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Pharmacogenomics Mar 2002
Review
Topics: Forecasting; Humans; Pharmacogenetics; Reproducibility of Results; Sensitivity and Specificity
PubMed: 11972438
DOI: 10.1517/14622416.3.2.157 -
Clinical Genetics Oct 1999Adverse drug reactions, due at least in part to interindividual variability in drug response, rank between the 4th and 6th leading causes of death in the USA. The field... (Review)
Review
Adverse drug reactions, due at least in part to interindividual variability in drug response, rank between the 4th and 6th leading causes of death in the USA. The field of 'pharmacogenetics', which is 'the study of variability in drug response due to heredity', should help in reducing drug-caused morbidity and mortality. The recently coined term 'pharmacogenomics' usually refers to 'the field of new drug development based on our rapidly increasing knowledge of all genes in the human genome'. However, the two terms - pharmacogenetics and pharmacogenomics - are often used interchangeably. A classification of more than five dozen pharmacogenetic differences is presented here. Most of these variations occur in drug-metabolizing enzyme (DME) genes, with some presumed to exist in the DME receptor and drug transporter genes, and others have not yet been explained on a molecular basis. A method for unequivocally defining a quantitative phenotype (drug efficacy, toxicity, etc.) is proposed; this is where help from the clinical geneticist can be especially important. Our current appreciation of the degree of variability (including single-nucleotide polymorphisms, SNPs) in the human genome is described, with emphasis on the need to prove that a particular genotype is indeed the cause of a specific phenotype; this topic has been termed 'functional genomics'. Furthermore, the current amount of admixture amongst almost all ethnic groups will obviously make studies of gene-drug interactions more complicated, as will the withholding of ethnic information about DNA samples during any molecular epidemiologic study. DME genes and DME receptor and drug transporter genes can be regarded as 'modifier genes', because they influence disorders as diverse as risk of cancer, bone marrow toxicity resulting from occupational exposure, and Parkinson's disease; for this reason, the clinical geneticist, as well as the medical genetics counselor, should be knowledgeable in the rapidly expanding fields of pharmacogenetics and pharmacogenomics.
Topics: Enzymes; Genome, Human; Genotype; History, 20th Century; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable
PubMed: 10636440
DOI: 10.1034/j.1399-0004.1999.560401.x -
Pharmacogenomics Dec 2005
Topics: Drug Industry; Pharmacogenetics; Pharmacokinetics
PubMed: 16296941
DOI: 10.2217/14622416.6.8.793 -
Pharmacogenomics Aug 2008Etanercept is one of several TNF inhibitors approved for rheumatoid arthritis (RA) and a variety of other immune-mediated inflammatory conditions. Given the plethora of... (Review)
Review
Etanercept is one of several TNF inhibitors approved for rheumatoid arthritis (RA) and a variety of other immune-mediated inflammatory conditions. Given the plethora of drugs approved for RA, and the wide variations in cost and treatment response, markers of efficacy would be very useful. Several candidate genes, including HLA-DRB1 alleles and those encoding TNF, TNF receptors and Fc receptors, have been examined for a role in the response to treatment with etanercept. In this review, we discuss pharmacogenetic studies of etanercept in RA and other diseases, and comment on the future of such analyses to advance the goal of personalized medicine in RA.
Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Etanercept; Humans; Immunoglobulin G; Pharmacogenetics; Receptors, Tumor Necrosis Factor
PubMed: 18681777
DOI: 10.2217/14622416.9.8.1011 -
Nature Reviews. Drug Discovery Aug 2005Although considerable progress has been made in basic pharmacogenetic research, less has been demonstrated in the application of pharmacogenetics (PGx)-based diagnostics... (Review)
Review
Although considerable progress has been made in basic pharmacogenetic research, less has been demonstrated in the application of pharmacogenetics (PGx)-based diagnostics to drug development and in clinical practice. There are drugs that are currently used in the clinic for which individualized therapy could be beneficial based on PGx data. However, specific, actionable recommendations on how to implement individualized therapy--particularly with respect to dosage--still have to be developed. Moreover, to apply PGx efficiently in clinical drug development, and later in drug therapy, study designs and the generation and handling of PGx data need to become more standardized. Here, we argue for the development of concise guidelines for implementation of PGx analyses in drug development and therapy.
Topics: Clinical Trials as Topic; Drug Industry; Drug Therapy; Humans; Pharmacogenetics; Practice Patterns, Physicians'; Terminology as Topic
PubMed: 16056390
DOI: 10.1038/nrd1801 -
Journal of Psychosocial Nursing and... Dec 2012Understanding pharmacogenetic differences in drug response and tolerability has been an important area of research in personalized medicine, but the clinical utility of... (Review)
Review
Understanding pharmacogenetic differences in drug response and tolerability has been an important area of research in personalized medicine, but the clinical utility of pharmacogenetics testing has not been established. Identification of genetic polymorphisms due to single nucleotide polymorphisms is the most common approach, but this does not take into account the potential relevance of copy number variants, noncoding RNA gene regulation, gene-gene and gene-interactions, and epigenetic modifications, which increase the complexity of pharmacogenomics research.
Topics: Animals; DNA Copy Number Variations; Epigenomics; Epistasis, Genetic; Gene Expression Regulation; Genome, Human; Humans; Mental Disorders; Pharmacogenetics; Polymorphism, Single Nucleotide; Precision Medicine; Psychotropic Drugs
PubMed: 23457712
DOI: 10.3928/02793695-20121114-01 -
Philosophical Transactions of the Royal... Aug 2005Pharmacogenetic factors operate at pharmacokinetic as well as pharmacodynamic levels-the two components of the dose-response curve of a drug. Polymorphisms in drug... (Review)
Review
Pharmacogenetic factors operate at pharmacokinetic as well as pharmacodynamic levels-the two components of the dose-response curve of a drug. Polymorphisms in drug metabolizing enzymes, transporters and/or pharmacological targets of drugs may profoundly influence the dose-response relationship between individuals. For some drugs, although retrospective data from case studies suggests that these polymorphisms are frequently associated with adverse drug reactions or failure of efficacy, the clinical utility of such data remains unproven. There is, therefore, an urgent need for prospective data to determine whether pre-treatment genotyping can improve therapy. Various regulatory guidelines already recommend exploration of the role of genetic factors when investigating a drug for its pharmacokinetics, pharmacodynamics, dose-response relationship and drug interaction potential. Arising from the global heterogeneity in the frequency of variant alleles, regulatory guidelines also require the sponsors to provide additional information, usually pharmacogenetic bridging data, to determine whether data from one ethnic population can be extrapolated to another. At present, sponsors explore pharmacogenetic influences in early clinical pharmacokinetic studies but rarely do they carry the findings forward when designing dose-response studies or pivotal studies. When appropriate, regulatory authorities include genotype-specific recommendations in the prescribing information. Sometimes, this may include the need to adjust a dose in some genotypes under specific circumstances. Detailed references to pharmacogenetics in prescribing information and pharmacogenetically based prescribing in routine therapeutics will require robust prospective data from well-designed studies. With greater integration of pharmacogenetics in drug development, regulatory authorities expect to receive more detailed genetic data. This is likely to complicate the drug evaluation process as well as result in complex prescribing information. Genotype-specific dosing regimens will have to be more precise and marketing strategies more prudent. However, not all variations in drug responses are related to pharmacogenetic polymorphisms. Drug response can be modulated by a number of non-genetic factors, especially co-medications and presence of concurrent diseases. Inappropriate prescribing frequently compounds the complexity introduced by these two important non-genetic factors. Unless prescribers adhere to the prescribing information, much of the benefits of pharmacogenetics will be squandered. Discovering highly predictive genotype-phenotype associations during drug development and demonstrating their clinical validity and utility in well-designed prospective clinical trials will no doubt better define the role of pharmacogenetics in future clinical practice. In the meantime, prescribing should comply with the information provided while pharmacogenetic research is deservedly supported by all concerned but without unrealistic expectations.
Topics: Dose-Response Relationship, Drug; Drug Design; Drug Therapy; Drug and Narcotic Control; Genotype; Pharmacogenetics; Pharmacokinetics; Polymorphism, Genetic
PubMed: 16096112
DOI: 10.1098/rstb.2005.1693 -
Journal of Molecular Medicine (Berlin,... Jan 2004Current pharmacotherapies for psychiatric disorders are generally incompletely effective. Many patients do not respond well or suffer adverse reactions to these drugs,... (Review)
Review
Current pharmacotherapies for psychiatric disorders are generally incompletely effective. Many patients do not respond well or suffer adverse reactions to these drugs, which can result in poor patient compliance and poor treatment outcome. Adverse drug reactions and non-response are likely to be influenced by genetic polymorphisms. Pharmacogenetics holds some promise for improving the treatment of mood disorders by utilising information about genetic polymorphisms to match patients to the drug therapy that is the most effective with the fewest side effects. Pharmacogenomics promises to facilitate the development of new drugs for treatment. However, these technologies raise many ethical, economic and regulatory issues that need to be addressed before they can be integrated into psychiatry, and medicine more generally. We discuss ethical and policy issues arising from pharmacogenetic testing and pharmacogenomics research, such as informed consent, privacy and confidentiality, research on vulnerable persons and discrimination; and economic viability of pharmacogenetics and pharmacogenomics. We conclude with recommendations for the regulation and distribution of pharmacogenetic testing services and pharmacogenomic drugs.
Topics: Central Nervous System Agents; Genotype; Health Personnel; Humans; Mental Disorders; Pharmacogenetics
PubMed: 14598045
DOI: 10.1007/s00109-003-0496-x -
Pharmacogenomics Jul 2004The field of pharmacogenetics will soon celebrate its 50th anniversary. Although science has delivered an impressive amount of information in these 50 years,... (Review)
Review
The field of pharmacogenetics will soon celebrate its 50th anniversary. Although science has delivered an impressive amount of information in these 50 years, pharmacogenetics has suffered from lack of integration into clinical practice. There are several reasons for this, including the unmet need for education at medical schools and the lack of awareness about the impact of genetic medicine on healthcare in the community. Recently, the FDA announced that it considers pharmacogenomics one of three major opportunities on the critical path to new medical products. This notion by the FDA is filling the regulatory void that existed between drug developers and drug users. However, in order to bring pharmacogenetic testing to the prescription pad successfully, healthcare professionals and policy makers, as well as patients, need to have the necessary background knowledge for making educated treatment decisions. To effectively move pharmacogenetics into everyday medicine, it is therefore imperative for scientists and teachers in the field to take on the challenge of disseminating pharmacogenetic insights to a broader audience.
Topics: Health Personnel; Humans; Patient Education as Topic; Personal Health Services; Pharmacogenetics; Residence Characteristics
PubMed: 15212593
DOI: 10.1517/14622416.5.5.571 -
Omics : a Journal of Integrative Biology Dec 2012Osteoporosis is a complex multifactorial bone disorder with a strong genetic basis. It is the most common, severe, progressive skeletal illness that has been increasing,... (Review)
Review
Osteoporosis is a complex multifactorial bone disorder with a strong genetic basis. It is the most common, severe, progressive skeletal illness that has been increasing, particularly in developed countries. Osteoporosis will no doubt constitute a serious clinical burden in healthcare management in the coming decades. The genetics of osteoporosis should be analyzed from both the disease susceptibility and the pharmacogenetic treatment perspectives. The former has been widely studied and discussed, while the latter still requires much more information and research. This article provides a synthesis of the literature on the genetics of osteoporosis and an update on progress made in pharmacogenetics of osteoporosis in recent years, specifically regarding the new molecular targets for antiresorptive drugs. In-depth translation of osteoporosis pharmacogenetics approaches to clinical practice demands a new vision grounded on the concept of "theranostics," that is, the integration of diagnostics for both disease susceptibility testing, as well as for prediction of health intervention outcomes. In essence, theranostics signals a broadening in the scope of inquiry in diagnostics medicine. The upcoming wave of theranostics medicine also suggests more distributed forms of science and knowledge production, both by experts and end-users of scientific products. Both the diagnosis and personalized treatment of osteoporosis could conceivably benefit from the emerging postgenomics field of theranostics.
Topics: Animals; Humans; Osteoporosis; Pharmacogenetics; Precision Medicine
PubMed: 23215803
DOI: 10.1089/omi.2011.0150