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American Journal of Nephrology 2020Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists... (Review)
Review
BACKGROUND
Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity.
SUMMARY
There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.
Topics: Antihypertensive Agents; Arylamine N-Acetyltransferase; Dose-Response Relationship, Drug; Drug Resistance; Humans; Hydralazine; Hypertension; Nephrology; Pharmacogenomic Testing; Pharmacogenomic Variants; Practice Guidelines as Topic; Precision Medicine; Treatment Outcome
PubMed: 32927458
DOI: 10.1159/000510433 -
Journal of the American College of... May 2018
Topics: Acute Coronary Syndrome; Humans; Pharmacogenetics; Pharmacogenomic Testing; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride
PubMed: 29699613
DOI: 10.1016/j.jacc.2018.03.021 -
Clinical Pharmacology and Therapeutics Dec 2022Pharmacogenomic (PGx) testing has emerged as a compelling strategy that clinicians can use to inform antidepressant medication selection and dosing, but the clinical... (Meta-Analysis)
Meta-Analysis
Pharmacogenomic (PGx) testing has emerged as a compelling strategy that clinicians can use to inform antidepressant medication selection and dosing, but the clinical efficacy of this strategy has been questioned. We systematically reviewed and meta-analyzed clinical trials for an association between the use of PGx-guided antidepressant therapy and depressive symptom remission in patients with major depressive disorder (MDD). We included prospective, controlled clinical trials published in English up to July 12, 2022. Data extraction and synthesis adhered to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Each trial was assessed for risk of bias and a random-effects model was used to estimate pooled risk ratios. Thirteen trials comprising 4,767 patients were analyzed, including 10 randomized controlled trials, and three open label trials. Across all included trials, those that received PGx-guided antidepressant therapy (n = 2,395) were 1.41 (95% confidence interval (CI) = 1.15-1.74, P = 0.001) more likely to achieve remission compared with those that received unguided antidepressant therapy (n = 2,372). Pooled risk ratios for randomized controlled trials and open label trials were 1.46 (95% CI: 1.13-1.88) and 1.26 (95% CI = 0.84-1.88), respectively. These results suggest that PGx-guided antidepressant therapy is associated with a modest but significant increase in depressive symptom remission in adults with MDD. Efforts to address the heterogeneity in PGx test composition (i.e., genes and alleles tested) and accompanying prescribing recommendations across trials will likely reduce the uncertainty about the efficacy of PGx-guided antidepressant therapy in the literature.
Topics: Adult; Humans; Antidepressive Agents; Depression; Depressive Disorder, Major; Pharmacogenomic Testing; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 36111494
DOI: 10.1002/cpt.2748 -
British Journal of Clinical Pharmacology Oct 2022Pharmacogenomics (PGx) relates to the study of genetic factors determining variability in drug response. Implementing PGx testing in paediatric patients can enhance drug... (Review)
Review
Pharmacogenomics (PGx) relates to the study of genetic factors determining variability in drug response. Implementing PGx testing in paediatric patients can enhance drug safety, helping to improve drug efficacy or reduce the risk of toxicity. Despite its clinical relevance, the implementation of PGx testing in paediatric practice to date has been variable and limited. As with most paediatric pharmacological studies, there are well-recognised barriers to obtaining high-quality PGx evidence, particularly when patient numbers may be small, and off-label or unlicensed prescribing remains widespread. Furthermore, trials enrolling small numbers of children can rarely, in isolation, provide sufficient PGx evidence to change clinical practice, so extrapolation from larger PGx studies in adult patients, where scientifically sound, is essential. This review paper discusses the relevance of PGx to paediatrics and considers implementation strategies from a child health perspective. Examples are provided from Canada, the Netherlands and the UK, with consideration of the different healthcare systems and their distinct approaches to implementation, followed by future recommendations based on these cumulative experiences. Improving the evidence base demonstrating the clinical utility and cost-effectiveness of paediatric PGx testing will be critical to drive implementation forwards. International, interdisciplinary collaborations will enhance paediatric data collation, interpretation and evidence curation, while also supporting dedicated paediatric PGx educational initiatives. PGx consortia and paediatric clinical research networks will continue to play a central role in the streamlined development of effective PGx implementation strategies to help optimise paediatric pharmacotherapy.
Topics: Child; Cost-Benefit Analysis; Humans; Netherlands; Pediatrics; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 34907575
DOI: 10.1111/bcp.15181 -
Clinical Pharmacology and Therapeutics Feb 2018The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase (DPYD) genotype tests so that the results can...
The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase (DPYD) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5-fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost-effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC ) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/).
Topics: Antimetabolites, Antineoplastic; Capecitabine; Clinical Decision-Making; Dihydrouracil Dehydrogenase (NADP); Drug Dosage Calculations; Fluorouracil; Genotype; Humans; Patient Selection; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Phenotype; Precision Medicine; Predictive Value of Tests
PubMed: 29152729
DOI: 10.1002/cpt.911 -
Current Problems in Pediatric and... Feb 2018Significant advances have been made in the application of pharmacogenomic testing for the treatment of patients with psychiatric disorders. Over the past decade, a... (Review)
Review
Significant advances have been made in the application of pharmacogenomic testing for the treatment of patients with psychiatric disorders. Over the past decade, a number of studies have evaluated the utility of pharmacogenomic testing in pediatric patients with psychiatric disorders. The evidence base for pharmacogenomic testing in youth with depressive and anxiety disorders as well as attention/deficit hyperactivity disorder (ADHD) is reviewed in this article. General pharmacogenomic principles are summarized and functional polymorphisms in P450 enzymes (and associated metabolizer phenotypes), the serotonin transporter promoter polymorphisms, serotonin 2A receptor genes (e.g., HT2AR) and catecholamine pathway genes (e.g., COMT) are reviewed. These commonly tested pharmacogenomic markers are discussed with regard to studies of drug levels, efficacy and side effects. The translation of pharmacogenomics to individualized/precision medicine in pediatric patients with ADHD, anxiety and depressive disorders has accelerated; however, its application remains challenging given that there are numerous divergent pathways between medication/medication dose and clinical response and side effects. Nonetheless, by leveraging variations in individual genes that may be relevant to medication metabolism or medication target engagement, pharmacogenomic testing may have a role in predicting treatment response, side effects and medication selection in youth with ADHD, depressive and anxiety disorders.
Topics: Adolescent; Adolescent Psychiatry; Antidepressive Agents, Second-Generation; Anxiety Disorders; Attention Deficit Disorder with Hyperactivity; Catechol O-Methyltransferase; Child; Child Psychiatry; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 Enzyme System; Depressive Disorder; Humans; Pharmacogenetics; Pharmacogenomic Testing; Receptor, Serotonin, 5-HT2A; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 29325731
DOI: 10.1016/j.cppeds.2017.12.003 -
Pharmacogenomics Apr 2021Despite the expansion of pharmacogenetics (PGx), the views of pediatric patients remain unknown. This study explores adolescents' understanding and perceptions of PGx...
Despite the expansion of pharmacogenetics (PGx), the views of pediatric patients remain unknown. This study explores adolescents' understanding and perceptions of PGx testing. Adolescents who had PGx testing were interviewed and their electronic health records were reviewed. Adolescents accurately described reason for testing and most felt the results impacted their current and future care. None perceived risks to securing future employment or insurance. All felt PGx would benefit their peers. Adolescents understand the reasons for PGx and perceive testing to be useful, low risk and applicable to peers. Findings from this study advocate for the inclusion of adolescents in shared decision-making regarding testing and for active engagement in the discussion of results.
Topics: Adolescent; Attitude; Child; Electronic Health Records; Employment; Female; Humans; Insurance, Health; Male; Pharmacogenomic Testing; Young Adult
PubMed: 33849282
DOI: 10.2217/pgs-2020-0177 -
Mayo Clinic Proceedings Jan 2017Recent technological advances have radically changed genetic testing from an expensive and burdensome undertaking to a rapid and less costly option for many purposes.... (Review)
Review
Recent technological advances have radically changed genetic testing from an expensive and burdensome undertaking to a rapid and less costly option for many purposes. The utility of "next-generation" sequencing has been found to establish the diagnosis for hundreds of genetic disorders, to assess pharmacogenomic variants, and to identify treatable targets within malignant neoplasms. The ready availability of genomic information has led to the question of whether there would be clinical benefit of sequencing the genome of individuals who are not seeking a diagnosis, that is, genomic screening in generally healthy people, to provide anticipatory insights for their health care. Little research has been conducted in this area. We examine the considerable unresolved scientific and ethical issues encountered when considering whole-genome sequencing of healthy people.
Topics: Gene Expression Profiling; Genetic Predisposition to Disease; Genome, Human; Humans; Pharmacogenomic Testing; Precision Medicine; Sequence Analysis, DNA
PubMed: 28062062
DOI: 10.1016/j.mayocp.2016.10.019 -
Basic & Clinical Pharmacology &... May 2021Predictive biomarkers play an important role in our efforts to individualize pharmacotherapy, and within recent years, a number of different types of assays have been... (Review)
Review
Predictive biomarkers play an important role in our efforts to individualize pharmacotherapy, and within recent years, a number of different types of assays have been introduced. These biomarkers may potentially support the selection and dosage of specific drugs in order to maximize efficacy and minimize adverse reactions in the individual patient. However, in many instances, the scientific and clinical evidence is insufficient to support the prescribing decision. When predictive biomarkers are used to guide pharmacotherapy, it is important to secure that decisions are based on solid clinical evidence. Here, the regulatory authorities, especially the FDA, have been at the forefront in relation to regulate this type of biomarker assay in order to secure patient safety. The approval process for companion diagnostics is an example of this effort, where the scientific validity of the biomarker and assay is in focus. With the approaching implementation of the new IVD Regulation, greater attention will also be paid to analytical and clinical validity of biomarker assays in the EU. For any type of predictive biomarker assay, including pharmacogenetic and tumour profiling tests, the clinical evidence needs to be in place before they are used routinely in the clinic.
Topics: Biological Assay; Biomarkers; Diagnostic Test Approval; European Union; Pharmacogenomic Testing; Precision Medicine; Reagent Kits, Diagnostic; United States; United States Food and Drug Administration
PubMed: 33665955
DOI: 10.1111/bcpt.13578 -
Neurologia May 2022Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly... (Review)
Review
INTRODUCTION
Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.
DEVELOPMENT
We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.
CONCLUSIONS
Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing.
Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Biomarkers; Donepezil; Humans; Pharmacogenomic Testing
PubMed: 35595404
DOI: 10.1016/j.nrleng.2018.03.022