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CNS Drugs Dec 2016Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic... (Review)
Review
Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic variants, among these the SCL6A4, BDNF, FKBP5, GNB3, GRIK4, and ABCB1 genes, have come to the forefront in this regard. However, small effects sizes, mixed results in independent samples, and conflicting meta-analyses results led to inherent difficulties in the field of pharmacogenetics translating these findings into clinical practice. Nearly all antidepressant pharmacogenetic variants have potentially pleiotropic effects in which they are associated with major depressive disorder, intermediate phenotypes involved in emotional processes, and brain areas affected by antidepressant treatment. The purpose of this article is to provide a comprehensive review of the advances made in the field of pharmacogenetics of antidepressant efficacy and side effects, imaging findings of antidepressant response, and the latest results in the expanding field of imaging-pharmacogenetics studies. We suggest there is mounting evidence that genetic factors exert their impact on treatment response by influencing brain structural and functional changes during antidepressant treatment, and combining neuroimaging and genetic methods may be a more powerful way to detect biological mechanisms of response than either method alone. The most promising imaging-pharmacogenetics findings exist for the SCL6A4 gene, with converging associations with antidepressant response, frontolimbic predictors of affective symptoms, and normalization of frontolimbic activity following antidepressant treatment. More research is required before imaging-pharmacogenetics informed personalized medicine can be applied to antidepressant treatment; nevertheless, inroads have been made towards assessing genetic and neuroanatomical liability and potential clinical application.
Topics: Animals; Antidepressive Agents; Depressive Disorder, Major; Genetic Variation; Humans; Pharmacogenetics; Precision Medicine
PubMed: 27752945
DOI: 10.1007/s40263-016-0385-9 -
Pathologie-biologie Mar 2005Much progress has been made in treating human malignancies and there are now multiple treatment options with similar efficacy for nearly every type of cancer. However,... (Review)
Review
Much progress has been made in treating human malignancies and there are now multiple treatment options with similar efficacy for nearly every type of cancer. However, the narrow therapeutic index of most chemotherapeutic agents and the severe consequences of undertreatment or overdosing have led to research molecular predictive factors of the toxicity and efficacy of cancer treatments. Genetic factors affecting drug metabolism and transport partly explain interindividual variability in drug response. Pharmacogenetic focuses on the molecular mechanisms involved in drug response, and its ultimate goal is the optimisation of the treatments, that combines the optimal efficacy and the minimal risk of severe side effects. Polymorphisms in genes encoding specific drug-metabolising enzymes can result in individuals in the general population being characterised as low, rapid or even ultra-rapid metabolisers. Phenotyping and genotyping tests are now available that determine or predict the metabolic status of an individual and, thus, enable the evaluation of risk of drug failure or toxicity. Some clinical applications of pharmacogenetics (5-FU, irinotecan, thiopurines) have already been developed in routine medicine resulting in significant improvement in patient treatment. The clinical validation of an increasing number of pharmacogenetic tests, as well as the development of new highly efficient technologies for genotyping (real-time PCR, DNA chips...) should further promote pharmacogenetics in clinical practice and lead to the development of a patient-tailored drug therapy.
Topics: Antineoplastic Agents; Genotype; Humans; Neoplasms; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Xenobiotics
PubMed: 15708657
DOI: 10.1016/j.patbio.2004.05.001 -
Addiction (Abingdon, England) Dec 2017Precision, personalized or stratified medicine, which promises to deliver the right treatment to the right patient, is a topic of international interest in both the lay... (Review)
Review
BACKGROUND AND AIMS
Precision, personalized or stratified medicine, which promises to deliver the right treatment to the right patient, is a topic of international interest in both the lay press and the scientific literature. A key aspect of precision medicine is the identification of biomarkers that predict the response to medications (i.e. pharmacogenetics). We examined why, despite the great strides that have been made in biomarker identification in many areas of medicine, only in oncology has there been substantial progress in their clinical implementation. We also considered why progress in this effort has lagged in addiction medicine.
METHODS
We compared the development of pharmacogenetic biomarkers in oncology, cardiovascular medicine (where developments are also promising) and addictive disorders.
RESULTS
The first major reason for the success of oncologic pharmacogenetics is ready access to tumor tissue, which allows in-vitro testing and insights into cancer biology. The second major reason is funding, with cancer research receiving, by far, the largest allocation by the National Institutes of Health (NIH) during the past two decades. The second largest allocation of research funding has gone to cardiovascular disease research. Addictions research received a much smaller NIH funding allocation, despite the major impact that tobacco use, alcohol consumption and illicit drug use have on the public health and healthcare costs.
CONCLUSIONS
Greater support for research on the personalized treatment of addictive disorders can be expected to yield disproportionately large benefits to the public health and substantial reductions in healthcare costs.
Topics: Addiction Medicine; Biomarkers; Humans; Medical Oncology; Pharmacogenetics; Precision Medicine
PubMed: 28431457
DOI: 10.1111/add.13818 -
Pharmacogenomics Dec 2006Pharmacoeconomics and pharmacogenetics are two fields converging together as it is increasingly recognized that genetic markers predicting efficacy and toxicity to drugs... (Review)
Review
Pharmacoeconomics and pharmacogenetics are two fields converging together as it is increasingly recognized that genetic markers predicting efficacy and toxicity to drugs can cost-effectively improve patient care. While pharmacogenetics aims at identifying genetic markers underlying the response to drugs, pharmacoeconomics aims at delivering healthcare cost-effectively. Several studies have investigated the potential cost-effectiveness of pharmacogenetic-based approaches. Recent evidences include screening for thiopurine methyltransferase gene polymorphisms to prevent azathioprine-induced myelosuppression, or screening for human leukocyte antigen (HLA)B5701 to prevent hypersensitivity reactions to abacavir therapy. Furthermore, examples suggesting a cost-effectiveness of markers predicting drug efficacy include screening the angiotensin-converting enzyme gene polymorphisms for statins therapy, the alpha-adducin gene variant for diuretic therapy and the assessment of human epidermal growth factor receptor (HER2) expression for trastuzumab therapy. However, thus far, all these pharmacoeconomic analyses are exploratory and validations in prospective randomized clinical trials are warranted.
Topics: Cost-Benefit Analysis; Drug Therapy; Economics, Pharmaceutical; Genetic Testing; Humans; Pharmacogenetics
PubMed: 17184205
DOI: 10.2217/14622416.7.8.1175 -
Nature Reviews. Genetics Sep 2004Pharmacogenetics provides opportunities for informed decision-making along the pharmaceutical pipeline. There is a growing literature of retrospective studies of... (Review)
Review
Pharmacogenetics provides opportunities for informed decision-making along the pharmaceutical pipeline. There is a growing literature of retrospective studies of marketed medicines that describe efficacy or safety on the basis of patient genotypes. These studies emphasize the potential prospective use of genome information to enhance success in finding new medicines. An example of a prospective efficacy pharmacogenetic Phase-IIA proof-of-concept study is described. Inserting a rapidly performed efficacy pharmacogenetic step after initial clinical data are obtained can provide confidence for a commitment to full drug development. The rapid identification of adverse events during and after drug development using genomic mapping tools is also reviewed.
Topics: Animals; Drug Design; Drug Evaluation; Humans; Pharmacogenetics
PubMed: 15372086
DOI: 10.1038/nrg1432 -
Nature Reviews. Genetics Sep 2004Physicians have long been aware of the subtle differences in the responses of patients to medication. The recognition that a part of this variation is inherited, and... (Review)
Review
Physicians have long been aware of the subtle differences in the responses of patients to medication. The recognition that a part of this variation is inherited, and therefore predictable, created the field of pharmacogenetics fifty years ago. Knowing the gene variants that cause differences among patients has the potential to allow 'personalized' drug therapy and to avoid therapeutic failure and serious side effects.
Topics: Genetic Variation; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Pharmacogenetics
PubMed: 15372089
DOI: 10.1038/nrg1428 -
Clinical Pharmacokinetics 2001Genetic variability in drug response occurs as a result of molecular alterations at the level of drug-metabolising enzymes, drug targets/receptors, and drug transport... (Review)
Review
Genetic variability in drug response occurs as a result of molecular alterations at the level of drug-metabolising enzymes, drug targets/receptors, and drug transport proteins. In this paper, we discuss the possibility that therapeutic drug monitoring (TDM) in the future will involve not the mere measurement and interpretation of drug concentrations but will include both traditional TDM and pharmacogenetics-oriented TDM. In contrast to traditional TDM, which cannot be performed until after a drug is administered to the patient. pharmacogenetics-oriented TDM can be conducted even before treatment begins. Other advantages of genotyping over traditional TDM include, but are not limited to, the following: (i) it does not require the assumption of steady-state conditions (or patient compliance) for the interpretation of results; (ii) it can often be performed less invasively (with saliva, hair root or buccal swab samples); (iii) it can provide predictive value for multiple drugs [e.g. a number of cytochrome P450 (CYP) 2D6, CYP2C 19 or CYP2C9 substrates] rather than a single drug; (iv) it provides mechanistic, instead of merely descriptive, information; and (v) it is constant over an individual's lifetime (and not influenced by concurrent drug administration, alteration in hormonal levels or disease states). Pharmacogenetic information can be applied a priori for initial dose stratification and identification of cases where certain drugs are simply not effective. However, traditional TDM will still be required for all of the reasons that we use it now. In current clinical practice, pharmacogenetic testing is performed for only a few drugs (e.g. mercaptopurine, thioguanine, azathioprine, trastuzumab and tacrine) and in a limited number of teaching hospitals and specialist academic centres. We propose that other drugs (e.g. warfarin, phenytoin, codeine, oral hypoglycaemics, tricyclic antidepressants, aminoglycosides, digoxin, cyclosporin, cyclophosphamide, ifosfamide, theophylline and clozapine) are potential candidates for pharmacogenetics-oriented TDM. However, prospective studies of phaymacogenetics-oriented TDM must be performed to determine its efficacy and cost effectiveness in optimising therapeutic effects while minimising toxicity. In the future, in addition to targeting a patient's drug concentrations within a therapeutic range, pharmacists are likely to be making dosage recommendations for individual drugs on the basis of the individual patient's genotype. As we enter the era of personalised drug therapy, we will be able to identify not only the best drug to be administered to a particular patient, but also the most effective and safest dosage from the outset of therapy.
Topics: Cytochrome P-450 Enzyme System; Drug Monitoring; Drug Therapy; Drug Utilization; Genetic Variation; Humans; Membrane Transport Proteins; Pharmacogenetics; Predictive Value of Tests
PubMed: 11735602
DOI: 10.2165/00003088-200140110-00001 -
Expert Review of Clinical Pharmacology Jan 2024The implementation of pharmacogenetic analysis within clinical trials faces methodological, ethical, and regulatory challenges, as well as tackling the difficulty in... (Review)
Review
INTRODUCTION
The implementation of pharmacogenetic analysis within clinical trials faces methodological, ethical, and regulatory challenges, as well as tackling the difficulty in obtaining actionable information with a sufficient level of evidence to enable its integration into routine clinical practice.
AREAS COVERED
We discuss the current status of pharmacogenetics integration in clinical trials, underscore the associated challenges, and make some suggestions on the aspects to address in any clinical trial including a pharmacogenetic evaluation. We conducted a literature review, thoroughly reviewed the applicable regulations and available guidelines, and assessed the application dossiers submitted for evaluation to the Ethics committee of Hospital La Paz (Madrid, Spain) to extract information related to inclusion of pharmacogenetics evaluations.
EXPERT OPINION
The integration of pharmacogenetics into clinical trials is becoming increasingly common. However, several regulatory, methodological and ethical aspects involved are insufficiently addressed. There is a need for specific and transparent guidelines that establish unified and compliant criteria for methodology, proper handling of samples in compliance with regulations, and the protection of data privacy and confidentiality. Participants should receive complete and appropriate information regarding the purpose, handling, storage, and transfer of their samples and data, and should have the right to decide about their processing.
Topics: Humans; Confidentiality; Pharmacogenetics; Spain; Clinical Trials as Topic
PubMed: 38088171
DOI: 10.1080/17512433.2023.2293999 -
Nature Reviews. Drug Discovery Oct 2008The ability to predict a patient's drug response on the basis of their genetic information is expected to decrease attrition during the development of new, innovative... (Review)
Review
The ability to predict a patient's drug response on the basis of their genetic information is expected to decrease attrition during the development of new, innovative drugs, and reduce adverse events by being able to predict individual patients at risk. Most pharmacogenetic investigations have focused on drug-metabolism genes or candidate genes that are thought to be involved in specific diseases. However, robust new genetic tools now enable researchers to carry out multi-candidate gene-association and genome-wide studies for target discovery and drug development. Despite the expanding role of pharmacogenetics in industry, however, there is a paucity of published data. New forms of effective and efficient collaboration between industry and academia that may enhance the systematic collection of pharmacogenetic data are necessary to establish genetic profiles related to drug response, confirm pharmacogenetic associations and expedite the development of new drugs and diagnostic tests.
Topics: Animals; Drug Design; Humans; Pharmaceutical Preparations; Pharmacogenetics; Protein Biosynthesis; Research; Research Design
PubMed: 18806753
DOI: 10.1038/nrd2593 -
Pharmacogenomics Nov 2001The overall objective of pharmacogenetics is to determine the genetic basis of variability in drug efficacy and safety, and to use this information to benefit the... (Review)
Review
The overall objective of pharmacogenetics is to determine the genetic basis of variability in drug efficacy and safety, and to use this information to benefit the patient. Genetics can be used to develop drugs that are suitable for the majority of patients and to help identify those patients for whom a certain drug may not be the most appropriate. This review will cover some background to pharmacogenetics and various issues including confidentiality, data protection, coding of samples and genetic data, informed consent, and drug development guidelines. International, national and regional variation in the legal and regulatory basis for pharmacogenetics presents challenges for researchers attempting to increase scientific understanding in the field. Examples of national and international regulations and guidelines will be given. It is clear that pharmacogenetics today is a long way from the 'personalised medicine' advocated by some individuals in recent years. The aim of pharmacogenetic research should always be to make sure that patients have the best treatment available and that patients are not exposed to drugs to which they are genetically unable to respond. This vision must continue to inspire researchers and regulators who are working together to make it a widespread reality.
Topics: Clinical Trials as Topic; Genetic Privacy; Guidelines as Topic; Humans; Informed Consent; Pharmacogenetics; Polymorphism, Genetic
PubMed: 11722282
DOI: 10.1517/14622416.2.4.317