Publications by authors named "Larisa H Cavallari"

142 Publications

Utilizing a Human-Computer Interaction Approach to Evaluate the Design of Current Pharmacogenomics Clinical Decision Support.

J Pers Med 2021 Nov 18;11(11). Epub 2021 Nov 18.

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA.

A formal assessment of pharmacogenomics clinical decision support (PGx-CDS) by providers is lacking in the literature. The objective of this study was to evaluate the usability of PGx-CDS tools that have been implemented in a healthcare setting. We enrolled ten prescribing healthcare providers and had them complete a 60-min usability session, which included interacting with two PGx-CDS scenarios using the "Think Aloud" technique, as well as completing the Computer System Usability Questionnaire (CSUQ). Providers reported positive comments, negative comments, and suggestions for the two PGx-CDS during the usability testing. Most provider comments were in favor of the current PGx-CDS design, with the exception of how the genotype and phenotype information is displayed. The mean CSUQ score for the PGx-CDS overall satisfaction was 6.3 ± 0.95, with seven strongly agreeing and one strongly disagreeing for overall satisfaction. The implemented PGx-CDS at our institution was well received by prescribing healthcare providers. The feedback collected from the session will guide future PGx-CDS designs for our healthcare system and provide a framework for other institutions implementing PGx-CDS.
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http://dx.doi.org/10.3390/jpm11111227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618963PMC
November 2021

Machine Learning for Prediction of Stable Warfarin Dose in US Latinos and Latin Americans.

Front Pharmacol 2021 29;12:749786. Epub 2021 Oct 29.

Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, AZ, United States.

Populations used to create warfarin dose prediction algorithms largely lacked participants reporting Hispanic or Latino ethnicity. While previous research suggests nonlinear modeling improves warfarin dose prediction, this research has mainly focused on populations with primarily European ancestry. We compare the accuracy of stable warfarin dose prediction using linear and nonlinear machine learning models in a large cohort enriched for US Latinos and Latin Americans (ULLA). Each model was tested using the same variables as published by the International Warfarin Pharmacogenetics Consortium (IWPC) and using an expanded set of variables including ethnicity and warfarin indication. We utilized a multiple linear regression model and three nonlinear regression models: Bayesian Additive Regression Trees, Multivariate Adaptive Regression Splines, and Support Vector Regression. We compared each model's ability to predict stable warfarin dose within 20% of actual stable dose, confirming trained models in a 30% testing dataset with 100 rounds of resampling. In all patients ( = 7,030), inclusion of additional predictor variables led to a small but significant improvement in prediction of dose relative to the IWPC algorithm (47.8 versus 46.7% in IWPC, = 1.43 × 10). Nonlinear models using IWPC variables did not significantly improve prediction of dose over the linear IWPC algorithm. In ULLA patients alone ( = 1,734), IWPC performed similarly to all other linear and nonlinear pharmacogenetic algorithms. Our results reinforce the validity of IWPC in a large, ethnically diverse population and suggest that additional variables that capture warfarin dose variability may improve warfarin dose prediction algorithms.
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http://dx.doi.org/10.3389/fphar.2021.749786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585774PMC
October 2021

β1-receptor polymorphisms and junctional ectopic tachycardia in children after cardiac surgery.

Clin Transl Sci 2021 Oct 29. Epub 2021 Oct 29.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Junctional ectopic tachycardia (JET) is a potentially life-threatening postoperative arrhythmia in children with specific congenital heart defects and can contribute significantly to postoperative morbidity for at-risk populations. In adults, β1-adrenergic receptor (ADRB1) and β2-adrenergic receptor (ADRB2) genotypes have been associated with increased risk for arrhythmias. However, their association with arrhythmia risk in children is unknown. We aimed to test associations between ADRB1 and ADRB2 genotypes and postoperative JET in patients with congenital heart defects. Children who underwent cardiac surgery were genotyped for the ADRB1 p.Ser49Gly (rs1801252; c.145A>G), p.Arg389Gly (rs1801253; c.1165C>G), ADRB2 p.Arg16Gly (rs1042713; c.46A>G), and p.Glu27Gln (rs1042714; c.79G>C) polymorphisms. The occurrence of postoperative JET was assessed via cardiologist-interpreted electrocardiograms. Genotype associations with JET were analyzed via logistic regression, adjusted for clinical variables associated with JET, with separate analysis in patients not on a β-blocker. Of the 343 children included (median age 8 months, 53% boys, 69% European ancestry), 45 (13%) developed JET. The Arg389Arg genotype was not significantly associated with JET in the overall population (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 0.96-4.03, p = 0.064), but was nominally associated in patients not taking a β-blocker (n = 324, OR = 2.25, 95% CI = 1.05-4.80. p = 0.034). None of the other variants were associated with JET. These data suggest that the ADRB1 Arg389Arg genotype may predict risk for JET following cardiac surgery in pediatric patients in the absence of β-blockade. Whether treatment with a β-blocker ameliorates this association requires further research.
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http://dx.doi.org/10.1111/cts.13178DOI Listing
October 2021

Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking β-blockers.

Pharmacogenomics J 2021 Oct 12. Epub 2021 Oct 12.

Center for Pharmacogenomics and Precision Medicine, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA.

Single nucleotide polymorphisms (SNPs) have been associated with differential beta-blocker (BB) effects on heart rate, blood pressure, and left ventricular ejection fraction in various patient populations. This study aimed to determine if SNPs previously associated with BB response are also associated with differential survival in heart failure (HF) patients receiving BBs. HF patient data were derived from electronic health records and the Social Security Death Index. Associations and interactions between BB dose, SNP genotype, and the outcome of death were assessed using a Cox proportional-hazard model adjusting for covariates known to be associated with differential survival in HF patients. Two SNPs, ADRB1 Arg389Gly and ADRB2 Glu27Gln, displayed significant interactions (P = 0.043 and P = 0.017, respectively) with BB dose and their association with mortality. Our study suggests that ADRB2 27Glu and ADRB1 389Arg may confer a larger survival benefit with higher BB doses in patients with HF.
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http://dx.doi.org/10.1038/s41397-021-00257-1DOI Listing
October 2021

NR3C2 genotype is associated with response to spironolactone in diastolic heart failure patients from the Aldo-DHF trial.

Pharmacotherapy 2021 Sep 27. Epub 2021 Sep 27.

Center for Pharmacogenomics and Precision Medicine and Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Study Objective: This study aimed to determine if variants in NR3C2, which codes the target protein of spironolactone, or CYP11B2, which is involved in aldosterone synthesis, were associated with spironolactone response, focused on the primary end point of diastolic function (E/e'), in Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) participants.

Design: Post-hoc genetic analysis.

Data Source: Data and samples were derived from the multi-center, randomized, double-blind, placebo-controlled Aldo-DHF trial.

Patients: Aldo-DHF participants treated with spironolactone (n = 184) or placebo (n = 178) were included.

Intervention: Participants were genotyped for NR3C2 rs5522, NR3C2 rs2070951 and CYP11B2 rs1799998 via pyrosequencing.

Measurements: In the placebo and spironolactone arms, separate multivariable linear regression analyses were performed for change in E/e' with each single nucleotide polymorphism (SNP), adjusted for age, sex, and baseline E/e'. To discern potential mechanisms of a genotype effect, associated SNPs were further examined for their association with change in blood pressure, circulating procollagen type III N-terminal peptide (PIIINP), and left atrial area.

Main Results: Carriers of the rs5522 G allele in the placebo arm had a greater increase in E/e' over the 12-month course of the trial compared to noncarriers (β = 1.10; 95% confidence interval [CI]: 0.05-2.16; p = 0.04). No corresponding E/e' worsening by rs5522 genotype was observed in the spironolactone arm. None of the other genotypes were associated with change in E/e'. Compared to noncarriers, rs5522 G carriers also had a greater increase in left atrial area with placebo (β = 0.83; 95% CI: 0.17-1.48; p = 0.01) and a greater reduction in diastolic blood pressure with spironolactone (β = -3.56; 95% CI: -6.73 to -0.39; p = 0.03). Serum PIIINP levels were similar across rs5522 genotypes.

Conclusions: Our results suggest that spironolactone attenuates progression of diastolic dysfunction associated with the NR3C2 rs5522 G allele. Validation of our findings is needed.
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http://dx.doi.org/10.1002/phar.2626DOI Listing
September 2021

Multisite evaluation of institutional processes and implementation determinants for pharmacogenetic testing to guide antidepressant therapy.

Clin Transl Sci 2021 Sep 25. Epub 2021 Sep 25.

University of Minnesota Medical School, Minneapolis, Minnesota, USA.

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best-worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx-guided pharmacotherapy for antidepressant management.
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http://dx.doi.org/10.1111/cts.13154DOI Listing
September 2021

Genetic and Non-Genetic Factors Impact on INR Normalization in Preprocedural Warfarin Management.

Pharmgenomics Pers Med 2021 28;14:1069-1080. Epub 2021 Aug 28.

College of Pharmacy, QU Health, Qatar University, Doha, Qatar.

Background: Annually, 10% of warfarin patients will likely need to stop warfarin prior to elective surgery to achieve a baseline international normalization ratio (INR) level (INR ≤ 1.2) at the time of the procedure. This study explores the influence of genetic and non-genetic factors on INR normalization in the Arab (major part of Near Eastern) population in preprocedural warfarin management.

Methods: An observational prospective cohort study was designed to recruit Arab patients taking warfarin and scheduled for an elective procedure. Two INR readings were recorded. DNA extraction and genotyping of variants in , and (rs5896) and (rs3093229) genes using real-time polymerase chain reaction were performed.

Results: Data from 116 patients were included in the analysis. and genetic variants carriers required lower maintenance dose compared to non-carriers. The analysis showed that ciprofloxacin, antiplatelet medications, and INR index (INR at visit 1) are the only factors associated with the INR decline rate. Also, the proportion of carriers with normal INR (≤1.2) on the day of surgery was significantly lower than those with wild-type genotype (28% vs 60%, =0.013). In addition, heparin bridging, INR target, and Sudanese nationality are significant predictors of INR normalization (≤1.2) on the day of the procedure.

Conclusion: Despite the confirmed effect of genetic factors on warfarin maintenance dose, the study was not able to find a significant effect of any genetic factor on the rate of INR normalization possibly due to the small sample size. Index INR and interacting medications showed to be significant predictors of INR decline rate.
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http://dx.doi.org/10.2147/PGPM.S322743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409603PMC
August 2021

Cox-sMBPLS: An Algorithm for Disease Survival Prediction and Multi-Omics Module Discovery Incorporating -Regulatory Quantitative Effects.

Front Genet 2021 2;12:701405. Epub 2021 Aug 2.

Informatics Institute, University of Florida, Gainesville, FL, United States.

Background: The development of high-throughput techniques has enabled profiling a large number of biomolecules across a number of molecular compartments. The challenge then becomes to integrate such multimodal Omics data to gain insights into biological processes and disease onset and progression mechanisms. Further, given the high dimensionality of such data, incorporating prior biological information on interactions between molecular compartments when developing statistical models for data integration is beneficial, especially in settings involving a small number of samples.

Results: We develop a supervised model for time to event data (e.g., death, biochemical recurrence) that simultaneously accounts for redundant information within Omics profiles and leverages prior biological associations between them through a multi-block PLS framework. The interactions between data from different molecular compartments (e.g., epigenome, transcriptome, methylome, etc.) were captured by using -regulatory quantitative effects in the proposed model. The model, coined Cox-sMBPLS, exhibits superior prediction performance and improved feature selection based on both simulation studies and analysis of data from heart failure patients.

Conclusion: The proposed supervised Cox-sMBPLS model can effectively incorporate prior biological information in the survival prediction system, leading to improved prediction performance and feature selection. It also enables the identification of multi-Omics modules of biomolecules that impact the patients' survival probability and also provides insights into potential relevant risk factors that merit further investigation.
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http://dx.doi.org/10.3389/fgene.2021.701405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366414PMC
August 2021

Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing.

Genet Med 2021 Dec 19;23(12):2335-2341. Epub 2021 Jul 19.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, University of Florida College of Pharmacy, Gainesville, FL, USA.

Purpose: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear.

Methods: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates.

Results: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low.

Conclusion: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.
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http://dx.doi.org/10.1038/s41436-021-01269-9DOI Listing
December 2021

How to Integrate CYP2D6 Phenoconversion Into Clinical Pharmacogenetics: A Tutorial.

Clin Pharmacol Ther 2021 09 28;110(3):677-687. Epub 2021 Jul 28.

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

CYP2D6 genotype is increasingly being integrated into practice to guide prescribing of certain medications. The CYP2D6 drug metabolizing enzyme is susceptible to inhibition by concomitant drugs, which can lead to a clinical phenotype that is different from the genotype-based phenotype, a process referred to as phenoconversion. Phenoconversion is highly prevalent but not widely integrated into practice because of either limited experience on how to integrate or lack of knowledge that it has occurred. We built a calculator tool to help clinicians integrate a standardized method of assessing CYP2D6 phenoconversion into practice. During tool-building, we identified several clinical factors that need to be considered when implementing CYP2D6 phenoconversion into clinical practice. This tutorial shares the steps that the University of Florida Health Precision Medicine Program took to build the calculator tool and identified clinical factors to consider when implementing CYP2D6 phenoconversion in clinical practice.
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http://dx.doi.org/10.1002/cpt.2354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404400PMC
September 2021

Corrigendum to "Periprocedural Anticoagulation Management of Patients receiving Warfarin in Qatar: A Prospective Cohort Study". [Current Problems in Cardiology Volume 46, Issue 6, June 2021, 100816].

Curr Probl Cardiol 2021 Dec 19;46(12):100899. Epub 2021 Jun 19.

College of Pharmacy, QU Health, Qatar University, Doha, Qatar; Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar. Electronic address:

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http://dx.doi.org/10.1016/j.cpcardiol.2021.100899DOI Listing
December 2021

Recommendations for Clinical CYP2D6 Genotyping Allele Selection: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy.

J Mol Diagn 2021 09 10;23(9):1047-1064. Epub 2021 Jun 10.

The Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and Laboratory Medicine and Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.

The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing, and to determine a minimal set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations on a minimal panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories in designing assays for PGx testing. When developing these recommendations, the Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations with regard to PGx testing. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document is focused on clinical CYP2D6 PGx testing that may be applied to all cytochrome P450 2D6-metabolized medications. These recommendations are not meant to be interpreted as prescriptive but to provide a reference guide for clinical laboratories that may be either implementing PGx testing or reviewing and updating their existing platform.
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http://dx.doi.org/10.1016/j.jmoldx.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579245PMC
September 2021

PharmVar GeneFocus: CYP2C9.

Clin Pharmacol Ther 2021 09 12;110(3):662-676. Epub 2021 Jul 12.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri, USA.

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C9 gene. Genetic variation within the CYP2C9 gene locus impacts the metabolism or bioactivation of many clinically important drugs, including nonsteroidal anti-inflammatory drugs, phenytoin, antidiabetic agents, and angiotensin receptor blockers. Variable CYP2C9 activity is of particular importance regarding efficacy and safety of warfarin and siponimod as indicated in their package inserts. This GeneFocus provides a comprehensive overview and summary of CYP2C9 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase and the Clinical Pharmacogenetics Implementation Consortium.
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http://dx.doi.org/10.1002/cpt.2333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607432PMC
September 2021

Moving Pharmacogenetics Into Practice: It's All About the Evidence!

Clin Pharmacol Ther 2021 09 7;110(3):649-661. Epub 2021 Jul 7.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

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.
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http://dx.doi.org/10.1002/cpt.2327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376790PMC
September 2021

Determining the potential clinical value of panel-based pharmacogenetic testing in patients with chronic pain or gastroesophageal reflux disease.

Pharmacogenomics J 2021 Dec 1;21(6):657-663. Epub 2021 Jun 1.

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.

We aimed to determine the potential value of panel-based pharmacogenetic (PGx) testing in patients with chronic pain or gastroesophageal reflux disease (GERD) who underwent single-gene PGx testing to guide opioid or proton pump inhibitor (PPI) therapy, respectively. Of 448 patients included (chronic pain, n = 337; GERD, n = 111), mean age was 57 years, 68% were female, and 73% were white. Excluding opiates for the pain cohort and PPIs for the GERD cohort, 76.6% of patients with pain and 71.2% with GERD were prescribed at least one additional medication with a high level of PGx evidence, most commonly ondansetron or selective serotonin reuptake inhibitors. The most common genes that could inform PGx drug prescribing were CYP2C19, CYP2D6, CYP2C9, and SLCO1B1. Our findings suggest that patients with chronic pain or GERD are commonly prescribed drugs with a high level of evidence for a PGx-guided approach, supporting panel-based testing in these populations.
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http://dx.doi.org/10.1038/s41397-021-00244-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605985PMC
December 2021

Genetic testing in patients undergoing percutaneous coronary intervention: rationale, evidence and practical recommendations.

Expert Rev Clin Pharmacol 2021 Aug 26;14(8):963-978. Epub 2021 May 26.

Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States.

Introduction: Clopidogrel is the most frequently utilized P2Y inhibitor and is characterized by broad interindividual response variability resulting in impaired platelet inhibition and increased risk of thrombotic complications in a considerable number of patients. The potent P2Y inhibitors, prasugrel and ticagrelor, can overcome this limitation but at the expense of an increased risk of bleeding. Genetic variations of the cytochrome P450 (CYP) 2 C19 enzyme, a key determinant in clopidogrel metabolism, have been strongly associated with clopidogrel response profiles prompting investigations of genetic-guided selection of antiplatelet therapy.

Areas Covered: The present manuscript focuses on the rationale for the use of genetic testing to guide the selection of platelet P2Y inhibitors among patients undergoing percutaneous coronary intervention (PCI). Moreover, a comprehensive appraisal of the available evidence and practical recommendations is provided.

Expert Commentary: Implementation of genetic testing as a strategy to guide the selection of therapy can result in escalation (i.e. switching to prasugrel or ticagrelor) or de-escalation (i.e. switching to clopidogrel) of P2Y inhibiting therapy. Most recent investigations support the clinical benefit of a genetic guided selection of antiplatelet therapy in patients undergo PCI. Integrating the results of genetic testing with clinical and procedural variables represents a promising strategy for a precision medicine approach for the selection of antiplatelet therapy among patients undergoing PCI.
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http://dx.doi.org/10.1080/17512433.2021.1927709DOI Listing
August 2021

Pharmacogenetics to guide cardiovascular drug therapy.

Nat Rev Cardiol 2021 Sep 5;18(9):649-665. Epub 2021 May 5.

Center for Pharmacogenomics and Precision Medicine and Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA.

Over the past decade, pharmacogenetic testing has emerged in clinical practice to guide selected cardiovascular therapies. The most common implementation in practice is CYP2C19 genotyping to predict clopidogrel response and assist in selecting antiplatelet therapy after percutaneous coronary intervention. Additional examples include genotyping to guide warfarin dosing and statin prescribing. Increasing evidence exists on outcomes with genotype-guided cardiovascular therapies from multiple randomized controlled trials and observational studies. Pharmacogenetic evidence is accumulating for additional cardiovascular medications. However, data for many of these medications are not yet sufficient to support the use of genotyping for drug prescribing. Ultimately, pharmacogenetics might provide a means to individualize drug regimens for complex diseases such as heart failure, in which the treatment armamentarium includes a growing list of medications shown to reduce morbidity and mortality. However, sophisticated analytical approaches are likely to be necessary to dissect the genetic underpinnings of responses to drug combinations. In this Review, we examine the evidence supporting pharmacogenetic testing in cardiovascular medicine, including that available from several clinical trials. In addition, we describe guidelines that support the use of cardiovascular pharmacogenetics, provide examples of clinical implementation of genotype-guided cardiovascular therapies and discuss opportunities for future growth of the field.
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http://dx.doi.org/10.1038/s41569-021-00549-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364496PMC
September 2021

Cost-effectiveness analysis of genotyping for HLA-B*15:02 in Indonesian patients with epilepsy using a generic model.

Pharmacogenomics J 2021 08 6;21(4):476-483. Epub 2021 Apr 6.

Health Policy & Behavioral Sciences, Georgia State University, Atlanta, GA, USA.

Carbamazepine (CBZ)-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are strongly associated with the HLA-B*15:02 allele. Screening HLA-B*15:02 before CBZ administration might prevent CBZ-induced SJS/TEN by enabling clinicians to prescribe alternative therapy for positive patients. Similar to other Southeastern Asian countries, HLA-B*15:02 is highly prevalent in Indonesia. Therefore, we assessed the economic value of HLA-B*15:02 screening before CBZ prescription to patients with epilepsy in Indonesia. A generic cost-effectiveness model and decision support tool, developed to enable users to perform an initial cost-effectiveness analysis from a healthcare provider/payer perspective, were used to assess the value of HLA-B*15:02 genotyping. The incremental cost-effectiveness ratio of adopting universal HLA-B*15:02 screening was 656,444,671 Indonesian Rupiah (IDR)/quality-adjusted life year (QALY) gained for patients compared with 2,634,975,574 IDR/QALY gained for providing valproic acid (alternative drug) without screening. Thus, neither HLA-B*15:02 screening nor substitution with VPA meets the Indonesian threshold for cost effectiveness. However, the improved outcomes with this test in other Asian countries may inform the desirability of implementation in Indonesia even with suboptimal cost-effectiveness.
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http://dx.doi.org/10.1038/s41397-021-00225-9DOI Listing
August 2021

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network.

Genet Med 2021 07 29;23(7):1185-1191. Epub 2021 Mar 29.

Division of Genomic Medicine, National Human Genome Research Institute, NIH, Bethesda, MD, USA.

Purpose: A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions.

Methods: The Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation.

Results: Two pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression.

Conclusion: IGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.
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http://dx.doi.org/10.1038/s41436-021-01118-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263480PMC
July 2021

Periprocedural Anticoagulation Management of Patients receiving Warfarin in Qatar: A Prospective Cohort Study.

Curr Probl Cardiol 2021 Jun 15;46(6):100816. Epub 2021 Feb 15.

College of Pharmacy, QU Health, Qatar University, Doha, Qatar; Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar. Electronic address:

Background: The use of anticoagulant bridging remains controversial. This study was conducted to evaluate our warfarin periprocedural management in Qatar and investigate the associated clinical outcomes with such management.

Methods: A prospective cohort study was designed to describe the periprocedural clinical practice in warfarin patients in Qatar and to compare clinical safety and efficacy outcomes between anticoagulant bridging and nonbridging.

Results: 103 patients were recruited. Bridging occurred in 82% of the participants. No thromboembolic events were observed, while 39.1% of patients experienced bleeding events during the study period. The incidence of overall bleeding and major bleeding were numerically higher for bridging group compared to nonbridging but did not reach statistical significance ([30.6% vs 22.2%, P = 0.478] and [12.9% vs 5.6%, P = 0.375], respectively).

Conclusion: Warfarin interruption and bridging are overwhelmingly used in warfarin-treated patients in Qatar. While bridging was numerically associated with increased bleeding events, there is no statistical difference in reported clinical events between bridging and nonbridging strategies.
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http://dx.doi.org/10.1016/j.cpcardiol.2021.100816DOI Listing
June 2021

Opportunity for Genotype-Guided Prescribing Among Adult Patients in 11 US Health Systems.

Clin Pharmacol Ther 2021 07 16;110(1):179-188. Epub 2021 Feb 16.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

The value of utilizing a multigene pharmacogenetic panel to tailor pharmacotherapy is contingent on the prevalence of prescribed medications with an actionable pharmacogenetic association. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has categorized over 35 gene-drug pairs as "level A," for which there is sufficiently strong evidence to recommend that genetic information be used to guide drug prescribing. The opportunity to use genetic information to tailor pharmacotherapy among adult patients was determined by elucidating the exposure to CPIC level A drugs among 11 Implementing Genomics In Practice Network (IGNITE)-affiliated health systems across the US. Inpatient and/or outpatient electronic-prescribing data were collected between January 1, 2011 and December 31, 2016 for patients ≥ 18 years of age who had at least one medical encounter that was eligible for drug prescribing in a calendar year. A median of ~ 7.2 million adult patients was available for assessment of drug prescribing per year. From 2011 to 2016, the annual estimated prevalence of exposure to at least one CPIC level A drug prescribed to unique patients ranged between 15,719 (95% confidence interval (CI): 15,658-15,781) in 2011 to 17,335 (CI: 17,283-17,386) in 2016 per 100,000 patients. The estimated annual exposure to at least 2 drugs was above 7,200 per 100,000 patients in most years of the study, reaching an apex of 7,660 (CI: 7,632-7,687) per 100,000 patients in 2014. An estimated 4,748 per 100,000 prescribing events were potentially eligible for a genotype-guided intervention. Results from this study show that a significant portion of adults treated at medical institutions across the United States is exposed to medications for which genetic information, if available, should be used to guide prescribing.
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http://dx.doi.org/10.1002/cpt.2161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217370PMC
July 2021

A hybrid implementation-effectiveness randomized trial of CYP2D6-guided postoperative pain management.

Genet Med 2021 04 8;23(4):621-628. Epub 2021 Jan 8.

Department of Pharmacotherapy and Translation Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Purpose: Cytochrome P450 2D6 (CYP2D6) genotype-guided opioid prescribing is limited. The purpose of this type 2 hybrid implementation-effectiveness trial was to evaluate the feasibility of clinically implementing CYP2D6-guided postsurgical pain management and determine that such an approach did not worsen pain control.

Methods: Adults undergoing total joint arthroplasty were randomized 2:1 to genotype-guided or usual pain management. For participants in the genotype-guided arm with a CYP2D6 poor (PM), intermediate (IM), or ultrarapid (UM) metabolizer phenotype, recommendations were to avoid hydrocodone, tramadol, codeine, and oxycodone. The primary endpoints were feasibility metrics and opioid use; pain intensity was a secondary endpoint. Effectiveness outcomes were collected 2 weeks postsurgery.

Results: Of 282 patients approached, 260 (92%) agreed to participate. In the genotype-guided arm, 20% had a high-risk (IM/PM/UM) phenotype, of whom 72% received an alternative opioid versus 0% of usual care participants (p < 0.001). In an exploratory analysis, there was less opioid consumption (200 [104-280] vs. 230 [133-350] morphine milligram equivalents; p = 0.047) and similar pain intensity (2.6 ± 0.8 vs. 2.5 ± 0.7; p = 0.638) in the genotype-guided vs. usual care arm, respectively.

Conclusion: Implementing CYP2D6 to guide postoperative pain management is feasible and may lead to lower opioid use without compromising pain control.
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http://dx.doi.org/10.1038/s41436-020-01050-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525217PMC
April 2021

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy.

Clin Pharmacol Ther 2021 10 9;110(4):888-896. Epub 2021 Feb 9.

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.
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http://dx.doi.org/10.1002/cpt.2149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249478PMC
October 2021

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients.

JAMA Netw Open 2020 12 1;3(12):e2029411. Epub 2020 Dec 1.

Personalized Medicine Initiative, Nicklaus Children's Health System, Miami, Florida.

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation.

Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions.

Design, Setting, And Participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020.

Exposures: Prescription of 38 level A medications based on electronic health records.

Main Outcomes And Measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally.

Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes.

Conclusions And Relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.29411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737091PMC
December 2020

Implications of Polymorphisms in the BCKDK and GATA-4 Gene Regions on Stable Warfarin Dose in African Americans.

Clin Transl Sci 2021 03 16;14(2):492-496. Epub 2020 Dec 16.

Department of Pharmacotherapy & Translational Research, Center for Pharmacogenomics & Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

VKORC1 and CYP2C9 genotypes explain less variability in warfarin dose requirements in African Americans compared with Europeans. Variants in BCKDK and GATA-4 gene regions, purported to regulate VKORC1 and CYP2C9 expression, have been shown to play an important role in warfarin dose requirements in Europeans and Asians, respectively. We sought to determine whether rs56314408 near BCKDK or GATA-4 rs2645400 influence warfarin dose requirements in 200 African Americans. Unlike the strong linkage disequilibrium (LD) between rs56314408 and VKORC1 rs9923231 in Europeans, they were not in LD in African Americans. No associations were found on univariate analysis. On multivariable analysis, rs56314408 was associated (P = 0.027) with dose in a regression model excluding VKORC1 rs9923231, and GATA-4 rs2645400 was associated (P = 0.032) with dose in a model excluding CYP2C (CYP2C9*2, *3, *5, *6, *8, and *11, CYP2C rs12777823) variants. Neither variant contributed to dose in the model that included both VKORC1 rs9923231 and CYP2C variants. Our results do not support contributions of the studied variants to warfarin dose requirements in African Americans. However, they illustrate the value of studies in African descent populations, who have low LD in their genome, in teasing out genetic variation underlying drug response associations. They also emphasize the importance of confirming associations in persons of African ancestry.
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http://dx.doi.org/10.1111/cts.12939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993290PMC
March 2021

Acceptability, Feasibility, and Utility of Integrating Pharmacogenetic Testing into a Child Psychiatry Clinic.

Clin Transl Sci 2021 03 9;14(2):589-598. Epub 2020 Nov 9.

Department of Psychiatry, College of Medicine, Center for OCD, Anxiety, and Related Disorders, University of Florida, Gainesville, Florida, USA.

Pharmacogenetic (PGx) testing is a tool to identify patients at a higher risk of adverse events or treatment failure. The concern for unwanted side effects can limit medication adherence, particularly in children and adolescents. We conducted a pragmatic study to evaluate the acceptability and feasibility and gather pilot data on the utility of PGx testing in a child and adolescent psychiatry clinic. Both physicians and families participated in the study and answered pre-survey and post-survey questionnaires to examine their attitudes toward PGx testing. Patients were randomized into implementation (N = 25) and control groups (N = 24) and underwent PGx testing at the beginning or end of the study, respectively. Clinical consult notes with genotype-guided recommendations were provided to physicians for their consideration in clinical decisions. Patient-reported symptom severity and antidepressant-related side effects were assessed at baseline and for 12 weeks. Both participating physicians and families agreed that PGx testing is a useful tool to improve medication selection. The time from sample collection to having PGx test results was ~ 10 days and 15 days to having consult notes available, which may have impaired test utility in clinical decision making. There were no differences in any clinical end point between the implementation and control arms; however, there were higher antidepressant side effect scores for CYP2D6 poor and intermediate metabolizers after the eighth week of treatment. Our findings revealed benefits and pitfalls with the use of PGx testing in the real-world clinical setting, which may inform the methodology of a larger trial focused on outcomes.
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http://dx.doi.org/10.1111/cts.12914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993320PMC
March 2021

Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype-Derived Activity Scores.

CPT Pharmacometrics Syst Pharmacol 2020 12 3;9(12):678-685. Epub 2020 Nov 3.

Department of Pharmacotherapy and Translation Research, Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.
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http://dx.doi.org/10.1002/psp4.12563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762806PMC
December 2020

Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Clin Pharmacol Ther 2021 03 2;109(3):705-715. Epub 2020 Oct 2.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida, USA.

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.
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http://dx.doi.org/10.1002/cpt.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902344PMC
March 2021

Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos.

Clin Transl Sci 2021 01 8;14(1):268-276. Epub 2020 Sep 8.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida, USA.

We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β = -0.29, P < 2.0 × 10 ; β = -0.21, P = 4.7 × 10 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (β = 0.10, P = 2 × 10 ; β = 0.10, P = 0.01, respectively). Associations with VKORC1 (β = -0.14, P = 2.0 × 10 ), CYP2C9 (β = -0.07, P = 5.6 × 10 ), and CYP4F2 (β = 0.03, P = 3 × 10 ), but not NQO1*2 (β = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil.
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http://dx.doi.org/10.1111/cts.12854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877858PMC
January 2021

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing.

Clin Pharmacol Ther 2021 06 20;109(6):1417-1423. Epub 2020 Sep 20.

Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

Proton pump inhibitors (PPIs) are widely used for acid suppression in the treatment and prevention of many conditions, including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, Helicobacter pylori infection, and pathological hypersecretory conditions. Most PPIs are metabolized primarily by cytochrome P450 2C19 (CYP2C19) into inactive metabolites, and CYP2C19 genotype has been linked to PPI exposure, efficacy, and adverse effects. We summarize the evidence from the literature and provide therapeutic recommendations for PPI prescribing based on CYP2C19 genotype (updates at www.cpicpgx.org). The potential benefits of using CYP2C19 genotype data to guide PPI therapy include (i) identifying patients with genotypes predictive of lower plasma exposure and prescribing them a higher dose that will increase the likelihood of efficacy, and (ii) identifying patients on chronic therapy with genotypes predictive of higher plasma exposure and prescribing them a decreased dose to minimize the risk of toxicity that is associated with long-term PPI use, particularly at higher plasma concentrations.
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http://dx.doi.org/10.1002/cpt.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868475PMC
June 2021
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