and their limitations development is advantageous for all sectors, drug industries Pharmacogenomic data may be integrated in the labeling tend to have a difference of opinion among themselves on this of a product. Such data might be useful in identifying patients issue.[45] who require dose adjustments for the prevention of adverse As mentioned above, a well-established pharmacogenetic effects or lack of efficacy. The FDA has approved inclusion of test is required as a valid biomarker for making regulatory pharmacogenetic data in the labelling of drugs like warfarin[32] decisions by the FDA. For a pharmacogenetic test to be accepted and irinotecan,[42] mainly for safety concerns. The inclusion of as a valid biomarker, the test should have a sound scientific pharmacogenetic data for improving the efficacy of a drug is a framework and well established characteristics. An example difficult task to achieve, owing to reasons like low predictability for a valid biomarker in pharmacogenetic tests would be those with pharmacogenetic testing involving single gene mutations for drug metabolizing enzymes as a marker for drug efficacy and the potential compromise of marketing for the product. and safety. Patients with variant alleles of the gene CYP2C9 However, this change in labelling can be productive only if there and VKORC1 require lower doses of warfarin, as compared to are genotyping facilities available, which is yet to happen in patients with normal wild type alleles. This is a valid biomarker many developing countries. It is, however, recommended by and pharmacogenetic data has been incorporated in the drug the FDA that while labelling with pharmacogenetic data, the label for warfarin.[2,30,32] industry should also develop methods of pharmacogenetic The FDA has made submission of a complete pharmacogenetic testing for that biomarker and give complete information about data report mandatory, if these results have been used for the test and its interpretation, and the dose modulation.[43] decision making in the animal study, to support the safety of Although the FDA encourages inclusion of pharmacogenetic the drug, or in clinical trials, for the selection of subjects, dose data in product labels, there are certain limitations of range or its modification. The complete data is also required application of pharmacogenetic methods. The variability in the in cases where the sponsor uses the pharmacogenetic test drug response due to non genetic factors cannot be predicted. results to validate safety, efficacy, dosage selection and Data obtained by genetic testing must be taken only with the in the clinical trials. However, in cases limitation that there are also other factors determining the where such pharmacogenetic test results are not being used response. by the sponsor to support the results of the trial, but the test Ethnic diversity of human population has made it necessary is a valid biomarker for that drug, an abbreviated report of for pharmacogenetic testing to be done in every ethnic group the pharmacogenetic test has to be submitted to the FDA. In for the product to be utilized by that group.[44] In addition to cases where the pharmacogenetic testing has been done as an pharmacogenetic data of various ethnic groups, it is required exploratory study or for research, it is not mandatory to submit that there are pharmacogenetic testing centers in countries such data, as they cannot be considered as valid biomarkers. where the drug is intended to be marketed. This also requires However, the FDA encourages voluntary submission of such that a standard pharmacogenetic testing method is adopted exploratory pharmacogenetic test data. In future, as more uniformly to avoid variation in test results. The cost of testing information becomes available, exploratory pharmacogenetic must be substantially low for the general public. Moreover, the test data will also need to be submitted to the FDA. extent of usage of product labels by clinicians is insufficient to Submission of pharmacogenetic data is beneficial for both make an impact on patient therapeutics. Clinicians may hesitate the sponsor as well as the FDA. This can help in familiarizing to use a product that requires pharmacogenetic testing, as it the FDA with pharmacogenetic principles and thus reduce would incur additional cost for the patient. This highlights the unnecessary delay in reviewing future submissions where need for imparting relevant knowledge to the clinicians on how pharmacogenetic testing has been used as an integral part of the to modulate therapeutics based on pharmacogenetic data. Until drug development. Also, sponsors get to meet the FDA experts this goal is achieved, a pharmaceutical firm would restrain itself informally, discuss scientific data and get their peer opinion. The from using pharmacogenomics in drug development. sponsor can use the pharmacogenetic test results to support [46] FDA, Pharmacogenomics and drug development the safety and efficacy of the drug compound. The FDA has provided certain guidelines for submission of Conclusion pharmacogenetic test data by the pharmaceutical industries, as a part of drug development.[43] As most of the pharmacogenetic Pharmacogenomics in pharmaceutical industry is a test results are not well-established scientifically, such potential tool, awaiting use for the maximum benefit. Currently studies cannot be used by the FDA for regulatory decisions. pharmacogenetic methods are being used worldwide, Currently, the FDA has made submission of pharmacogenetic particularly for assessing the safety profile of drugs. Translation data mandatory for specific cases and supports voluntary of the pharmacogenetic test results into clinical practice has submission for other specific cases, which are described below. been possible only for a small fraction of the total number Guidelines have also been released pertaining to the time when of pharmacogenetic studies done. As the need for analysis a complete pharmacogenetic report is to be submitted and when of multiple genes has been realised, haplotype analysis and an abbreviated report is to be submitted. Further, there are genome wide scan methods were designed. However, with separate guidelines for submission of pharmacogenetic data the current cost of analysis for one SNP, haplotype analysis for applications and unapproved and and genome wide scans will not enter clinical practice for approved marketing applications. However, even though the testing in patients. Yet, these methods can be utilized by the FDA is of the opinion that pharmacogenomic integration in drug pharmaceutical industry for their drug development process.

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Gradual inclusion of pharmacogenomic studies in drug clinical program in HER2-overexpressing metastatic breast cancer: Herceptin discovery and development will cause substantial reduction Multinational Investigator Study Group. Semin Oncol 1999;26:71-7. 23. de Maat MP, Jukema JW, Ye S, Zwinderman AH, Moghaddam PH, Beekman M, in the expenses involved in drug development, ensure a safe et al. Effect of the stromelysin-1 promoter on effi cacy of pravastatin in coronary clinical trial and reduce failures. Thus, many potential drugs atherosclerosis and restenosis. Am J Cardiol 1999;83:852-6. which may be lost due to the effects on the outliers in a study 24. Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen C, Hansen PS et can be retained when pharmacogenomic study is used in the al. The apolipoprotein epsilon4 allele determines prognosis and the effect on future. prognosis of simvastatin in survivors of myocardial infarction: A substudy of the Scandinavian simvastatin survival study. Circulation 2000;101:1366-71. 25. Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, References Bruschke AVG, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis: The Regression 1. McCarthy AD, Kennedy JL, Middleton LT. Pharmacogenetics in drug development. Growth Evaluation Study Group. N Engl J Med 1998;338:86-93. Philos Trans R Soc Lond B Biol Sci 2005;360:1579-88. 26. Ordovas JM, Lopez-Miranda J, Perez-Jimenez F, Rodriguez C, Park JS, Cole T, et 2. Lee SY, Nam MH, Kim JS, Kim JW. A case report of a patient carrying CYP2C9*3/4 al. Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein genotype with extremely low warfarin dose requirement. J Korean Med Sci response to HMG CoA reductase inhibitor therapy. Atherosclerosis 1995;113:157- 2007;22:557-9. 66. 3. Yong WP, Innocenti F, Ratain MJ. The role of pharmacogenetics in cancer 27. Preventiongenetics. Research genotyping. [webpage in internet] 2008, Feb 29. therapeutics. Br J Clin Pharmacol 2006;62:35-46. Available from: http://www.preventiongenetics.com/resgeno/ listofprices.htm. 4. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR. Impaired [cited on 2008 Mar 6]. (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. 28. Mani S. UGT1A1 polymorphism predicts irinotecan toxicity: Evolving proof. AAPS Pharmacogenetics 1994;4:39-42. PharmSci 2001;3:2. 5. Tsai CT, Fallin D, Chiang FT, Hwang JJ, Lai LP, Hsu KL, et al. Angiotensinogen 29. Huang SM, Goodsaid F, Rahman A, Frueh F, Lesko LJ. Application of gene haplotype and hypertension: interaction with ACE gene I allele. Hypertension pharmacogenomics in clinical pharmacology. Toxicol Mechanisms Met 2003;41:9-15. 2006;16:89-99. 6. Turki J, Pak J, Green SA, Martin RJ, Liggett SB. Genetic polymorphisms of the 30. Lee SY, Kim JS, Kim JW. A case of intolerance to warfarin dosing in an intermediate beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma: Evidence that metabolizer of CYP2C9. Yonsei Med J 2005;46:843-6. Gly16 correlates with the nocturnal phenotype. J Clin Invest 1995;95:1635-41. 31. Shi MM, Bleavins MR, de la Iglesia F. Pharmacogenetic application in drug 7. Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB. The serotonin development and clinical trials. Drug Metab Dispos 2001;29:591-5. transporter polymorphism, 5HTTLPR, is associated with a faster response 32. Gage BF, Lesko LJ. Pharmacogenetics of warfarin: Regulatory, scientifi c, and time to sertraline in an elderly population with major depressive disorder. clinical issues. J Thromb Thrombolysis 2008;25:45-51. (Berl) 2004;174:525-9. 33. Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of 8. Kronenberg S, Apter A, Brent D, Schirman S, Melhem N, Pick N, et al. Serotonin cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users Transporter Polymorphism (5-HTTLPR) and Citalopram Effectiveness and Side of oral contraceptives. N Engl J Med 1998;338:1793-7. Effects in Children with Depression and/or Anxiety Disorders. J Child Adolesc 34. Relling MV, Giacomini KM. Pharmacogenetics. In: Laurence LB, John SL, Keith Psychopharmacol 2007;17:741-50. LP, editors. Goodman & Gilmans’ The pharmacological basis of therapeutics. 9. Dorado P, Peñas-Lledó EM, González AP, Cáceres MC, Cobaleda J, Llerena 11th ed. New Delhi: McGrawHill 2005; p. 93-115. A. Increased risk for major depression associated with the short allele of the 35. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, serotonin transporter promoter region (5-HTTLPR-S) and the CYP2C9*3 allele. et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes Fundam Clin Pharmacol 2007;21:451-3. alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci 10. Dubey AK, Subish PP, Ravi SP, Prabhu M, Bista D, Khadka CA. Understanding U S A 2000;97:10483-8. the essentials of pharmacogenomics- the potential implications for the future 36. Kohno M, Yokokawa K, Minami M, Kano H, Yasunari K, Hanehira T, et al. pharmacotherapy. J Clin Diagn Res 2008;2:681-9. Association between angiotensin-converting enzyme gene polymorphisms and 11. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between regression of left ventricular hypertrophy in patients treated with angiotensin- genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in converting enzyme inhibitors. Am J Med 1999;106:544-9. children with and without a history of wheezing. J Clin Invest 1997;100:3184-8. 37. Cannella G, Paoletti E, Barocci S, Massarino F, Delfi no R, Ravera G, et al. 12. Tsuchihashi Z, Dracopoli NC. Progress in high throughput SNP genotyping Angiotensin-converting enzyme gene polymorphism and reversibility of uremic methods. Pharmacogenomics J 2002;2:103-10. left ventricular hypertrophy following long-term antihypertensive therapy. Kidney 13. Dickson M, Gagnon JP. The cost of new drug discovery and development. Discov Int 1998;54:618-26. Med 2004;4:172-9. 38. Hernandez D, Lacalzada J, Salido E, Linares J, Barragan A, Lorenzo V, et al. 14. DiMasi JA, Hansen RW, Grabowski HG. The price of : new estimates Regression of left ventricular hypertrophy by lisinopril after renal transplantation: of drug development costs. J Health Econ 2003;22:151-85. Role of ACE gene polymorphism. Kidney Int 2000;58:889-97. 15. Burgess J, Golden J. Cracking the druggable genome. Bio-IT World [online] 2002 39. Kwon JM, Goate AM. The candidate gene approach. Alcohol Res Health [cited 2008 March 7] Available from: http:// www.bio-itworld. com/archive/100902 2000;24:164-8. /fi rstbase.html. 40. Roses AD. Pharmacogenetics and the practice of . Nature 2000;405:857- 16. Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov 2002;1:727- 65. 30. 41. Johnson JA. Drug target pharmacogenomics: An overview. Am J 17. Imming P, Sinning C, Meyer A. Drugs, their targets and the nature and number Pharmacogenomics 2001;1:271-81. of drug targets. Nat Rev Drug Discov 2006;5:821-34. 42. Innocenti F, Ratain MJ. Pharmacogenetics of irinotecan: Clinical perspectives on 18. Cavallari U, Trabetti E, Malerba G, Biscuola M, Girella D, Olivieri O, et al. Gene the utility of genotyping. Pharmacogenomics 2006;7:1211-21. sequence variations of the platelet P2Y12 receptor are associated with coronary 43. Guidance for industry. Pharmacogenomic data submission [pdf document in artery disease. BMC Med Genet 2007;8:59. internet] 2005. Available from http://www.fda.gov/ Cber/gdlns /pharmdtasub.htm. 19. Birkett DJ, Mackenzie PI, Veronese ME, Miners LO. In vitro approaches can [cited on 2008 Feb 29]. predict human . Trends Pharmacol Sci 1993;14:292-4. 44. Rosemary J, Adithan C. The Pharmacogenetics of CYP2C9 and CYP2C19: ethnic 20. Abraham BK, Adithan C. Genetic polymorphism of CYP2D6. Indian J Pharmacol variation and clinical signifi cance. Curr Clin Pharmacol 2007;2:93-109. 2001;33:147-69. 45. Little S. The impact of FDA guidance on pharmacogenomic data submissions on 21. Monica RP, Snehal G. Pharmacogenomics and modern therapy. Indian J Pharm drug development. I Drugs 2005;8:648-50. Sci 2007;69:167-72. 46. Bullock PL. Pharmacogenetics and its impact on drug development. Drug Benefi t 22. Shak S. Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody Trends 1999;11:53-4.

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