Priorities and standards in pharmacogenetic research (original) (raw)

A perspective on Pharmacogenetics and Pharmacogenomics

2013

"Pharmacogenetics is the study of variability in drug response and toxicity due to genetic factors. Pharmacogenomics applies the information gained by pharmacogenetics to the development of medications. The field of pharmacogenomics has led to the development of genotyping technologies which has allowed for wider screening for inherited causes of variable outcomes following drug administration."

Pharmacogenomics and Pharmacogenetics

2008

Pharmacogenetics describes the impact of a person's genetic make-up on drug action or response. Genetic variability is a major factor contributing to inter-individual variability in drug response, toxicity and side effects. The impact of genetic variability is evident not only on drug pharmacokinetics, via altered absorption, distribution and elimination processes, but also on drug pharmacodynamics, via altered drug targets. This chapter will commence with some definitions and terminology, a brief overview of genetics and the link to medicines/drugs, a history of pharmacogenetics. It will also deal with the

Pharmacogenetics: Genetic basis for rational drug therapy

Indian Journal of Pharmaceutical Sciences, 2007

Pharmacogenetics has revolutionized the way in which drug metabolism was looked upon in the pre-genomic era. Today with the advent of genomics it is possible to genotype an individual. The genetic differences, which determine the disposition of a given drug in an individual, ultimately give differences in drug response. Genotyping and phenotyping tests to predict dose requirement are now increasingly introduced during preclinical and clinical studies of new drugs. However, the hypothesis for the genotype and the phenotype correlation has to be established. Once this correlation will be established and technology to genotype advances enough to give predictive values over 90%, pharmacogenetics will enter the clinics. Pharmacogenetics will help to tailor the drug type and its dosage according to the individual's genotype. It will help to minimize adverse drug reactions as well as cases of nonresponders to the drug therapy. In addition, this will provide better understanding of pharmacogenetic variations both within as well as among major populations/groups of the world.

Pharmacogenetics: An Important Part of Drug Development with A Focus on Its Application

International Journal of Biomedical Investigation , 2018

Since the human genome project in 2003, the view of personalized medicine to improve diagnosis and cure diseases at the molecular level became more real. Sequencing the human genome brought some benefits in medicine such as early detection of diseases with a genetic predisposition, treating patients with rare diseases, the design of gene therapy and the understanding of pharmacogenetics in the metabolism of drugs. This review explains the concepts of pharmacogenetics, polymorphisms, mutations, variations, and alleles, and how this information has helped us better understand the metabolism of drugs. Multiple resources are presented to promote reducing the gap between scientists, physicians, and patients in understanding the use and benefits of pharmacogenetics. Some of the most common clinical examples of genetic variants and how pharmacogenetics was used to determine treatment options for patients having these variants were discussed. Finally, we evaluated some of the challenges of implementing pharmacogenetics in a clinical setting and proposed actions to be taken to make pharmacogenetics a standard diagnostic tool in personalized medicine.

Fundamentals and applications of pharmacogenetics for the clinical laboratory

PubMed, 1999

Metabolism and disposition of foreign compounds, including pharmaceuticals, is dependent upon a host of factors. However, a genetic basis for individuality in drug metabolism has long been recognized and more recently has been confirmed. It is now well understood that a finite number of inherited sequence variants (alleles) of genes encoding drug-metabolizing enzymes give rise to discrete drug metabolism phenotypes. This primer in pharmacogenetics will introduce the clinical laboratorian to the mechanistic basis underlying the influence of genetics on pharmacology. We begin with an overview of pharmacology and introduce the importance of protein structure in maintaining steady-state drug concentrations. After review of fundamental concepts related to drug-metabolizing enzymes and genetics, we then give examples of how discrete genetic variations (polymorphism) alter the response (phenotype) to certain therapeutics in select individuals. We conclude with several analytical and interpretive considerations which must be considered by laboratories offering pharmacogenetic services.

Clinical Pharmacogenetics and Potential Application in Personalized Medicine

Current Drug Metabolism, 2008

The current 'fixed-dosage strategy' approach to medicine, means there is much inter-individual variation in drug response. Pharmacogenetics is the study of how inter-individual variations in the DNA sequence of specific genes affect drug responses. This article will highlight current pharmacogenetic knowledge on important drug metabolizing enzymes, drug transporters and drug targets to understand interindividual variability in drug clearance and responses in clinical practice and potential use in personalized medicine. Polymorphisms in the cytochrome P450 (CYP) family may have had the most impact on the fate of pharmaceutical drugs. CYP2D6, CYP2C19 and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in phase I metabolism of drugs since nearly 80% of drugs in use today are metabolised by these enzymes. Approximately 5% of Europeans and 1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant drug metabolising enzyme that demonstrates genetic variants. Studies into CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and CYP2C9*3 alleles. Extensive polymorphism also occurs in a majority of Phase II drug metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyl transferases (TPMT) that catalyzes the S-methylation of thiopurine drugs. With respect to drug transport polymorphism, the most extensively studied drug transporter is P-glycoprotein (P-gp/MDR1), but the current data on the clinical impact is limited. Polymorphisms in drug transporters may change drug's distribution, excretion and response. Recent advances in molecular research have revealed many of the genes that encode drug targets demonstrate genetic polymorphism. These variations, in many cases, have altered the targets sensitivity to the specific drug molecule and thus have a profound effect on drug efficacy and toxicity. For example, the 2-adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically significant genetic variation in drug targets. The variable number tandem repeat polymorphisms in serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. The distribution of the common variant alleles of genes that encode drug metabolizing enzymes, drug transporters and drug targets has been found to vary among different populations. The promise of pharmacogenetics lies in its potential to identify the right drug at the right dose for the right individual. Drugs with a narrow therapeutic index are thought to benefit more from pharmacogenetic studies. For example, warfarin serves as a good practical example of how pharmacogenetics can be utilized prior to commencement of therapy in order to achieve maximum efficacy and minimum toxicity. As such, pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and licensed drugs.

Pharmacogenetics in clinical practice

The availability of data from pharmacogenetic studies is reflected in therapeutic practice, and pharmacogenetics is slowly entering the medical arena. Preconditions for the utilisation of pharmacogenetic knowledge are that: 1) genetic variation and prevalence are known 2) pharmacological consequences (concerning efficacy or toxicity) are known 3) clinical relevance is demonstrated 4) data from pharmacogenetic studies are translated in to practical guidelines 5) knowledge and techniques are available.

Pharmacogenetic and Pharmacogenomic Studies Impact on Drug Discovery and Drug Development

Therapie, 2003

The topics discussed in this article are concerned with studying genomic polymorphism and identifying new therapeutic targets, the role of genetics in preclinical and clinical drug development, and cultural, regulatory and logistical aspects of the development of pharmacogenetics in France. The conclusions are that from a physiological, biochemical or genomic point of view, the study of human genetic polymorphism has obvious potential value for drug development, because it can help to identify new therapeutic targets, and to predict drug efficacy and tolerability more effectively. There are already several examples of the latter approach, which relies on studying the genetic variability of enzymes involved in drug metabolism, and that of the effector molecules of the pharmacological activity. Pharmacogenetics could eventually make it possible to personalise drug treatments, as methods for analysing genes are simplified and their cost reduced. To help attain this still far-off goal, certain recommendations have been proposed.