-
Clinical Pharmacology and Therapeutics Sep 2021Pharmacogenetics (PGx) association studies are used to discover, replicate, and validate the association between an inherited genotype and a treatment outcome. The... (Review)
Review
Pharmacogenetics (PGx) association studies are used to discover, replicate, and validate the association between an inherited genotype and a treatment outcome. The objective of this tutorial is to provide trainees and novice PGx researchers with an overview of the major decisions that need to be made when designing and conducting a PGx association study. The first critical decision is to determine whether the objective of the study is discovery, replication, or validation. Next, the researcher must identify a patient cohort that has all of the data necessary to conduct the intended analysis. Then, the investigator must select and define the treatment outcome, or phenotype, that will be analyzed. Next, the investigator must determine what genotyping approach and genetic data will be included in the analysis. Finally, the association between the genotype and phenotype is tested using some statistical analysis methodology. This tutorial is divided into five sections; each section describes commonly used approaches and provides suggestions and resources for designing and conducting a PGx association study. Successful PGx association studies are necessary to discover and validate associations between inherited genetic variation and treatment outcomes, which enable clinical translation to improve efficacy and reduce toxicity of treatment.
Topics: Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing; Phenotype; Prospective Studies; Retrospective Studies
PubMed: 33880756
DOI: 10.1002/cpt.2270 -
International Journal of Psychiatry in... Mar 2021The treatment of depression represents a major challenge for healthcare systems and choosing among the many available drugs without objective guidance criteria is an... (Review)
Review
The treatment of depression represents a major challenge for healthcare systems and choosing among the many available drugs without objective guidance criteria is an error-prone process. Recently, pharmacogenetic biomarkers entered in prescribing guidelines, giving clinicians the possibility to use this additional tool to guide prescription and improve therapeutic outcomes. This marked an important step towards precision psychiatry, which aim is to integrate biological and environmental information to personalise treatments. Only genetic variants in cytochrome enzymes are endorsed by prescribing guidelines, but in the future polygenic predictors of treatment outcomes may be translated into the clinic. The integration of genetics with other relevant information (e.g., concomitant diseases and treatments, drug plasma levels) could be managed in a standardised way through ad hoc software. The overcoming of the current obstacles (e.g., staff training, genotyping and informatics facilities) can lead to a broad implementation of precision psychiatry and represent a revolution for psychiatric care.Key pointsPrecision psychiatry aims to integrate biological and environmental information to personalise treatments and complement clinical judgementPharmacogenetic biomarkers in cytochrome genes were included in prescribing guidelines and represented an important step towards precision psychiatryTherapeutic drug monitoring is an important and cost-effective tool which should be integrated with genetic testing and clinical evaluation in order to optimise pharmacotherapyOther individual factors relevant to pharmacotherapy response (e.g., individual's symptom profile, concomitant diseases) can be integrated with genetic information through artificial intelligence to provide treatment recommendationsThe creation of pharmacogenetic services within healthcare systems is a challenging and multi-step process, education of health professionals, promotion by institutions and regulatory bodies, economic and ethical barriers are the main issues.
Topics: Antidepressive Agents; Artificial Intelligence; Depressive Disorder; Drug Monitoring; Humans; Pharmacogenetics; Precision Medicine; Psychiatry
PubMed: 32852246
DOI: 10.1080/13651501.2020.1809680 -
The Journal of Pharmacology and... Aug 2023The use of pharmacogenetic guidelines in personalizing treatments has shown the potential to reduce interindividual variability in drug response by enabling... (Review)
Review
The use of pharmacogenetic guidelines in personalizing treatments has shown the potential to reduce interindividual variability in drug response by enabling genotype-matched dosing and drug selection. However, other important factors, such as patient gender, may interact strongly with pharmacogenetics in determining the individual profile of toxicity and efficacy but are still rarely considered when planning pharmacological treatment. The literature indicates that males and females respond differently to drugs, with women being at higher risk for toxicity and having different plasma exposure to drugs at standard doses. Recent studies have shown that pharmacogenetic variants may have different predictive value in different sexes, as in the case of treatment with opioids, angiotensin-converting enzyme inhibitors, or proton pump inhibitors. Of particular interest is the case of treatment with fluoropyrimidines for cancer. A significant increase in toxicity has been described in female patients, with a more pronounced effect of specific and polymorphisms also noted. This manuscript reviews the major findings in the field of sex-specific pharmacogenomics. SIGNIFICANCE STATEMENT: Interindividual variability in drug response is an emerging issue in pharmacology. The genetic profile of patients, as well as their gender, may play a role in the identification of patients more exposed to the risk of adverse drug reactions or poor efficacy. This article reviews the current state of research on the interaction between gender and pharmacogenetics in addressing interindividual variability.
Topics: Female; Humans; Pharmacogenetics; Polymorphism, Genetic; Genotype; Neoplasms
PubMed: 37001987
DOI: 10.1124/jpet.122.001416 -
Current Allergy and Asthma Reports Dec 2021Several genome-wide association studies (GWASs) of bronchodilator response (BDR) to albuterol have been published over the past decade. This review describes current... (Review)
Review
PURPOSE OF REVIEW
Several genome-wide association studies (GWASs) of bronchodilator response (BDR) to albuterol have been published over the past decade. This review describes current knowledge gaps, including pharmacogenetic studies of albuterol response in minority populations, effect modification of pharmacogenetic associations by age, and relevance of BDR phenotype characterization to pharmacogenetic findings. New approaches, such as leveraging additional "omics" data to focus pharmacogenetic interrogation, as well as developing polygenic risk scores in asthma treatment responses, are also discussed.
RECENT FINDINGS
Recent pharmacogenetic studies of albuterol response in minority populations have identified genetic polymorphisms in loci (DNAH5, NFKB1, PLCB1, ADAMTS3, COX18, and PRKG1), that are associated with BDR. Additional studies are needed to replicate these findings. Modification of the pharmacogenetic associations for SPATS2L and ASB3 polymorphisms by age has also been published. Evidence from metabolomic and epigenomic studies of BDR may point to new pharmacogenetic targets. Lastly, a polygenic risk score for response to albuterol has been developed but requires validation in additional cohorts. In order to expand our knowledge of pharmacogenetics of BDR, additional studies in minority populations are needed. Consideration of effect modification by age and leverage of other "omics" data beyond genomics may also help uncover novel pharmacogenetic loci for use in precision medicine for asthma treatment.
Topics: Albuterol; Bronchodilator Agents; Genome-Wide Association Study; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 34958416
DOI: 10.1007/s11882-021-01023-w -
Clinical Pharmacology and Therapeutics Aug 2023Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of...
Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of cardiovascular diseases. One of the major barriers to the clinical implementation of cardiovascular pharmacogenetics is limited education on this field for current healthcare providers and students. The abundance of pharmacogenetic literature underscores its promise, but it can also be challenging to learn such a wealth of information. Moreover, current clinical recommendations for cardiovascular pharmacogenetics can be confusing because they are outdated, incomplete, or inconsistent. A myriad of misconceptions about the promise and feasibility of cardiovascular pharmacogenetics among healthcare providers also has halted clinical implementation. Therefore, the main goal of this tutorial is to provide introductory education on the use of cardiovascular pharmacogenetics in clinical practice. The target audience is any healthcare provider (or student) with patients that use or have indications for cardiovascular drugs. This tutorial is organized into the following 6 steps: (1) understand basic concepts in pharmacogenetics; (2) gain foundational knowledge of cardiovascular pharmacogenetics; (3) learn the different organizations that release cardiovascular pharmacogenetic guidelines and recommendations; (4) know the current cardiovascular drugs/drug classes to focus on clinically and the supporting evidence; (5) discuss an example patient case of cardiovascular pharmacogenetics; and (6) develop an appreciation for emerging areas in cardiovascular pharmacogenetics. Ultimately, improved education among healthcare providers on cardiovascular pharmacogenetics will lead to a greater understanding for its potential in improving outcomes for a leading cause of morbidity and mortality.
Topics: Humans; Pharmacogenetics; Cardiovascular Agents; Cardiovascular Diseases; Drug-Related Side Effects and Adverse Reactions; Health Personnel
PubMed: 37303270
DOI: 10.1002/cpt.2957 -
Clinical Pharmacology and Therapeutics Dec 2022The objective of this study was to evaluate the evidence on cost-effectiveness of pharmacogenetic (PGx)-guided treatment for drugs with Clinical Pharmacogenetics...
The objective of this study was to evaluate the evidence on cost-effectiveness of pharmacogenetic (PGx)-guided treatment for drugs with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. A systematic review was conducted using multiple biomedical literature databases from inception to June 2021. Full articles comparing PGx-guided with nonguided treatment were included for data extraction. Quality of Health Economic Studies (QHES) was used to assess robustness of each study (0-100). Data are reported using descriptive statistics. Of 108 studies evaluating 39 drugs, 77 (71%) showed PGx testing was cost-effective (CE) (N = 48) or cost-saving (CS) (N = 29); 21 (20%) were not CE; 10 (9%) were uncertain. Clopidogrel had the most articles (N = 23), of which 22 demonstrated CE or CS, followed by warfarin (N = 16), of which 7 demonstrated CE or CS. Of 26 studies evaluating human leukocyte antigen (HLA) testing for abacavir (N = 8), allopurinol (N = 10), or carbamazepine/phenytoin (N = 8), 15 demonstrated CE or CS. Nine of 11 antidepressant articles demonstrated CE or CS. The median QHES score reflected high-quality studies (91; range 48-100). Most studies evaluating cost-effectiveness favored PGx testing. Limited data exist on cost-effectiveness of preemptive and multigene testing across disease states.
Topics: Humans; Pharmacogenomic Testing; Pharmacogenetics; Cost-Benefit Analysis; Warfarin; Carbamazepine
PubMed: 36149409
DOI: 10.1002/cpt.2754 -
Clinical Pharmacology and Therapeutics Nov 2019
Topics: Databases, Genetic; Decision Support Systems, Clinical; Electronic Health Records; Humans; Leadership; Pharmacogenetics; Pharmacogenomic Variants; Precision Medicine
PubMed: 31498426
DOI: 10.1002/cpt.1600 -
Annual Review of Genomics and Human... Aug 2022Pharmacogenomic testing can be an effective tool to enhance medication safety and efficacy. Pharmacogenomically actionable medications are widely used, and approximately... (Review)
Review
Pharmacogenomic testing can be an effective tool to enhance medication safety and efficacy. Pharmacogenomically actionable medications are widely used, and approximately 90-95% of individuals have an actionable genotype for at least one pharmacogene. For pharmacogenomic testing to have the greatest impact on medication safety and clinical care, genetic information should be made available at the time of prescribing (preemptive testing). However, the use of preemptive pharmacogenomic testing is associated with some logistical concerns, such as consistent reimbursement, processes for reporting preemptive results over an individual's lifetime, and result portability. Lessons can be learned from institutions that have implemented preemptive pharmacogenomic testing. In this review, we discuss the rationale and best practices for implementing pharmacogenomics preemptively.
Topics: Genotype; Humans; Pharmacogenetics; Precision Medicine
PubMed: 35537468
DOI: 10.1146/annurev-genom-111621-102737 -
Journal of Human Genetics May 2020Increasing enthusiasm for clinical pharmacogenetic testing and the availability of pharmacogenetic-based guidelines indicate that pediatricians will increasingly be...
Increasing enthusiasm for clinical pharmacogenetic testing and the availability of pharmacogenetic-based guidelines indicate that pediatricians will increasingly be expected to interpret and apply pharmacogenetic test results into medical care. Previous studies have identified a lack of knowledge on pharmacogenetics across many physician specialties; however, this has not been systematically assessed among pediatricians. To evaluate pediatrician knowledge, attitude, and educational interest in pharmacogenetics, we surveyed physician cohorts from both the United States (U.S.) and Japan. A total of 282 pediatricians (210 from the U.S. and 72 from Japan) participated in an anonymous survey (online or hardcopy) on pharmacogenetics knowledge, perception, and education. Over 50% of all respondents had >10 years of clinical experience and >75% had some prior education in genetics. However, <10% felt they were familiar with pharmacogenetics, which was very consistent with <20% of the U.S. pediatricians correctly responding to a codeine/CYP2D6 pharmacogenetics knowledge question and <10% of U.S. pediatricians being aware of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Despite being generally unfamiliar with pharmacogenetics, >80% of all respondents indicated that implementation of clinical pharmacogenetic testing will improve efficacy and safety, and that pediatricians should be capable of applying this testing to their practice. Moreover, the majority (83.1%) were interested in educational opportunities on pharmacogenetics, particularly on result interpretation and therapeutic recommendations. Taken together, these data indicate that although practical knowledge of pharmacogenetics among pediatricians in the U.S. and Japan is currently very low, their interest in clinical pharmacogenetics and related education is high, which will likely facilitate future implementation.
Topics: Adult; Female; Health Knowledge, Attitudes, Practice; Humans; Japan; Male; Middle Aged; Pediatricians; Pharmacogenetics; United States
PubMed: 31983733
DOI: 10.1038/s10038-020-0723-0 -
Trends in Pharmacological Sciences Oct 2022Recent advances in next-generation sequencing (NGS) have resulted in the identification of tens of thousands of rare pharmacogenetic variations with unknown functional... (Review)
Review
Recent advances in next-generation sequencing (NGS) have resulted in the identification of tens of thousands of rare pharmacogenetic variations with unknown functional effects. However, although such pharmacogenetic variations have been estimated to account for a considerable amount of the heritable variability in drug response and toxicity, accurate interpretation at the level of the individual patient remains challenging. We discuss emerging strategies and concepts to close this translational gap. We illustrate how massively parallel experimental assays, artificial intelligence (AI), and machine learning can synergize with population-scale biobank projects to facilitate the interpretation of NGS data to individualize clinical decision-making and personalized medicine.
Topics: Artificial Intelligence; High-Throughput Nucleotide Sequencing; Humans; Machine Learning; Pharmacogenetics; Precision Medicine
PubMed: 36008164
DOI: 10.1016/j.tips.2022.07.002