Larisa Humma Cavallari

• PharmD
• Managing Director at University of Florida

Pharmacogenetic (PGx) testing can individualize pharmacotherapy, but many current panels lack inclusivity for diverse populations and are often cost‐prohibitive for medically underserved communities. This study aimed to develop and validate GatorPGx Plus, a low‐cost, preemptive PGx panel tailored for diverse patient populations. Pharmacogenes were...

African Americans (AAs) are underrepresented in pharmacogenomics which has led to a significant gap in knowledge. AAs are admixed and can inherit specific loci from either their African or European ancestor, known as local ancestry (LA). A previous study in AAs identified single nucleotide polymorphisms (SNPs) located in the CYP2C cluster that are...

In the past decade, pharmacogenomic (PGx) testing to predict drug response have emerged into clinical care. Clinical decision support (CDS) has and continues to play a key role in educating prescribers and facilitating the integration of pharmacogenomic results into routine clinical practice. The Epic Genomics module, an add‐on to Epic's base clini...

Pharmacogenomic (PGx) considerations are increasingly influencing health system formularies, prompting Pharmacy and Therapeutics (P&T) committees to integrate genetic insights into their decision‐making processes. This can be the case in several clinical scenarios, including (1) Prioritizing the use of lower‐cost drugs, where PGx testing is applied...

Introduction: Identifying patients at risk for ischemic events after percutaneous coronary intervention (PCI) relies on traditional analysis of limited clinical and imaging variables. Machine learning (ML) has shown promise in effectively predicting cardiovascular risk in population studies. While existing ML models mainly predict mortality and inc...

Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual’s genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practic...

Warfarin dose requirements are highly variable due to clinical and genetic factors. While genetic variants influencing warfarin dose have been identified in European and East Asian populations, more work is needed to identify African-specific genetic variants to help optimize warfarin dosing. We performed genome-wide association studies (GWAS) in f...

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no‐function allele that reduces the effectiveness of clopidogrel, but not...

The ABCD‐GENE score was developed to predict poor response to clopidogrel and includes A ge, B ody mass index, C hronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m ² ), D iabetes, and CYP2C19 GENE variants; a score ≥ 10 is predictive of reduced clopidogrel effectiveness after percutaneous coronary interventio...

There is significant variability in the efficacy and safety of oral P2Y12 inhibitors, which are used to prevent ischemic outcomes in common diseases such as coronary and peripheral arterial disease and stroke. Clopidogrel, a prodrug, is the most used oral P2Y12 inhibitor and is activated primarily after being metabolized by a highly polymorphic hep...

The ability of freely available in silico tools to predict the effect of non‐synonymous single nucleotide polymorphisms (nsSNPs) in pharmacogenes on protein function is not well defined. We assessed the performance of seven sequence‐based (SIFT, PolyPhen2, mutation accessor, FATHMM, PhD‐SNP, MutPred2, and SNPs & Go) and five structure‐based (mCSM,...

Background Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel...

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic ra...

The University of Florida Health Precision Medicine Program plays a crucial role in delivering pharmacogenomics (PGx) result notes to providers who request PGx testing. Despite this, there is currently a lack of a formal assessment of provider needs and established best practice design principles to guide the ongoing development of PGx result notes...

Pharmacogenomics is a growing area of medicine, and pharmacists across clinical practice settings have the opportunity to individualize medication selection and dosing using genetic data. However, many practicing pharmacists may feel ill‐equipped to interpret pharmacogenomic test results because of insufficient education and training. Evidence‐base...

This prospective ex vivo and in vitro pharmacodynamic (PD)/pharmacokinetic investigation was conducted in patients with diabetes mellitus with (n = 31) and without chronic kidney disease (n = 30). PD assessments included platelet reactivity index, maximum platelet aggregation, and P2Y12 reaction units. Ex vivo pharmacokinetic assessments included p...

Previous findings suggest that medically underserved patients are prescribed medications with pharmacogenetic (PGx) guidelines at a high frequency. Thus, underserved patients may especially benefit from PGx testing, but little evidence exists regarding the effect of testing in this population. This pilot study aimed to generate key feasibility data...

Given the high prevalence of pain in older adults and current trends in opioid prescribing, inclusion of genetic information in risk prediction tools may improve opioid risk assessment. Our objectives were to (1) determine the feasibility of recruiting socioeconomically disadvantaged and racially diverse middle aged and older adult populations for...

The objective of this study was to characterize clinician response following standardization of pharmacogenetic (PGx) clinical decision support alerts at University of Florida (UF) Health. A retrospective analysis of all PGx alerts that fired at a tertiary academic medical center from August 2020 through May 2022 was performed. Alert acceptance rat...

Introduction The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer‐related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6 ‐guided opioid prescribing for patients with cancer and report pilot outcome data. Methods Adult patients from two cancer cent...

Introduction: This manuscript reports on a pilot program focused on implementing pharmacogenetic testing within the framework of an employer-sponsored medical plan at University of Florida (UF) Health. The aim was to understand the challenges associated with program implementation and to gather insights into patient attitudes towards PGx testing. M...

Introduction: Pharmacogenetics (PGx) has the potential to improve health outcomes but cost of testing is a barrier for equitable access. Reimbursement by insurance providers may lessen the financial burden for patients, but the extent to which PGx claims are covered in clinical practice has not been well-characterized in the literature. Methods: A...

The goals of the Association for Molecular Pathology (AMP) Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provide recommendatio...

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...

Background: The authors aimed to assess outcomes with a pharmacogenetic (PGx)-informed, pharmacist-guided, personalized consult service for warfarin dosing. Methods: This retrospective cohort study included patients admitted with thromboembolic events. Eligible subjects received either PGx-informed (n = 389) or historical non-PGx pharmacist-guided...

Purpose To describe the implementation of CYP2C19 testing into clinical practice at University of Florida (UF) Health Gainesville hospital to guide proton pump inhibitor (PPI) dosing and the lessons learned from this experience. Summary Different CYP2C19 genotypes are associated with variability in PPI plasma concentrations and intragastric pH, wh...

Importance: A platelet ADP P2Y12 receptor (P2Y12) inhibitor plus aspirin is standard therapy for patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). Compared with clopidogrel, prasugrel and ticagrelor are associated with superior antiatherothrombotic effects but increased bleeding risk; with recent guide...

Swen et al.1 examine the utility of multi-gene pharmacogenetic testing in a large multi-national cohort. They show fewer adverse drug reactions among patients receiving testing and prescribing recommendations based on genotype results compared with those receiving usual care.

Oral P2Y12 inhibitors are commonly prescribed for cardiovascular disease and include clopidogrel, prasugrel, and ticagrelor. Each of these drugs has its strengths and weaknesses. Prasugrel and ticagrelor are more potent inhibitors of platelet aggregation and were shown to be superior to clopidogrel in preventing major adverse cardiovascular events...

The anticoagulant warfarin is commonly used to control and prevent thrombotic disorders such as venous thromboembolism (VTE), which disproportionately afflicts African Americans (AAs). Despite the importance of copy number variants (CNVs), few studies have focused on characterizing and understanding their role in drug response and disease risk amon...

Introduction: Many patients with chronic pain use prescription opioids. Epigenetic modification of the μ-opioid receptor 1 (OPRM1) gene, which codes for the target protein of opioids, may influence vulnerability to opioid abuse and response to opioid pharmacotherapy, potentially affecting pain outcomes. Objective: Our objective was to investigat...

Accuracy of warfarin dose prediction algorithms may be improved by including data from diverse populations in genetic studies of dose variability. Here, we surveyed single nucleotide polymorphisms in vitamin K‐related genes for association with warfarin dose requirements in two admixed Latino populations in standard‐principal component adjusted and...

Abstract Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from nine sites tha...

The vast majority of patients possess one or more pharmacogenetic variants that can influence optimal medication use. When pharmacogenetic data are used to guide drug choice and dosing, evidence points to improved disease outcomes, fewer adverse effects, and lower healthcare spending. Although its science is well established, clinical use of pharma...

Background: In the United States, hypertension disproportionately afflicts over half of African American adults, many of whom also experience racial discrimination. Understanding gene x discrimination effects may help explain racial disparities in hypertension. Methods: We tested for main effects and interactive effects of five candidate single...

Opioid prescribing for postoperative pain management is challenging because of inter‐patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., int...

The goals of the Association for Molecular Pathology (AMP) Clinical Practice Committee’s Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendati...

Dual antiplatelet therapy with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin remains the standard of care for all patients undergoing percutaneous coronary intervention (PCI). It is well-established that patients carrying CYP2C19 no function alleles have impaired capacity to convert clopidogrel into its active metabolite and...

There are limited comparison data throughout the dosing interval for generic versus brand metoprolol extended‐release (ER) tablets. We compared the pharmacokinetics (PK) and pharmacodynamics (PD) of brand name versus two generic formulations (Drugs 1 and 2) of metoprolol ER tablets with different time to maximum concentration (Tmax) in adults with...

Background Despite the increased demand for pharmacogenetic (PGx) testing to guide antidepressant use, little is known about how to implement testing in clinical practice. Best–worst scaling (BWS) is a stated preferences technique for determining the relative importance of alternative scenarios and is increasingly being used as a healthcare assessm...

The ABCD‐GENE score was developed to identify patients at risk for diminished antiplatelet effects with clopidogrel after percutaneous coronary intervention (PCI) and utilizes Age, Body mass index, Chronic kidney disease, Diabetes and CYP2C19 GENEtic variants. The objective of this study was to validate the ability of ABCD‐GENE score to predict ris...

Introduction: One-third of patients have clopidogrel resistance that may lead to major adverse cardiac events (MACEs). By contrast, it was found that some clopidogrel-treated patients have hyperresponsive platelets that are associated with higher bleeding risk. Several studies have shown that polymorphisms in the gene encoding the CYP2C19 contribu...

Background: Multiple clinical trials have evaluated the efficacy and safety of aldosterone receptor antagonist (ARA) use in heart failure (HF). They indicate that not all HF patients have the same level of hyperkalemia risk or morbidity risk reduction on ARAs. Identification of clinical predictors of patient response to ARAs would allow for treatme...

Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss‐of‐function (LOF) variant carriers versus non‐carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real‐world outcomes with the clinical implementation of CYP2C19 ‐guided antiplatelet therapy after...

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...

Pharmacogenetic dosing improves the accuracy of warfarin dosing, but current pharmacogenetic dosing algorithms are less accurate in populations of African ancestry. The cytochrome P450 2C9*5 (CYP2C9*5) allele is found almost exclusively in populations of African ancestry, and in‐vitro studies suggest CYP2C9*5 is associated with reduced clearance of...

Aim: We evaluated the clinical acceptance and feasibility of a pharmacist-guided personalized consult service following its transition from a mandatory (mPGx) to optional (oPGx) CYP2C9/ VKORC1/ CYP4F2 genotyping for warfarin. Methods: A total of 1105 patients were included. Clinical acceptance and feasibility outcomes were analyzed using bivariate...

Ineffective pain control is the most commonly cited reason for misuse of prescription opioids and is influenced by genetics. In particular, the gene encoding the CYP2D6 enzyme, which metabolizes some of the most commonly prescribed opioids (eg, tramadol, hydrocodone) to their more potent forms, is highly polymorphic and can lead to reduced concentr...

Aims Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the compara...

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 ye...

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...

Introduction: Few genome-wide association studies (GWAS) of heart failure (HF) mortality have been published, with most focused on incidence or surrogate endpoints. Our aim was to identify genomic predictors of HF mortality in a racially diverse population. Hypothesis: Both ancestry-specific and trans-ancestry variants are associated with survival...

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 incre...

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 pr...

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...

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...

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) pop...

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...

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 countr...

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 dec...

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 hi...

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...

The goals of the Association for Molecular Pathology (AMP) Clinical Practice Committee’s Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and determine a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides re...

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 NSAIDs, phenytoin, anti‐diabetic agents and angiotensin receptor blocker. Variable CYP2C9...

Abstract: 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 pat...

Introduction Clopidogrel is the most frequently utilized P2Y12 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 P2Y12 inhibitors, prasugrel and ticagrelor, can overcome this limitation...

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 g...

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. 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...

Introduction Although the majority of pharmacy schools are teaching pharmacogenetics in their curricula, there is limited coverage of important clinical concepts and pharmacists report low comfortability in utilizing pharmacogenetic results. Objectives To compare the effectiveness of a combined didactic and patient case‐based, interactive teaching...

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. Method : A prospective cohort study was designed to describe the periprocedural clinical practice in warfarin patients in Q...

The value of utilizing a multi‐gene 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 evid...

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. Adults undergoing total joint arthropl...

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 which have been studied for their association w...

VKORC1 and CYP2C9 genotypes explain less variability in warfarin dose requirements in African Americans (AAs) compared to 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 t...

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 b...

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...

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 clas...

Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers (genotype-guided escalation). Cost-effectiveness analyses (CEA) are t...

We conducted a multi‐site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from five institutions in the U.S. (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...

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 p...

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, H. pylori infection, and pathological hypersecretory conditions. Most PPIs are metabolized primarily by CYP2C19 into inactive metabolites,...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Introduction Clinical adoption of genomic medicine has lagged behind the pace of scientific discovery. Practice-based resources can help overcome implementation challenges. Methods In 2015, the IGNITE (Implementing GeNomics In pracTicE) Network created an online genomic medicine implementation resource toolbox that was expanded in 2017 to incorpor...