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Application of Pharmacogenomics on Drug Discovery and Development

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Application of Pharmacogenomics on Drug Discovery and Development CONTINUING PROFESSIONAL CONTINUINGDEVELOPMENT MEDICAL EDUCATION Akreditasi PP IAI–2 SKP Application of Pharmacogenomics on Drug Discovery and Development Ratih Dewi Yudhani Pharmacology Departement, Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia ABSTRACT Individual variations in the response to drugs and drug toxicity occur commonly in the clinical setting and in drug development research protocols. Cumulative evidence strongly suggests that genetic polymorphisms in drug metabolizing enzymes, transporters, receptors and other drug targets are contributing to inter-individual diff erences in the effi cacy and toxicity of drugs. Pharmacogenomics refers to the application of genome-wide approaches in order to understand genetic infl uence on drug response and to develop novel drugs. This application of pharmacogenomics has implications in predicting a patient’s response to medications, reducing adverse events and improving rationality of drug development. Pharmacogenomics profoundly change the way clinical drug trials are conducted, as well as infl uencing drug development process. This review provides an overview of the pharmacogenomics application on drug discovery and development. Key words: Pharmacogenomics, drug, discovery, development ABSTRAK Variasi respons individual dan toksisitas terhadap obat sering ditemui di klinik dan selama proses penelitian dan pengembangan obat baru. Beberapa bukti jelas mengindikasikan bahwa polimorfi sme genetik pada gen-gen yang meregulasi ekspresi enzim yang terkait dengan metabolisme obat, transporter, reseptor, dan target obat yang lain, berperan dalam menentukan perbedaan efi kasi dan toksisitassuatu obat di antara individu. Farmakogenomik mengacu pada aplikasi genomik untuk memahami pengaruh genetik pada respons obat dan aplikasinya dalam proses penelitian dan pengembangan obat baru. Farmakogenomik dapat diaplikasikan untuk memprediksi respons individu terhadap pengobatan, mengurangi kejadian yang tidak diinginkan terkait dengan pemberian obat dan meningkatkan rasionalitas dalam proses pengembangan obat. Karena itu, farmakogenomik menyebabkan pergeseran paradigma terkait penelitian dalam rangka penemuan obat baru di tahap preklinik dan bagaimana perancangan uji klinis obat. Tinjauan ini memberi gambaran aplikasi farmakogenomik pada proses penelitian dalam rangka penemuan dan pengembangan obat baru. Ratih Dewi Yudhani. Aplikasi Farmakogenomik dalam Penemuan dan Pengembangan Obat. Kata kunci: Farmakogenomik, obat, penemuan, pengembangan INTRODUCTION Although ‘pharmacogenomics’ and the older drug discovery research and the development Pharmacogenomics is a science of determining term ‘pharmacogenetics’ are often used process, and are improving the strategies how genetic variability infl uences physiological interchangeably, pharmacogenomics is of medical care. The Human Genome and responses to drugs, from absorption and broader in scope, and refers to the complex International HapMap project has opened metabolism to pharmacologic action and interactions of genes across the genome. the chance for new generation of diagnostics therapeutic eff ects.1 Pharmacogenomics Pharmacogenomics includes identifying tools aimed at identifi ying and characterizing refers to the application of genome-wide candidate genes and polymorphisms, human diversity. In particular, they have approaches in order to understanding genetic correlating these polymorphisms with possible provided a large resources of SNPs that infl uences on drug response and to developing therapies, predicting drug response and explain much of variation between diff erent novel drugs. Historically, pharmacogenetics clinical outcomes, reducing adverse events individuals and diff erent ethnic groups. studies were developed initially to and selecting dosing of therapeutic drugs on The diff erences in response to medications understand individual diff erences in drug the basis of genotype.3 are often greater amongst members of a pharmacokinetics and metabolism, and were population than they are within the same often focused on single gene polymorphisms In the 21st century, emerging genome science person or between monozygotic twins. The (SNPs), especially in drug metabolism genes.2 and technologies are shifting the paradigm of existence of large population diff erences with Alamat korespondensi email: [email protected] CDK-214/ vol. 41 no. 3, th. 2014 181 CONTINUING PROFESSIONAL DEVELOPMENT small intra-patient variability is consistent with the idea of genetic inheritance as a determinant of drug response.4 The source of individual variation in response to drugs may be SNPs or mutations.5 SNPs are abundant in the human genome and may aff ect the pharmacokinetics and pharmacodynamics of a drug.6 Cumulative evidence strongly suggests that genetics polymorphisms in drug metabolizing enzymes, transporters, receptors and other drug targets are contributing to inter individual diff erences in the effi cacy and toxicity of drugs.4 Individuals respond diff erently to drugs and sometimes the eff ects are unpredictable. The use of pharmacogenomics is to identify genetic polymorphisms that predispose patients to adverse drug eff ects, although Figure 1 Pharmacogenomics involment in the drug discovery and development process they may occur in only a small subset of the Abbreviation people treated with a new drug. Given the FTIH : First in Human GCP : Good Clinical Practice potential value of knowing all the possible POC : Proof of Concept GPMSP : Good Post-Marketing Surveillance Practice factors that infl uence the eff ects of new Reg : Regulatory assessment PK : Pharmacokinetics agents, it is likely that pharmacogenomics will LCM : Life CycleManagement have an increasingly important role in drug discovery and development.7 This paper is during clinical trials. In current times, the in a vital pathway, a receptor, a transporter, a addressing the pharmacogenomics and its scenario has changed and with the availability protein in signal transduction or any protein application in the process of drug discovery of sophisticated pharmacogenetic tools, the produced in a pathological condition. After and development. attrition rate can be signifi cantly reduced. sequencing of the human genome, the This will be translated into reduction in loss number of drug target was estimated to be DISCUSSION of fi nancial resources for drug development. around 8000 and 4990 out of which could The process of drug development includes With in vitro methods, it can be identifi ed be actually acted on.12 These targets are pathway identifi cation and target selection, during preclinical studies, whether the drug known to exhibit variations owing to genetic screening of chemical compounds, drug is metabolized by polymorphic enzymes, and polymorphisms, and drugs which are based development, preclinical and clinical studies, a decision regarding continuation of the trial on targets showing wide polymorphisms and also drug marketing.8 The promise of can be made. This information can also help can have variations in their eff ect13. This can pharmacogenomics is that it will solve two in selecting appropriate patients with normal lead to inconsistent results in the preclinical major problems in healthcare, the diminishing metabolizing enzymes in phase I clinical trial, and clinical studies. Thus, the targets can be productivity of the drug development process it can also help prevent adverse events.10,11 characterised based on pharmacogenetic and the unacceptably high proportion of studies and suitable drug compounds selected patients who receive either no benefi ts The implementation of pharmacogenomics for further investment at an early stage.8 from drugs or experience adverse events. Its in effi cacy and safety studies has impacted proponents suggest that pharmacogenomics a broad spectrum of drug discovery and In most cases, variation in drug response will be part of a fundamental transformation in development activities. Figure 1 shows in a disease is attributed to many genes the drug discovery and development process, a framework for the application of the rather than a single gene mutation. In while current clinical trials are designed to pharmacogenomics process at various stages such cases, it would be appropriate to do a observe eff ects in populations rather than to throughout drug discovery including target pharmacogenomic study comparing SNPs give information on inter individual variation and candidate selection, clinical development, maps and gene expression between normal in drug response.9 drug approval and life cycle management and aff ected individuals to identify the genetic (LCM).4 factors associated with the disease, and thus The two most important concerns for new provide newer targets of drug development. drug development are effi cacy and safety. 1. Pharmacogenomics and Drug Target Potential future drug targets can be called Before the advent of pharmacogenetic tools, Selection as “tractable” or “drugable” targets.14 Novel the predictability of both these factors was very The process of drug discovery starts with the approaches for high throughout experiments low. This will be translated into heavy fi nancial identifi cation of a potential target at which to discern associations between disease and loss due to attrition of the drug compound the drug can act. The target can be an enzyme disease traits with large numbers of tractable 182 CDK-214/ vol. 41 no. 3, th. 2014 CONTINUING PROFESSIONAL DEVELOPMENT Table 1 Phases of clinical development
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