-
Genes Jun 2020Pharmacogenomics is one of the emerging approaches to precision medicine, tailoring drug selection and dosing to the patient's genetic features. In recent years, several...
Pharmacogenomics is one of the emerging approaches to precision medicine, tailoring drug selection and dosing to the patient's genetic features. In recent years, several pharmacogenetic guidelines have been published by international scientific consortia, but the uptake in clinical practice is still poor. Many coordinated international efforts are ongoing in order to overcome the existing barriers to pharmacogenomic implementation. On the other hand, existing validated pharmacogenomic markers can explain only a minor part of the observed clinical variability in the therapeutic outcome. New investigational approaches are warranted, including the study of the pharmacogenomic role of the immune system genetics and of previously neglected rare genetic variants, reported to account for a large part of the inter-individual variability in drug metabolism. In this Special Issue, we collected a series of articles covering many aspects of pharmacogenomics. These include clinical implementation of pharmacogenomics in clinical practice, development of tools or infrastractures to support this process, research of new pharmacogenomics markers to increase drug efficacy and safety, and the impact of rare genetic variants in pharmacogenomics.
Topics: Biomarkers; Humans; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 32580376
DOI: 10.3390/genes11060679 -
Lancet (London, England) Aug 2019Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be... (Review)
Review
Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be used to individualise drug therapy-the topic addressed here-is often viewed as within reach for genomic medicine. We have reviewed general mechanisms underlying variability in drug action, the role of genetic variation in mediating beneficial and adverse effects through variable drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics), available data from clinical trials, and ongoing efforts to implement pharmacogenetics in clinical practice.
Topics: Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Pharmacogenomic Variants
PubMed: 31395440
DOI: 10.1016/S0140-6736(19)31276-0 -
Trends in Pharmacological Sciences Dec 2022Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field,... (Review)
Review
Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation.
Topics: Humans; Pharmacogenetics; Depression; Precision Medicine; Psychotic Disorders; Medical Oncology
PubMed: 36307251
DOI: 10.1016/j.tips.2022.09.011 -
International Journal of Molecular... Dec 2021Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon... (Review)
Review
Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug-drug interactions. Pharmacogenomics (PGx) provides the physician effective clues for optimizing drug efficacy and safety in major problems of health such as cardiovascular disease and associated disorders, cancer and brain disorders. Important aspects to be considered are also the impact of immunopharmacogenomics in cutaneous ADRs as well as the influence of genomic factors associated with COVID-19 and vaccination strategies. Major limitations for the routine use of PGx procedures for ADRs prevention are the lack of education and training in physicians and pharmacists, poor characterization of drug-related PGx, unspecific biomarkers of drug efficacy and toxicity, cost-effectiveness, administrative problems in health organizations, and insufficient regulation for the generalized use of PGx in the clinical setting. The implementation of PGx requires: (i) education of physicians and all other parties involved in the use and benefits of PGx; (ii) prospective studies to demonstrate the benefits of PGx genotyping; (iii) standardization of PGx procedures and development of clinical guidelines; (iv) NGS and microarrays to cover genes with high PGx potential; and (v) new regulations for PGx-related drug development and PGx drug labelling.
Topics: Biomarkers; Cardiovascular Diseases; Central Nervous System Diseases; Cost-Benefit Analysis; Drug Development; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Neoplasms; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; COVID-19 Drug Treatment
PubMed: 34948113
DOI: 10.3390/ijms222413302 -
Nature Oct 2015After decades of discovery, inherited variations have been identified in approximately 20 genes that affect about 80 medications and are actionable in the clinic. And... (Review)
Review
After decades of discovery, inherited variations have been identified in approximately 20 genes that affect about 80 medications and are actionable in the clinic. And some somatically acquired genetic variants direct the choice of 'targeted' anticancer drugs for individual patients. Current efforts that focus on the processes required to appropriately act on pharmacogenomic variability in the clinic are moving away from discovery and towards implementation of an evidenced-based strategy for improving the use of medications, thereby providing a cornerstone for precision medicine.
Topics: Evidence-Based Medicine; Genetic Testing; Genetic Variation; Humans; Neoplasms; Pharmacogenetics; Precision Medicine
PubMed: 26469045
DOI: 10.1038/nature15817 -
Clinical Pharmacology and Therapeutics Oct 2012The Pharmacogenomics Knowledgebase (PharmGKB) is a resource that collects, curates, and disseminates information about the impact of human genetic variation on drug... (Review)
Review
The Pharmacogenomics Knowledgebase (PharmGKB) is a resource that collects, curates, and disseminates information about the impact of human genetic variation on drug responses. It provides clinically relevant information, including dosing guidelines, annotated drug labels, and potentially actionable gene-drug associations and genotype-phenotype relationships. Curators assign levels of evidence to variant-drug associations using well-defined criteria based on careful literature review. Thus, PharmGKB is a useful source of high-quality information supporting personalized medicine-implementation projects.
Topics: Databases, Genetic; Humans; Internet; Knowledge Bases; Pharmacogenetics; Precision Medicine
PubMed: 22992668
DOI: 10.1038/clpt.2012.96 -
Cell Jan 2018Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health....
Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug- and effector-binding sites in the human population. We experimentally show that certain variants of μ-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants could increase prescription precision, improving patients' quality of life, and relieve the economic and societal burden due to variable drug responsiveness. VIDEO ABSTRACT.
Topics: Binding Sites; Drug Prescriptions; HEK293 Cells; Humans; Pharmacogenetics; Pharmacogenomic Variants; Protein Binding; Receptors, G-Protein-Coupled; Software
PubMed: 29249361
DOI: 10.1016/j.cell.2017.11.033 -
Clinical Pharmacology and Therapeutics Sep 2021The evidence for pharmacogenetics has grown rapidly in recent decades. However, the strength of evidence required for the clinical implementation of pharmacogenetics is... (Review)
Review
The evidence for pharmacogenetics has grown rapidly in recent decades. However, the strength of evidence required for the clinical implementation of pharmacogenetics is highly debated. Therefore, the purpose of this review is to summarize different perspectives on the evidence required for the clinical implementation of pharmacogenetics. First, we present two patient cases that demonstrate how knowledge of pharmacogenetic evidence affected their care. Then we summarize resources that curate pharmacogenetic evidence, types of evidence (with an emphasis on randomized controlled trials [RCT]) and their limitations, and different perspectives from implementers, clinicians, and patients. We compare pharmacogenetics to a historical example (i.e., the evidence required for the clinical implementation of pharmacokinetics/therapeutic drug monitoring), and we provide future perspectives on the evidence for pharmacogenetic panels and the need for more education in addition to evidence. Although there are differences in the interpretation of pharmacogenetic evidence across resources, efforts for standardization are underway. Survey data illustrate the value of pharmacogenetic testing from the patient perspective, with their providers seen as key to ensuring maximum benefit from test results. However, clinicians and practice guidelines from medical societies often rely on RCT data to guide treatment decisions, which are not always feasible or ethical in pharmacogenetics. Thus, recognition of other types of evidence to support pharmacogenetic implementation is needed. Among pharmacogenetic implementers, consistent evidence of pharmacogenetic associations is deemed most critical. Ultimately, moving pharmacogenetics into practice will require consideration of multiple stakeholder perspectives, keeping particularly attuned to the voice of the ultimate stakeholder-the patient.
Topics: Drug Monitoring; Humans; Pharmacogenetics; Reference Standards; Surveys and Questionnaires
PubMed: 34101169
DOI: 10.1002/cpt.2327 -
Journal of Pharmacokinetics and... Apr 2019Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug-drug interactions and pharmacogenomic variance are observed. Following... (Review)
Review
Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug-drug interactions and pharmacogenomic variance are observed. Following multiple dosing to steady-state, oral systemic concentration-time curves appear to follow a one-compartment body model, with a shorter rate limiting half-life, often significantly shorter than the single dose terminal half-life. This simplified disposition model at steady-state allows comparisons of measurable parameters (i.e., area under the curve, half-life, maximum concentration and time to maximum concentration) following drug interaction or pharmacogenomic variant studies to be utilized to characterize whether a drug is low versus high hepatic extraction ratio, even without intravenous dosing. The characteristics of drugs based on the ratios of area under the curve, maximum concentration and half-life are identified with recognition that volume of distribution is essentially unchanged for drug interaction and pharmacogenomic variant studies where only metabolic outcomes are changed and transporters are not significantly involved. Comparison of maximum concentration changes following single dose interaction and pharmacogenomic variance studies may also identify the significance of intestinal first pass changes. The irrelevance of protein binding changes on pharmacodynamic outcomes following oral and intravenous dosing of low hepatic extraction ratio drugs, versus its relevance for high hepatic extraction ratio drugs is re-emphasized.
Topics: Area Under Curve; Drug Interactions; Half-Life; Humans; Metabolic Clearance Rate; Pharmaceutical Preparations; Pharmacogenetics
PubMed: 30911879
DOI: 10.1007/s10928-019-09626-7 -
British Journal of Clinical Pharmacology Oct 2001
Topics: Genome, Human; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 11678777
DOI: 10.1046/j.0306-5251.2001.01498.x