Pharmacogenomics In Clinical Practice Research Articles

Genetic profiling of NUDT15 in the Slovenian population.

Determining variant TPMT alleles to predict patient response to thiopurine therapy represents one of the first successful implementations of pharmacogenomics in clinical practice. However, despite the TPMT-adjusted thiopurine dosing, some TPMT wild-type patients still exhibit toxicity at standard doses. Over the past decade, the pharmacogene NUDT15 has emerged as a significant co-modulator of thiopurine therapy. Initially, NUDT15 was considered important predominantly in Asian populations, but recent studies have highlighted its relevance in European populations as well.To evaluate the pharmacogenetic significance of NUDT15 in the Slovenian population, we sequenced extended regions of exon 1 and exon 3 in 109 healthy individuals and 37 patients with acute lymphoblastic leukemia.We identified eight variants, including one with established clinical significance (allele *3) and one extremely rare variant (Chr13 at 48045861; GRCh38, NC_000013.11). The frequencies of most previously described variants in both the general population and in the ALL cohort were consistent with those reported in other European populations, except for rs45465203, which was less frequent in the Slovenian population. None of the variants, except for NUDT15*3, were associated with cumulative thiopurine doses in ALL patients. However, these variants warrant further investigation in larger ALL cohorts.

Strategy and technologies of distribution and implementation of pharmacogenomics in clinical practice: foreign experience

Strategy and technologies of distribution and implementation of pharmacogenomics in clinical practice: foreign experience

Pharmacogenomics in Clinical Practice for Older People.

Older people are over-represented among individuals that experience adverse drug reactions (ADR) and adverse drug events (ADE). Furthermore, older people are over-represented among individuals that visit emergency departments and are hospitalized because of ADRs. Moreover, older people are overrepresented among those who suffer ADEs while hospitalized. Finally, older people are among those most likely to have an anaphylactic response to prescription medications. Therefore, older people are prime candidates for efforts aimed at optimizing pharmacotherapeutic outcomes. Pharmacogenomics is an approach of using genetic data to optimize pharmacotherapeutic outcomes. Over the last two decades, pharmacogenomics grew from research initiatives into the current environment of pharmacogenomics implementation. Specifically, implementing pharmacogenomics into clinical settings or within health care systems has proven beneficial in optimizing pharmacotherapeutic outcomes. Therefore, pharmacists focused on optimizing pharmacotherapeutic outcomes for older people should be aware of the approaches to and resources available for implementing pharmacogenomics. KEY WORDS: Drug labeling biomarkers, Genes, Older adults, Pharmacogenomics.

Precision medicine in cardiovascular therapeutics: Evaluating the role of pharmacogenetic analysis prior to drug treatment.

Pharmacogenomics is the examination of how genetic variation influences drug metabolism and response, in terms of both efficacy and safety. In cardiovascular disease, patient-specific diplotypes determine phenotypes, thereby influencing the efficacy and safety of drug treatments, including statins, antiarrhythmics, anticoagulants and antiplatelets. Notably, polymorphisms in key genes, such as CYP2C9, CYP2C19, VKORC1 and SLCO1B1, significantly impact the outcomes of treatment with clopidogrel, warfarin and simvastatin. Furthermore, the CYP2C19 polymorphism influences the pharmacokinetics and safety of the novel hypertrophic cardiomyopathy inhibitor, mavacamten. In this review, we critically assess the clinical application of pharmacogenomics in cardiovascular disease and delineate present and future utilization of pharmacogenomics. This includes insights into identifying missing heritability, the integration of whole genome sequencing and the application of polygenic risk scores to enhance the precision of personalized drug therapy. Our discussion encompasses health economic analyses that underscore the cost benefits associated with pre-emptive genotyping for warfarin and clopidogrel treatments, albeit acknowledging the need for further research in this area. In summary, we contend that cardiovascular pharmacogenomic analyses are underpinned by a wealth of evidence, and implementation is already occurring for some of these gene-drug pairs, but as with any area of medicine, we need to continually gather more information to optimize the use of pharmacogenomics in clinical practice.

Pharmacogenomics knowledge within Neurology: A brief survey amongst physicians

Pharmacogenomics has emerged as a tool to optimise treatment. Many neurologists encounter drugs with pharmacogenomic associations with unclear guidelines. We therefore aimed to determine the knowledge, attitudes, and barriers to implementing pharmacogenomics in clinical practice within a neurology unit. We developed and administered a survey on pharmacogenomics to physicians working in a neurology unit. Three drug-gene pairs clinically relevant to neurology were presented as case scenarios to assess physicians’ perceived competency, attitudes, and risks towards pharmacogenomics. Thirty-two (27.4%) physicians responded to the survey. Respondents were most confident about activities involving the HLA-B*15:02 test, followed by the CYP2C19 test, and lastly the CYP2C9 test. However, perceived competency in drug-drug-gene interactions was consistently low for all three tests. Referring to the product information leaflet ranked highest in usefulness, followed by local practice guidelines. In conclusion, local clinical guidelines and training on the clinical applications of pharmacogenomics are important to facilitate the implementation of pharmacogenomics.

Impact of Pharmacogenomics in Clinical Practice.

Polymorphisms of genes encoding drug metabolizing enzymes and transporters can significantly modify pharmacokinetics, and this can be associated with significant differences in drug efficacy, safety, and tolerability. Moreover, genetic variants of some components of the immune system can explain clinically relevant drug-related adverse events. However, the implementation of drug dose individualization based on pharmacogenomics remains scarce. In this narrative review, the impact of genetic variations on the disposition, safety, and tolerability of the most commonly prescribed drugs is reported. Moreover, reasons for poor implementation of pharmacogenomics in everyday clinical settings are discussed. The literature analysis showed that knowledge of how genetic variations can modify the effectiveness, safety, and tolerability of a drug can lead to the adjustment of usually recommended drug dosages, improve effectiveness, and reduce drug-related adverse events. Despite some efforts to introduce pharmacogenomics in clinical practice, presently very few centers routinely use genetic tests as a guide for drug prescription. The education of health care professionals seems critical to keep pace with the rapidly evolving field of pharmacogenomics. Moreover, multimodal algorithms that incorporate both clinical and genetic factors in drug prescribing could significantly help in this regard. Obviously, further studies which definitively establish which genetic variations play a role in conditioning drug effectiveness and safety are needed. Many problems must be solved, but the advantages for human health fully justify all the efforts.

Pharmacogenomic Germline Testing: Applications in Oncology Nursing.

The implementation of pharmacogenomics in clinical practice has increased in clinical oncology practice. Pharmacogenomic germline testing can be used to develop and prescribe safer and more effective medications and treatment.

Investigation of Biomedical Students' Attitudes toward Pharmacogenomics and Personalized Medicine: A Cross-Sectional Study.

Background: The utilization of pharmacogenomics in everyday practice has shown several notable benefits. Keeping in mind the rising trend of applicability of pharmacogenomics and personalized medicine, we sought to compare the attitudes of future healthcare workers in different branches of the healthcare system. Methods: The present study was conducted as a questionnaire-based cross-sectional study in October of 2020. Students eligible to participate were all the students of the University of Split School of Medicine enrolled in the academic year 2020/2021. Results: The number of students that participated in the study was 503. Students were most interested in clinical examples of pharmacogenomics (31.4%) and the benefits of pharmacogenomics in clinical practice (36.4%). Furthermore, 72.6% of all students agreed that they should be able, in their future practice, to identify patients that could benefit from genetic testing. Conclusion: At the present time, the lack of education and appropriate clinical guidelines appear to be the major barriers to the clinical application of pharmacogenomics, especially in Croatia. Hence, in order to support health care professionals’ evidence-based therapeutic recommendations with patients’ pharmacogenomic data, universities should offer more pharmacogenomics education in their curricula.

Pharmacogenomics in clinical practice to prevent risperidone-induced hyperprolactinemia in autism spectrum disorder.

Autism spectrum disorder (ASD) is a global challenge that may disrupts family and social life significantly. There is robust evidence for the association of apharmacokinetic gene variant (e.g., CYP2D6) with risperidone-induced hyperprolactinemia in ASD. Association of apharmacodynamic gene variant (e.g., DRD2) with risperidone-induced hyperprolactinemia in ASD is also evident from multiple studies. In addition to genetic factors, dose, duration and drug-drug interactions of risperidone might also increase theserum prolactin level. There are several difficulties, such as reimbursement, knowledge and education of healthcare providers, in implementing risperidone pharmacogenomics into clinical practice. However, preparation of national and international pharmacogenomics-based dosing guidelines of risperidone may advance precision medicine of ASD.

Pharmacists Leading the Way to Precision Medicine: Updates to the Core Pharmacist Competencies in Genomics

Genomics is becoming an increasingly important part of health care, and pharmacists are well-positioned to be practice-based leaders in pharmacogenomics and precision medicine. Competencies available through the Genetics/Genomics Competency Center provide a framework for pharmacogenomics instruction in both pharmacy school curricula and continuing education programs. Given the significant advancements in pharmacogenomics over the past decade, the 2019-2020 American Association of Colleges of Pharmacy Pharmacogenomics Special Interest Group updated the pharmacist competencies. The process used a systematic approach which included mapping pharmacogenomics-specific competencies to the entrustable professional activities for pharmacists and seeking consensus from key stakeholders. The result is an expansion to 30 competencies that reflect the contemporary roles pharmacists play in the application of pharmacogenomics in clinical practice. When implemented into curricula, these competencies will ensure that learners are "practice ready" to integrate pharmacogenomics into patient care. Additional postgraduate training is needed for advanced roles in pharmacogenomics implementation, education, and research.

Knowledge, Attitude and Perception of Pharmacy Students towards Pharmacogenomics and Genetics: An Observational Study from King Saud University.

Pharmacists are considered among the most accessible healthcare workers in fundamental positions to implement new clinical initiatives, such as pharmacogenomics services. The scope of pharmacogenomics in improving health outcomes and the quality of health care is well-known. Implementation of such initiatives requires adequate knowledge, perception, and positive attitudes among pharmacists. A study was conducted on pharmacy students at King Saud University in Riyadh to analyze their attitudes, knowledge, and perceptions concerning pharmacogenomics to explore the feasibility of establishing full-time pharmacogenomics instruction and services. A cross-sectional study was carried out in one of the significant pharmacy schools of Saudi Arabia, using a simple questionnaire-based survey in pharmacy students pursuing Bpharm and PharmD courses to obtain preliminary information about pharmacogenomics among the surveyed population. The study’s secondary objective was to determine the perceived belief about pharmacogenomics implementation in clinical practice. Out of the total of 552 participants, 41.8% correctly defined pharmacogenomics and 81.3% understood that genetic change could lead to adverse reactions. More than half of the participants agreed that the FDA recommends pharmacogenomics testing for certain drugs. The knowledge about a year of use of pharmacogenomics in clinical practice was found to be very low; only 15.2% could correctly answer. Only 60% of students agreed on pharmacogenomics testing for selecting the therapy with the most negligible adverse effects. Due to the limited knowledge about and understanding of pharmacogenomics, there is a lack of interest among pharmacy students in implementing pharmacogenomics testing in clinical practice. Our study highlights the need for improving pharmacy students’ knowledge about pharmacogenomics and pharmacogenetics so that the implementation of pharmacogenomics testing in clinical practice will become easier. There is a need to introduce an up-to-date curriculum for pharmacy courses other pharmacogenomics-based health education programs in Saudi Arabia.

Application of long-read sequencing to elucidate complex pharmacogenomic regions: a proof of principle

The use of pharmacogenomics in clinical practice is becoming standard of care. However, due to the complex genetic makeup of pharmacogenes, not all genetic variation is currently accounted for. Here, we show the utility of long-read sequencing to resolve complex pharmacogenes by analyzing a well-characterised sample. This data consists of long reads that were processed to resolve phased haploblocks. 73% of pharmacogenes were fully covered in one phased haploblock, including 9/15 genes that are 100% complex. Variant calling accuracy in the pharmacogenes was high, with 99.8% recall and 100% precision for SNVs and 98.7% precision and 98.0% recall for Indels. For the majority of gene-drug interactions in the DPWG and CPIC guidelines, the associated genes could be fully resolved (62% and 63% respectively). Together, these findings suggest that long-read sequencing data offers promising opportunities in elucidating complex pharmacogenes and haplotype phasing while maintaining accurate variant calling.

A Systematic Review of Parkinson's Disease Pharmacogenomics: Is There Time for Translation into the Clinics?

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson’s disease. Methods: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson’s disease treatment, along with a manual search, and finally included a total of 116 publications in the review. Results: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. Conclusions: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.

A New Insight for the Identification of Oncogenic Variants in Breast and Prostate Cancers in Diverse Human Populations, With a Focus on Latinos.

Background: Breast cancer (BRCA) and prostate cancer (PRCA) are the most commonly diagnosed cancer types in Latin American women and men, respectively. Although in recent years large-scale efforts from international consortia have focused on improving precision oncology, a better understanding of genomic features of BRCA and PRCA in developing regions and racial/ethnic minority populations is still required. Methods: To fill in this gap, we performed integrated in silico analyses to elucidate oncogenic variants from BRCA and PRCA driver genes; to calculate their deleteriousness scores and allele frequencies from seven human populations worldwide, including Latinos; and to propose the most effective therapeutic strategies based on precision oncology. Results: We analyzed 339,100 variants belonging to 99 BRCA and 82 PRCA driver genes and identified 18,512 and 15,648 known/predicted oncogenic variants, respectively. Regarding known oncogenic variants, we prioritized the most frequent and deleterious variants of BRCA (n = 230) and PRCA (n = 167) from Latino, African, Ashkenazi Jewish, East Asian, South Asian, European Finnish, and European non-Finnish populations, to incorporate them into pharmacogenomics testing. Lastly, we identified which oncogenic variants may shape the response to anti-cancer therapies, detailing the current status of pharmacogenomics guidelines and clinical trials involved in BRCA and PRCA cancer driver proteins. Conclusion: It is imperative to unify efforts where developing countries might invest in obtaining databases of genomic profiles of their populations, and developed countries might incorporate racial/ethnic minority populations in future clinical trials and cancer researches with the overall objective of fomenting pharmacogenomics in clinical practice and public health policies.

76.3 How to Approach Pharmacogenomics in Clinical Practice

Pharmacogenomics has become more integrated into clinical practice and is now being used as a potential additional tool to improve the efficacy and tolerability of psychotropic medications. Over the past decade, this technology has evolved to include genes that influence a pharmacodynamic response of medications. This presentation will review the components of expanded pharmacogenomic panels that include both pharmacokinetic and pharmacodynamic genes and discuss ways to interpret testing results and consider the possible roles and limitations of such an expanded multigene profile.

26.4 Pharmacogenomics in Clinical Practice: Does It Always Predict Clinical Response?

Pharmacogenomics has become more integrated into clinical practice and is now being used as a potential additional tool to improve efficacy and tolerability of psychotropic medications. Over the past decade, this technology has evolved to include genes influencing a pharmacodynamic response of medications. This presentation will review the components of expanded pharmacogenomic panels that include both pharmacokinetic and pharmacodynamic genes and discuss ways to interpret testing results and consider the possible role and limitations of such an expanded multigene profile.

Simplifying the use of pharmacogenomics in clinical practice: Building the genomic prescribing system

BackgroundA barrier to the use of genomic information during prescribing is the limited number of software solutions that combine a user-friendly interface with complex medical data. We built and designed an online, secure, electronic custom interface termed the Genomic Prescribing System (GPS). MethodsActionable pharmacogenomic (PGx) information was reviewed, collected, and stored in the back-end of GPS to enable creation of customized drug- and variant-specific clinical decision support (CDS) summaries. The database architecture utilized the star schema to store information. Patient raw genomic data underwent transformation via custom-designed algorithms to enable gene and phenotype-level associations. Multiple external data sets (PubMed, The Systematized Nomenclature of Medicine (SNOMED), National Drug File – Reference Terminology (ND-FRT), and a publically-available PGx knowledgebase) were integrated to facilitate the delivery of patient, drug, disease, and genomic information. Institutional security infrastructure was leveraged to securely store patient genomic and clinical data on a HIPAA-compliant server farm. ResultsAs of May 17, 2016, the GPS back-end housed 257 CDS encompassing 112 genetic variants, 42 genes, and 46 PGx-actionable drugs. The GPS user interface presented patient-specific CDS alongside a recognizable traffic light symbol (green/yellow/red), denoting PGx risk for each genomic result. The number of traffic lights per visit increased with the corresponding increase in the number of available PGx-annotated drugs over time. An integrated drug and disease search functionality, links to primary literature sources, and potential alternative PGx drugs were indicated. The system, which was initially used as stand-alone CDS software within our clinical environment, was then integrated with the institutional electronic medical record for enhanced usability. There have been nearly 2000 logins in 43months since inception, with usage exceeding 56 logins per month and system up-times of 99.99%. For all patient-provider visits encompassing >3years of implementation, unique alert click-through rates corresponded to genomic risk: red lights clicked 100%, yellow lights 79%, green lights 43%. ConclusionsSuccessful deployment of GPS by combining complex data and recognizable iconography led to a tool that enabled point-of-care genomic delivery with high usability. Continued scalability and incorporation of additional clinical elements to be considered alongside PGx information could expand future impact.

Commentary: Should Pharmacogenomic Evidence Be Considered in Clinical Decision Making? Focus on Select Cardiovascular Drugs.

Despite advances in technology and guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) that focus on how to use pharmacogene test results, hurdles remain that have delayed the widespread application of pharmacogenomics in clinical practice. These hurdles include a lack of prospective randomized controlled trials to address the utility of pharmacogenomics on clinical outcomes, what the clinical algorithm for pharmacogenomics should be, and whether pharmacogenomics is cost-effective. However, the implementation of clinical practice guidelines, such as those from professional organizations, is commonplace and often termed the application of evidence-based medicine. Here, we draw an analogy between the evidence supporting many commonly cited clinical practice guidelines and U.S. Food and Drug Administration-approved labeling recommendations and the evidence supporting recommendations from CPIC. Although many clinical practice guideline recommendations are supported by the results of randomized controlled clinical trials, we cite examples of common clinical practices that are supported by levels and types of evidence similar to the evidence supporting many of the CPIC recommendations. Specifically, we discuss clinical recommendations for guidance related to drug-drug interactions, drug-gene interactions, therapeutic range selection, and dosage adjustments based on patient-specific factors within the context of a select set of cardiovascular therapeutic topics.

Pharmacogenomic Challenges in Cardiovascular Diseases: Examples of Drugs and Considerations for Future Integration in Clinical Practice.

Even if cardiovascular disease (CVD) drugs are supported by high level proofs, the results of CVD treatment present great disparities: there are still patients dying with supposed optimal treatment, patients facing adverse events and CVD remains the primary cause of death in the world. Pharmacogenomics is the basis of personalisation of the treatment able to allow higher medication success rates. In this review, we will present detailed examples of CVD drugs to highlight the complexity of this challenging field and we will discuss novel concepts that should be considered for a fastest integration of pharmacogenomics in clinical practice of CVD. Areas Covered: The complexity of pharmacogenetics and pharmacogenomics of CVD drugs are presented though examples of medications such as statins, with a focus on their effectiveness and adverse effects. Expert Opinion: The application of personalised medicine in the CVD medical practice requires the study of human genome with regard to drugs pharmacokinetics, pharmacodynamics, interactions and tolerance profile. The existing state -of-the-art of CVD drugs gives hopes for a future revolution in the drug development that will maximise cardiovascular patients benefit while decreasing their risks for adverse effects. Article Highlights Box: • Coronary heart disease (CHD) remains the first cause of death worldwide. • Cardiovascular treatment has a significant percentage of insufficient efficacy, poor tolerance and compliance. • Predicting the response to therapy while diminishing the side effects is the basis of personalised medicine; pharmacogenomics is leading towards this direction. • The response to CVD therapy and side effects are in the heart of CVD pharmacogenomics and significant progress has been noted. • The application of pharmacogenomics in the CVD medical practice is facing many methodological, technical, ethical, behavioral and financial issues, while cost-effectiveness is the main prerequisite. • The consideration of gene × gene × environment interactions and the inclusion of "omics" data in pharmacogenomic studies of CVD drugs will facilitate the generation of reliable results and will promote tailored treatments and new strategies of drug research and development.

Dosing recommendations for pharmacogenetic interactions related to drug metabolism.

Pharmacogenomic studies have established the important contribution of drug-metabolizing enzyme genotype toward drug toxicity and treatment failure; however, clinical implementation of pharmacogenomics has been slow. The aim of this study was to systematically review the information on drug-metabolizing enzyme pharmacogenomics available in the US drug labeling, practice guidelines, and recommendations. Drug-metabolizing enzyme genotype and phenotype information was assessed in US FDA drug labeling, clinical practice guidelines, and independent technology assessors to evaluate the consistency in information sources for healthcare providers. Eighty four gene-drug pairs were identified as having drug-metabolizing enzyme genotype or phenotype information within the label. The manner in which pharmacogenomic information was presented was heterogeneous both within the label and between clinical practice recommendations. For proper implementation of pharmacogenomics in clinical practice, information sources for healthcare providers should relay consistent and clear information for the appropriate use of biomarkers.