-
Journal of Molecular Medicine (Berlin,... Mar 2003Pharmacogenetics is today widely proclaimed to be about to revolutionize the face of medicine. In a more realistic assessment, the implementation of molecular genetics... (Review)
Review
Pharmacogenetics is today widely proclaimed to be about to revolutionize the face of medicine. In a more realistic assessment, the implementation of molecular genetics and biology will continue to provide us, as it has done already, with better ways to diagnose and treat illnesses, but it will do so at a stepwise and evolutionary pace, based on an improved understanding of the nature of disease, allowing more specific treatments, better risk prediction, and the implementation of preventive strategies. As such, future progress in biomedicine will travel the same well-trodden paths of improved differential diagnosis and risk prediction along which it has advanced in the past decades and centuries. Thus, while meaningful biomedical research today by and large depends on the use of the newly developed tools of genetics and genomics and the insights that we gain through them, it is unlikely fundamentally to change the direction of medical progress.
Topics: Clinical Medicine; Diagnosis, Differential; Drug Design; Environment; Genotype; Humans; Pharmacogenetics
PubMed: 12682723
DOI: 10.1007/s00109-002-0416-5 -
Drug Metabolism Reviews Nov 2003Pharmacogenetics fields of research was initially restricted to drug metabolism enzymes. It has recently progressed to drug transporters, receptors, and any kind of... (Review)
Review
Pharmacogenetics fields of research was initially restricted to drug metabolism enzymes. It has recently progressed to drug transporters, receptors, and any kind of targets that can modulate drug response. This rapid extension of pharmacogenetics to all the different medical specialties is in close relation with the recent completion of the draft sequence of the human genome and the discovery that about 0.1% of its sequence is polymorphic. The goal of pharmacogenetics for the next years is clearly to determine the clinical consequences of these 2-3 million single nucleotide polymorphisms (SNPs). Things can be schematically divided in two situations. (1) Frequent SNPs (allele frequency > 10%) which have a low impact on drug response (odds ratios < 2), even combined with other SNPs in haplotype combinations. Such situations, which are by far the most frequent, have no clinical relevance for a single patient to predict its response to a particular drug. CYP3A and MDR1 allelic variants are good examples of such frequent situations. (2) Rare SNPs, which dramatically alter the expression or the activity of a target protein, can sometimes have a real clinical relevance (odds ratios > 5), usually to predict drug side effects. Only few examples, such as TPMT and CYP2C9 genetic polymorphisms, can illustrate this rare situation. Unfortunately, less than 1% of the population is concerned by these rare SNPs, and genotyping can only explain a small part of the variability of the response to a single drug. Beside the impressive mass of data available for pharmacogenetics, it is surprising to observe its poor development in routine medical practice. This discrepancy relies mainly on educational and methodological problems, which might be solved in the decade. To promote pharmacogenetics in routine medical practice, large prospective randomized trials are needed to demonstrate that pharmacogenetic orientated prescription can sometimes predict drug response without dramatic increase in costs.
Topics: Animals; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 14705861
DOI: 10.1081/dmr-120026396 -
Expert Review of Molecular Diagnostics Mar 2006Pharmacogenetics is a rapidly evolving field that will undoubtedly lead to the development of pharmacogenetic tests. Such tests will need to be assimilated into... (Review)
Review
Pharmacogenetics is a rapidly evolving field that will undoubtedly lead to the development of pharmacogenetic tests. Such tests will need to be assimilated into healthcare systems, but represent a further call on scarce healthcare resources. Therefore, in order for a pharmacogenetic test to fulfill its potential beyond the laboratory and into the clinical environment, it must prove itself on a wide range of multifaceted criteria. The test must have proven and reproducible analytical and clinical validity, and stand up to critical appraisal of clinical utility and cost-effectiveness. Pharmacogenetic testing can be considered to be a form of screening, and the experience that has been gained to date in evaluating other forms of screening tests may prove beneficial in evaluating pharmacogenetic technology. It is essential that the goals of pharmacogenetic testing are defined as early as possible to ensure that appropriate studies can be designed to provide the evidence base, and thereby enable appropriate evaluation of the technology by clinicians and healthcare administrators for incorporation into clinical practice. This review focuses on issues that will need to be considered in the scientific assessment of pharmacogenetic testing.
Topics: Biomarkers; Genetic Predisposition to Disease; Humans; Laboratories; Models, Statistical; Molecular Diagnostic Techniques; Neoplasms; Personal Health Services; Pharmacogenetics; Reproducibility of Results; Sensitivity and Specificity
PubMed: 16512779
DOI: 10.1586/14737159.6.2.193 -
Life Sciences Feb 2002Pharmacogenetic evidence-based treatment strategies will have major implications for all aspects of the product pipeline, including drug discovery, high throughput... (Review)
Review
Pharmacogenetic evidence-based treatment strategies will have major implications for all aspects of the product pipeline, including drug discovery, high throughput target screening protocols, lead optimization, and drug formulation to produce series of medicines for a particular disease which will meet the efficacy needs of the majority of patients. The initial proof of principle experiments involves whole genome screening for DNA variants and determination of specific patterns of variants associated with adverse events of marketed products [SNP Print(sm)]. Pharmacogenetics has the potential of changing the pipeline model of drug discovery, clinical development, and mass customization marketing.
Topics: Drug Therapy; Evidence-Based Medicine; Genome, Human; Human Genome Project; Humans; Pharmaceutical Preparations; Pharmacogenetics
PubMed: 11895098
DOI: 10.1016/s0024-3205(01)01532-6 -
Pharmacogenomics Jul 2004Pharmacogenetic research in the area of neuropsychiatric illnesses is rapidly evolving. Due to the complexity of the human brain, it is not surprising that our knowledge... (Review)
Review
Pharmacogenetic research in the area of neuropsychiatric illnesses is rapidly evolving. Due to the complexity of the human brain, it is not surprising that our knowledge about the interaction between genetics and the treatment of these illnesses is very small. The Human Genome Project (HGP) has identified > 30,000 genes; several thousand of which have been found to occur in the brain or serve a role that enhances the brain's function. Much of the research in the post-HGP era is being driven by a desire to use genetics to predict which patients deviate from the norm in terms of drug response or side effects. By identifying these people, we will be able to direct clinical practice such that therapies for these disorders can be individualized. With this in mind, the following review is intended to cover a broad understanding of CNS pharmacogenetics with the goal of summarizing available literature on promising candidate gene targets, which may eventually help us predict clinical outcomes in patients taking medications commonly used to treat neuropsychiatric disorders.
Topics: Humans; Mental Disorders; Pharmacogenetics; Predictive Value of Tests; Risk Factors
PubMed: 15212583
DOI: 10.1517/14622416.5.5.463 -
Current Molecular Medicine 2014Pharmacogenetic studies rely on applied statistics to evaluate genetic data describing natural variation in response to pharmacotherapeutics such as drugs and vaccines.... (Review)
Review
Pharmacogenetic studies rely on applied statistics to evaluate genetic data describing natural variation in response to pharmacotherapeutics such as drugs and vaccines. In the beginning, these studies were based on candidate gene approaches that specifically focused on efficacy or adverse events correlated with variants of single genes. This hypothesis driven method required the researcher to have a priori knowledge of which genes or gene sets to investigate. According to rational design, the focus of these studies has been on drug metabolizing enzymes, drug transporters, and drug targets. As technology has progressed, these studies have transitioned to hypothesis-free explorations where markers across the entire genome can be measured in large scale, population based, genome-wide association studies (GWAS). This enables identification of novel genetic biomarkers, therapeutic targets, and analysis of gene-gene interactions, which may reveal molecular mechanisms of drug activities. Ultimately, the challenge is to utilize gene-drug associations to create dosing algorithms based individual genotypes, which will guide physicians and ensure they prescribe the correct dose of the correct drug the first time eliminating trial-and-error and adverse events. We review here basic concepts and applications of data science to the genetic analysis of pharmacologic outcomes.
Topics: Data Interpretation, Statistical; Genetic Association Studies; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 25109795
DOI: 10.2174/1566524014666140811112438 -
American Journal of Pharmaceutical... Apr 2019To evaluate students' knowledge, confidence, and skills after implementation of an active-learning laboratory session in clinical pharmacogenetics. Third-year pharmacy...
To evaluate students' knowledge, confidence, and skills after implementation of an active-learning laboratory session in clinical pharmacogenetics. Third-year pharmacy students (n=130) participated in an active-learning laboratory session on pharmacogenetics. In the laboratory activity, students evaluated patients' pharmacogenetic profiles and documented recommendations to providers based on their findings. Students also counseled a simulated patient on the interpretation of their pharmacogenetic profile. Students' knowledge and confidence were assessed before a lecture on clinical pharmacogenetics, after the lecture, and then after the laboratory activity. The assessment included 10 knowledge-based questions and five confidence questions regarding clinical pharmacogenetics. An evaluation of the laboratory activity was completed after the session. On average, students correctly answered 70.3% of the knowledge-based questions before the lecture, 82.8% after the lecture, and 88.7% after the laboratory session. Additionally, students' confidence improved in each of the five areas assessed. Based on evaluations (response rate: 98.5%), students found that the laboratory activity contributed to their professional development, was taught at an appropriate level for their understanding, and was relevant to pharmacy practice. An active-learning laboratory session to teach pharmacy students about clinical pharmacogenetics improved students' knowledge, confidence, and skills.
Topics: Clinical Competence; Curriculum; Education, Pharmacy; Educational Measurement; Humans; Knowledge; Patient Simulation; Pharmacogenetics; Problem-Based Learning; Program Evaluation; Students, Pharmacy
PubMed: 31065165
DOI: 10.5688/ajpe6605 -
Hematology. American Society of... 2006The genetic basis of a differential response to drugs has been understood for a limited number of agents for over 30 years. This knowledge has generated hope that the... (Review)
Review
The genetic basis of a differential response to drugs has been understood for a limited number of agents for over 30 years. This knowledge has generated hope that the individual basis for response to a wide range of drugs would be quickly known, and individualized drug selection and dosing would be possible for many or all disorders. Understanding the variable response to drugs seems particularly pressing in the field of oncology, in which the stakes are high (failure to cure cancer usually leads to death), drugs commonly have a narrow therapeutic index, and toxicities can be severe (a significant frequency of toxic death is a feature of most acute myeloid leukemia protocols, for example). However, in common with many new technologies, the generalizability and clinical application of pharmacogenetics has proved more challenging than expected. Difficulties include, in many examples, a modest clinical effect relative to genotype, therapy-specific, not broad, applicability and the very major challenge of unraveling the complexity of gene-gene interactions. In addition, ethical and economic challenges to the application of pharmacogenetics have moved to the fore in recent years, particularly in the context of racial differences in outcome of therapy. Genomic, rather than candidate gene approaches to identification of relevant loci are increasingly being explored, and significant progress is being made. However, greater understanding of the complexities of multiple gene modifiers of outcome, and the statistical challenge of understanding such data, will be needed before individualized therapy can be applied on a routine basis.
Topics: Genotype; Humans; Medicine; Neoplasms; Pharmacogenetics
PubMed: 17124048
DOI: 10.1182/asheducation-2006.1.111 -
Pharmacogenetics of immunosuppressive drugs: prospect of individual therapy for transplant patients.Pharmacogenomics May 2008The immunosuppressive drugs used in solid-organ transplantation are potent and toxic agents with narrow therapeutic ranges. Underdosing is associated with immunological... (Review)
Review
The immunosuppressive drugs used in solid-organ transplantation are potent and toxic agents with narrow therapeutic ranges. Underdosing is associated with immunological rejection of the transplanted organ, whereas overdosing results in infections, malignancy and direct toxicity to a number of organs. Pharmacokinetic heterogeneity makes initial dose determination difficult, as there is a poor correlation between dose and blood concentration. Therapeutic drug monitoring is available but the pharmacokinetic-pharmacodynamic association is imperfect and it does not help in achieving target blood concentrations during the critical early 2-3 days after transplantation. Genetic polymorphisms in drug targets, drug-metabolizing enzymes and drug efflux pumps have been identified as potential targets for developing a pharmacogenetic strategy to individualize initial drug choice and dose. To date, use of the CYP3A5 genotype to predict the appropriate initial dose of tacrolimus is the most promising option for individualization of drug therapy in organ transplantation.
Topics: Graft Rejection; Humans; Immunosuppressive Agents; Pharmacogenetics; Polymorphism, Genetic; Transplants
PubMed: 18466104
DOI: 10.2217/14622416.9.5.585 -
Personalized Medicine Mar 2022Patient knowledge and attitudes toward pharmacogenetic (PGx) testing may impact adoption of clinical testing. Questionnaires regarding knowledge, attitudes and ethics...
Patient knowledge and attitudes toward pharmacogenetic (PGx) testing may impact adoption of clinical testing. Questionnaires regarding knowledge, attitudes and ethics of PGx testing were distributed to 504 patients enrolled in the ADAPT study conducted at two urban hospitals in Philadelphia, Pennsylvania, USA. Responses were assessed using multivariable logistic regression. 311 completed the survey (62% response rate). 74% were unaware of PGx testing, but 79% indicated using PGx results to predict medication efficacy was important. In a multivariable model, higher education level (p = 0.031) and greater genetics knowledge (p < 0.001) were associated with more positive attitudes toward PGx testing. Greater patient knowledge of genetics was associated with a more positive attitude toward PGx testing, indicating that educational strategies aimed at increasing genetics knowledge may enhance adoption of PGx testing in the clinic.
Topics: Attitude; Cytochrome P-450 CYP2C19; Humans; Percutaneous Coronary Intervention; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 34984913
DOI: 10.2217/pme-2021-0064