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Clinicians have limited options outside controlled substances to address sleep disturbance, which left untreated can negatively affect patient outcomes in cardiovascular health, mental health, immunologic function, and more. For some, genetic factors may influence sleep disturbances. L-methylfolate, the active form of folate, plays a critical role in regulation of monoamine neurotransmitters known to have significant impact on sleep regulation: dopamine, serotonin, norepinephrine. Single nucleotide polymorphisms of the enzyme methylene-tetrahydrofolate-reductase are common and can impact monoamine production. The goal of this study was to evaluate effects of L-methylfolate supplementation on sleep in a cohort with reduced methylene tetrahydrofolate reductase (MTHFR) activity. A retrospective cohort of patients being treated with L-methylfolate in a concierge medical clinic setting was studied. Patients presenting with sleep complaints were evaluated using the Patient-Reported Outcomes Measurement Information System at baseline. Patients with known MTHFR polymorphisms at either C667T and/or A1298C were recommended 5 mg of L-methylfolate daily and were reevaluated at 2 wks, at 4 wks, and at 8 wks of supplementation. Statistical comparisons were made utilizing ANOVA and T-test comparisons. Ten were included in the final cohort: six male and four female, average age 43 ± 16 years. Beginning at wk 2, average sleep disturbance improved significantly by −6.94 points (p = 0.005) and by 8 wks, all patients had improvement with a −14.34 change in disturbance from baseline (p = 0.001). Improvement in sleep disturbance was seen in both low and intermediate function phenotypes. L-methylfolate may be useful for improving sleep in patients with MTHFR polymorphism. [ABSTRACT FROM AUTHOR]

Purpose Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US. Summary Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19 -clopidogrel, CYP2D6 -codeine, CYP2D6 -tramadol, CYP2B6 -efavirenz, TPMT -thiopurines, and NUDT15 -thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization. Conclusion A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing. [ABSTRACT FROM AUTHOR]

Introduction: Preemptive pharmacogenomic (PGx) testing is on the rise among United States health care centers, with the majority of testing performed in the primary care setting. For broader implementation, there is a call for descriptions of the implementation and workflow of successful PGx programs in a large variety of health care settings. Objective: The purpose of this study was to describe the implementation and initial outcomes of preemptive PGx (11‐gene, multipanel) testing in inpatient workflow at a Veterans Affairs medical center. Methods: The inpatient clinical pharmacist incorporated patient screening, informed consent, and PGx lab ordering into their daily workflow in March 2023. Included adult patients had to be enrolled into the facility's primary care program and able to provide informed consent. Patients were excluded if they had a history of bone marrow or liver transplant, were consulted for palliative or hospice care, or had altered mental status at the time of screening. A retrospective chart review was used to collect demographics and PGx results from March to August 2023. Results: There were 247 patients screened for PGx testing in the 6‐month study period. Of these, 74 already had PGx performed, 31 declined or deferred testing, and 142 consented to testing. Laboratory blood draw was not performed as ordered on 12 patients, leaving 130 samples with results. Of 130 patients, 129 (99%) had an actionable PGx variant, with most having multiple variants: one variant (6%), two variants (15%), three variants (32%), four variants (24%), five variants (18%), and six variants (3%). At the time of follow‐up, 64 (49%) patients were prescribed an affected medication: one medication (38%), two medications (8%), and three medications (3%). Conclusion: Incorporating preemptive PGx testing into inpatient workflow is feasible in a rural facility with a significant proportion of patients being affected by the results. [ABSTRACT FROM AUTHOR]

Clinical implementation of pharmacogenomic (PGx)‐guided prescribing in oncology lags behind research evidence generation. We aimed to identify healthcare professionals' (HCPs) and consumers' knowledge, attitudes, perspectives, and education needs to inform strategies for implementation of scalable and sustainable oncology PGx programs. Systematic review of original articles indexed in EMBASE, EMCARE, MEDLINE, and PsycInfo from January 2012 until June 2022, following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines and using the Mixed Methods Appraisal Tool. PROSPERO registration number CRD42022352348. Of 1442 identified studies; 23 met inclusion criteria with 87% assessed high quality. Of these, 52% reported on HCPs, 35% on consumers, and 13% on both HCPs and consumers. Most were conducted in the United States (70%) and included multiple cancer types (74%). Across studies, HCPs and consumers mostly perceived value in PGx, however, both groups reported barriers to utilization, including cost, lack of consistent recommendations across guidelines, and limited knowledge among HCPs; test accuracy, clear testing benefits, and genomic information confidentiality among consumers. HCPs and consumers value and want to engage in PGx strategies in oncology care, however, are inhibited by unmet needs and practice and knowledge gaps. Implementation strategies aimed at addressing these issues may best support increased PGx uptake in oncology practice. [ABSTRACT FROM AUTHOR]

The article discusses the American Society of Health-System Pharmacists (ASHP) House of Delegates' approved professional policies as of November 2023. Topics covered include the goals and sources of Education and Training in Digital Health, of Digital Therapeutics Products, of Interoperability of Patient-Care Technologies, Patient Medication Delivery Systems, and Education About Performance-Enhancing Substances. Also noted is the category of Support for Food and Drug Expanded Access Program.

Simple Summary: In the treatment of colorectal cancer, classic chemotherapy drugs such as 5-fluorouracil, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil have played a crucial role. Through the analysis of the top 100 most influential articles, we examined the evolution in research and current relevance, confirming the continued significance of this group of drugs despite the emergence of new treatments. The research reveals global collaboration among institutions, countries (primarily the United States, China, and Europe), and researchers, with three main themes driving the study: pharmacogenetics, new pharmaceutical formulations, and the use of adjuvants. In the landscape of colorectal cancer treatment, classical chemotherapeutic agents such as 5-fluorouracil, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil have historically played a pivotal role. This study presents a comprehensive bibliometric analysis of the top 100 most influential articles focusing on these classic chemotherapy drugs in the management of colorectal cancer. With this, we shed light on their current importance, despite the emergence of new therapeutic targets and treatments in the field of oncology. Systematically evaluating research outputs, this analysis reveals a prevalence of co-authorship among institutions, countries (led by the United States, China, and Europe), and researchers highlighting the global and collaborative nature of efforts in research, utilization, and development of these drugs. Three thematic axes lead the research: pharmacogenetics, the development of new pharmaceutical forms, and the use of adjuvants. This research serves as a foundation for future endeavors, aiding researchers, clinicians, and policymakers in making informed decisions about the direction of research and development in the dynamic field of colorectal cancer therapy. [ABSTRACT FROM AUTHOR]

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 wellcharacterized in the literature. Methods: A retrospective analysis of outpatient claims submitted to payers for PGx tests from 1/1/2019 through 12/31/2021 was performed. A reimbursement rate was calculated and compared across specific test types (e.g., single genes, panel), payers, indication, and the year the claim was submitted. Results: A total of 1,039 outpatient claims for PGx testing were analyzed. The overall reimbursement rate was 46% and ranged from 36%–48% across payers. PGx panels were reimbursed at a significantly higher rate than single gene tests (74% vs. 43%, p < 0.001). Discussion: Reimbursement of claims for PGx testing is variable based on the test type, indication, year the claim was submitted, number of diagnosis codes submitted, and number of unique diagnosis codes submitted. Due to the highly variable nature of reimbursement, cost and affordability should be discussed with each patient. [ABSTRACT FROM AUTHOR]

The article commends the authors of the Standardizing Laboratory Practices in Pharmacogenetics (STRIPE) Study Designs Task Force (SDTF) for describing the current status of pharmacogenetic (PGx) testing recommendations within U.S.-based clinical practice guidelines (CPGs). Topics include the most frequently addressed recommendations for testing, reasons for the limited and disparate uptake of PGx recommendations into CPGs, and suggestions to further advance the clinical uptake of PGx.

Underrepresentation of subpopulations within geo-ancestral groups engaged in research can exacerbate health disparities and impair progress toward personalized medicine. This is particularly important when implementing pharmacogenomics which uses genomic-based sources of variability to guide medication selection and dosing. This mini-review focuses on pharmacogenomic findings with Hmong in the United States and their potential clinical implications. By actively engaging Hmong community in pharmacogenomic-based research, several clinically relevant differences in allele frequencies were observed within key pharmacogenes such as CYP2C9 and CYP2C19 in Hmong compared to those in either East Asians or Europeans. Additionally, using state-of-the-art genome sequencing approaches, Hmong appear to possess novel genetic variants within CYP2D6, a critical pharmacogene affecting pharmacokinetics of a broad range of medications. The allele frequency differences and novel alleles in Hmong have translational impact and real-world clinical consequences. For example, Hmong patients exhibited a lower warfarin stable dose requirement compared to East Asian patients. This was predicted based on Hmong's unique genetic and non-genetic factors and confirmed using real-world data from clinical practice settings. By presenting evidence of the genetic uniqueness and its translational impact within subpopulations, such as the Hmong, we hope to inspire greater inclusion of other geo-ancestrally underrepresented subpopulations in pharmacogenomic-based research. [ABSTRACT FROM AUTHOR]

Abstract: Response to analgesic therapy is influenced by several factors including genetics and drug-drug interactions. Pharmacogenetic (PGx) variants in the CYP2D6 gene modify response to opioids by altering drug metabolism. We sought to determine the potential impact of PGx testing on the care of Veterans with noncancer pain prescribed opioids metabolized by CYP2D6 (codeine, hydrocodone, or tramadol). A retrospective analysis was performed within the Veterans Health Administration evaluating prescription records for pain medications metabolized by CYP2D6 and interacting drugs from 2012 to 2017. Among 2,436,654 Veterans Health Administration pharmacy users with at least 1 opioid prescription, 34% met the definition of chronic use (longer than 90 days with more than 10 prescriptions or 120 days-supply). Opioids were commonly coprescribed with antidepressants interacting with CYP2D6 (28%). An estimated 21.6% (n = 526,905) of these patients are at an elevated risk of an undesirable response to their opioid medication based on predicted phenotypes and drug-drug interactions: 3.5% are predicted CYP2D6 ultrarapid metabolizers and at increased risk for toxicity, 5.4% are poor metabolizers at higher risk for nonresponse, and 12.8% are normal or intermediate metabolizers coprescribed a CYP2D6 inhibitor leading to phenoconversion into poor metabolizer. Despite the high rate of coprescription of opioids and interacting drugs, CYP2D6 testing was infrequent in the sample (0.02%), and chart review suggests that test results were used to optimize antidepressant treatments rather than pain medications. Using PGx testing combined with consideration of phenoconversion may allow for an enhanced precision medicine approach to pain management in Veterans. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Drug-drug interactions (DDIs) are among the most common causes of adverse drug reactions and are further complicated by genetic variants of drug-metabolizing enzymes. The aim of this study is to quantify and describe potential DDIs, drug-gene interactions (DGIs), and drug-drug-gene interactions (DDGIs) in a community-based population. STUDY DESIGN: This was an analysis of deidentified retail pharmacy prescription data for 4761 individuals. METHODS: Data were first assessed for DDIs, and individuals were stratified to a risk category using the logic of a commercially available digital DDGI tool. To calculate the frequency of potential DGIs and DDGIs, genotypes were imputed and randomly allocated to the cohort 100 times via Monte Carlo simulation according to each variant's frequency in the general population. RESULTS: The probability of a DDI of any impact was 26.0% and increased to 49.6% (95% CI, 48.4%-50.7%) when drug-metabolizing phenotypes were ascribed according to the distribution of variants of 11 genes as found in a Caucasian population. There was a 7.8% probability of major DDIs, which increased to a 10.1% (95% CI, 9.5%-10.8%) probability with the addition of genetic contributions. The probability of DDGIs of any impact was correlated with the number of medications. Antidepressants, antiemetics, blood products and modifiers, analgesics, and antipsychotics had the highest probability of DDGIs. CONCLUSIONS: The probability of drug interaction risk increased when phenotypes associated with genetic polymorphisms were attributed to the population. These data suggest that pharmacogenomic assessment may be useful in predicting drug interactions and severity when evaluating patient medication profiles. [ABSTRACT FROM AUTHOR]

The article presents the highlights of the 2022 American Society of Health-System Pharmacists (ASHP) Commission on Goals meeting on March 15. The meeting focused on how to optimize the hospital-at-home (HAH) model of care, the needed changes to transform healthcare, and the need to develop other innovative care models. Also cited are the types of HAH model, namely, the substitutive HAH programs and early supported discharge or postacute transitional care program.

Background: In a previous study, ondansetron, a serotonin 5‐HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European‐ancestry (EA) participants with moderate‐to‐severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5‐HT3A (HTR3A), and 5‐HT3B (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron‐treated individuals with population‐specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B. Methods: In this 16‐week, double‐blind, placebo‐controlled, parallel‐group clinical trial, adults with AUD were randomized to receive low‐dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" versus "nonresponsive" genotype defined using population‐specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent‐to‐treat analysis were used to compare the treatment groups on the primary outcome—DPDD—and two secondary outcomes—heavy drinking days per week [HDD] and drinks per day [DPD] across the 16 weeks of treatment. Results: Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent‐to‐treat analysis, the ondansetron group averaged 0.40 more DPDD (p = 0.51), 1.35 times as many HDD (p = 0.16), and 1.06 times as many DPD (p = 0.59) as the placebo group. There were no significant interactions with genotype. There were no study‐related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems. Conclusions: We found no evidence that low‐dose oral ondansetron is beneficial in the treatment of AUD, irrespective of genotype, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions. [ABSTRACT FROM AUTHOR]

Purpose Results of the 2021 ASHP National Survey of Pharmacy Practice in Hospital Settings are presented. Methods Pharmacy directors at 1,498 general and children's medical/surgical hospitals in the United States were surveyed using a mixed-mode method of contact by email and mail. Survey completion was online. IQVIA supplied data on hospital characteristics; the survey sample was drawn from IQVIA's hospital database. Results The response rate was 21.9%. Pharmacists are routinely assigned to a majority of patients at least 8 hours per day, 5 days per week in 70.4% of hospitals. This is an increase from 60.8% in 2018 and has steadily increased over the past decade. Pharmacists independently prescribe medications pursuant to a diagnosis in 30.9% of hospitals, an increase from 21.1% in 2020. Pharmacists have prescribing authority in 67% of health-system ambulatory clinics and can recommend or schedule pharmacogenomics testing for drug and dosage selection in 11.4% of hospitals, an increase from 5.4% in 2019. Pharmacists are using electronic methods in 82.5% of hospitals to collect information for monitoring medication therapy. Shortages of entry-level pharmacy technicians are acute, with 73.4% of survey respondents reporting a shortage. Technician shortages have affected pharmacy operations and have prompted new recruitment and retention strategies. Conclusion Despite workforce challenges, clinical pharmacy services continue to expand to cover increasing numbers of patients with medication management services in both the inpatient and outpatient settings. The use of data analytics and pharmacy technicians has contributed to this evolution. Addressing the workforce challenges will be critical to sustain this progress. [ABSTRACT FROM AUTHOR]

The number of adverse drug events in the United States is critically high, with annual rates exceeding 1 million cases over the last nine years. One cause of adverse drug events is the underlying genetic variation that can alter drug responses. Pharmacogenomics is a growing field that seeks to better understand the relationship between a patient's genetics and drug efficacy. Currently, pharmacogenomics relies largely on human trials, as there is not a well-developed animal model for studying preventative measures and alternative treatments. Here, we analyzed pharmacogene expression at two developmental time points in zebrafish to demonstrate the potential of using this model organism for high-throughput pharmacogenomics research. We found that 76% of tiered human pharmacogenes have a zebrafish ortholog, and of these, many have highly conserved amino acid sequences. Additional gene ontology analysis was used to classify pharmacogenes and identify candidate pathways for future modeling in zebrafish. As precision medicine burgeons, adopting a high-throughput in vivo model such as the zebrafish could greatly increase our understanding of the molecular pathology underlying adverse drug events. [ABSTRACT FROM AUTHOR]

Purpose: This article describes the implementation and evaluation of pharmacogenomic testing within the hematology/oncology ambulatory care clinic at the William S. Middleton Memorial Veterans Hospital in Madison, WI., Summary: The Pharmacogenomic Testing for Veterans (PHASER) program provides preemptive pharmacogenomic testing for veterans nationally. Program implementation at the Madison Veterans Affairs site began in the hematology/oncology clinic with the goal of integrating the offer for pharmacogenomic testing, testing completion, and review of the results by the hematology/oncology clinical pharmacist practitioner (CPP) into current workflows to create a sustainable process for PHASER. The hematology/oncology CPP designed workflows outlining how testing would be offered to patients, how results would be reported and to whom, and how documentation would occur in the electronic medical record. Veterans are offered preemptive PHASER testing, before needing therapy requiring pharmacogenomic results. Exceptions to pharmacogenomic testing were patients with a history of liver or allogeneic hematopoietic stem cell transplantation., Conclusion: This article provides a summary of the role of the hematology/oncology CPP in the implementation of a pharmacogenomics service and the impact on medication management in a hematology/oncology clinic., (Published by Oxford University Press on behalf of the American Society of Health-System Pharmacists 2024.)

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment.Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes.Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications.Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978).Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters.Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45).Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission.Trial Registration: ClinicalTrials.gov Identifier: NCT03170362. [ABSTRACT FROM AUTHOR]

Hypertension is a leading risk factor for cardiovascular disease mortality. African Americans (AAs) have the highest prevalence of hypertension in the United States, and to alleviate the burden of hypertension in this population, better control of blood pressure (BP) is needed. Previous studies have shown considerable interpersonal differences in BP response to antihypertensive treatment, suggesting a genetic component. Utilizing data from 4297 AA participants randomized to chlorthalidone from the Genetics of Hypertension Associated Treatments (GenHAT) study, we aimed to identify variants associated with the efficacy of chlorthalidone. An additional aim was to find variants that contributed to changes in fasting glucose (FG) in these individuals. We performed genome-wide association analyses on the change of systolic and diastolic BP (SBP and DBP) over six months and FG levels over 24 months of treatment. We sought replication in the International Consortia of Pharmacogenomics Studies. We identified eight variants statistically associated with BP response and nine variants associated with FG response. One suggestive LINC02211-CDH9 intergenic variant was marginally replicated with the same direction of effect. Given the impact of hypertension in AAs, this study implies that understanding the genetic background for BP control and glucose changes during chlorthalidone treatment may help prevent adverse cardiovascular events in this population. [ABSTRACT FROM AUTHOR]

Pharmacogenomics is a pillar of personalized medicine that has the potential to deliver optimized treatment in many medical settings. Military medicine in the deployed setting is unique and therefore warrants separate assessment pertaining to its potential capabilities and impact. Pharmacogenomics for United States Active Duty Service Members medical care in the deployed setting has not, to our knowledge, been previously reviewed. We present potential applications of pharmacogenomics to forward medical care through two comprehensive references for deployed medical care, the Tactical Combat Casualty Care Guidelines (TCCC) and Emergency War Surgery (EWS) fifth edition. All drugs within the deployment manuals, TCCC guidelines and EWS book, were identified and the list was cross-referenced to the Clinical Pharmacogenetics Implementation Consortium guidelines and genes-drugs interactions list as well as the Food and Drug Administration Table of Pharmacogenomics Biomarkers in Drug Labeling. Ten pharmacologic categories were identified, consisting of 15 drugs, along with the classes, aminogylcosides, beta-blockers, and volatile anesthetics. Drugs and pharmacogenomics liabilities were tabulated. Eight specific drugs or classes are expounded upon given the belief of the authors of their potential for impacting future treatment on the battlefield in the setting of prolonged field care. This review outlines several genes with liabilities in the prolonged field care setting and areas that may produce improved care with further study. [ABSTRACT FROM AUTHOR]

Racial/ethnic differences cover clinical, biological, genetic, or epigenetic factors associated with disease risk, outcome, and treatment that are not related to socio-economic factors. The presence of these in type 2 diabetes mellitus produces a different perspective to the understanding and care in different races and ethnic groups. This becomes very important with individualized care that is not applied alongside these differences. Newer antidiabetic drugs with great promises do not have comparable efficacies across the races. New drug developments using genomics are similarly affected, so also their pharmacogenetic and pharmacogenomic applications. Racial/ethnic differences are found among the subgroups of type 2 diabetes mellitus in the aspects of epidemiology, pathogenesis, and diagnosis. These differences are, however, different and independent of the differences found in drug treatment, diabetic chronic kidney disease, and diabetic retinopathy. For the African Americans and other Blacks, the type 2 diabetes with its different manifestations has not been adequately studied. Even when data exist, they are not taken into cognizance in formulating guidelines. There is, therefore, a need for a call to action. Literature search was in PubMed, Medline, and Google, for search terms race, ethnic, differences, and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Introduction: Emergency departments (ED) use many medications with a range of therapeutic efficacy and potential significant side effects, and many medications have dosage adjustment recommendations based on the patient's specific genotype. How frequently medications with such pharmaco-genetic recommendations are used in United States (US) EDs has not been studied. Methods: We conducted a cross-sectional analysis of the 2010-2015 National Hospital Ambulatory Medical Care Survey (NHAMCS). We reported the proportion of ED visits in which at least one medication with Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendation of Level A or B evidence was ordered. Secondary comparisons included distributions and 95% confidence intervals of age, gender, race/ethnicity, ED disposition, geographical region, immediacy, and insurance status between all ED visits and those involving a CPIC medication. Results: From 165,155 entries representing 805,726,000 US ED visits in the 2010-2015 NHAMCS, 148,243,000 ED visits (18.4%) led to orders of CPIC medications. The most common CPIC medication was tramadol (6.3%). Visits involving CPIC medications had higher proportions of patients who were female, had private insurance and self-pay, and were discharged from the ED. They also involved lower proportions of patients with Medicare and Medicaid. Conclusion: Almost one fifth of US ED visits involve a medication with a pharmacogenetic recommendation that may impact the efficacy and toxicity for individual patients. While direct application of genotyping is still in development, it is important for emergency care providers to understand and support this technology given its potential to improve individualized, patientcentered care. [ABSTRACT FROM AUTHOR]

The article presents the professional policies approved by the American Society of Health System Pharmacists (ASHS) House of Delegates including the policies 2101-2112, 2113-2120, and 2121-2143 that were respectively approved in March, May, and June 2021. Policy topics covered include direct-to-consumer clinical genetic tests, pharmacogenomics, and universal influenza vaccination. Also noted is planned posting of the House of Delegates complete proceedings in the ASHA website.

Background Unwanted weight gain affects some people living with human immunodeficiency virus (HIV) who are prescribed integrase strand transfer inhibitors (INSTIs). Mechanisms and risk factors are incompletely understood. Methods We utilized 2 cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naive participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142, and A5202 and did not receive INSTIs. Results In the observational cohort (n = 61), CYP2B6 slow metabolizers had greater weight gain after switch (P  = .01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (n = 462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (P  = .001), but not those receiving efavirenz with abacavir (P  = .65). Findings were consistent when stratified by race/ethnicity and by sex. Conclusions Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Pharmacogenomics (PGx) is expanding across health-care practice settings, including the community pharmacy. In the United States, models of implementation of PGx in the community pharmacy have described independent services and those layered on to medication therapy management. The drug–gene pair of clopidogrel-CYP2C19 has been a focus of implementation of PGx in community pharmacy and serves as an example of the evolution of the application of drug–gene interaction information to help optimize drug therapy. Expanded information related to this drug–gene pair has been provided by the US Food and Drug Administration and clinical PGx guidelines have and continue to be updated to support clinical decision-making. Most recently direct-to-consumer (DTC) PGx has resulted in patient generated sample collection and submission to a genetic testing-related company for analysis, with reporting of genotype and related phenotype information directly to the patient without a health-care professional guiding or even being involved in the process. The DTC testing approach needs to be considered in the development or modification of PGx service models in the community pharmacy setting. The example of clopidogrel-CYP2C19 is discussed and current models of PGx implementation in the community pharmacy in the United States are presented. New approaches to PGx services are offered as implementation continues to evolve and may now include DTC information. [ABSTRACT FROM AUTHOR]

The article focuses on the future of medication management through precision medicine for populations. Topics include the high prevalence of prescription drug use and its associated costs, common adverse drug reactions (ADRs) caused by drug interactions and genetic factors, and the potential of pharmacogenomics (PGx) to guide personalized treatment by predicting drug-gene interactions and adverse reactions.

Many academic institutions are collecting blood samples from patients seeking treatment for coronavirus disease 2019 (COVID‐19) to build research biorepositories. It may be feasible to extract pharmacogenomic (PGx) information from biorepositories for clinical use. We sought to characterize the potential value of multigene PGx testing among individuals hospitalized with COVID‐19 in the United States. We performed a cross‐sectional analysis of electronic health records from consecutive individuals hospitalized with COVID‐19 at a large, urban academic health system. We characterized medication orders, focusing on medications with actionable PGx guidance related to 14 commonly assayed genes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, DPYD, G6PD, HLA‐A, HLA‐B, IFNL3, NUDT15, SLCO1B1, TPMT, UGT1A1, and VKORC1). A simulation analysis combined medication data with population phenotype frequencies to estimate how many treatment modifications would be enabled if multigene PGx results were available. Sixty‐four unique medications with PGx guidance were ordered at least once in the cohort (n = 1,852, mean age 60.1 years). Nearly nine in 10 individuals (89.7%) had at least one order for a medication with PGx guidance and 427 patients (23.1%) had orders for 4 or more actionable medications. Using a simulation, we estimated that 17 treatment modifications per 100 patients would be enabled if PGx results were available. The genes CYP2D6 and CYP2C19 were responsible for the majority of treatment modifications, and the medications most often affected were ondansetron, oxycodone, and clopidogrel. PGx results would be relevant for nearly all individuals hospitalized with COVID‐19 and would provide the opportunity to improve clinical care. [ABSTRACT FROM AUTHOR]

The article presents the therapeutic position statement (TPS) issued by the American Society of Health-System Pharmacists (ASHP) on the use of antipsychotic medications to treat adults with schizophrenia and schizoaffective disorder. Topics include the ASHP's recommendations on the use of first-generation antipsychotic (FGA) and second-generation antipsychotic (SGA) based on the individual characteristics of patients and the adverse effect profiles of the drugs.

Background: Pharmacogenomic (PGx) variants mediate how individuals respond to medication, and response differences among racial/ethnic groups have been attributed to patterns of PGx diversity. We hypothesized that genetic ancestry (GA) would provide higher resolution for stratifying PGx risk, since it serves as a more reliable surrogate for genetic diversity than self-identified race/ethnicity (SIRE), which includes a substantial social component. We analyzed a cohort of 8628 individuals from the United States (US), for whom we had both SIRE information and whole genome genotypes, with a focus on the three largest SIRE groups in the US: White, Black (African-American), and Hispanic (Latino). Our approach to the question of PGx risk stratification entailed the integration of two distinct methodologies: population genetics and evidence-based medicine. This integrated approach allowed us to consider the clinical implications for the observed patterns of PGx variation found within and between population groups. Results: Whole genome genotypes were used to characterize individuals' continental ancestry fractions—European, African, and Native American—and individuals were grouped according to their GA profiles. SIRE and GA groups were found to be highly concordant. Continental ancestry predicts individuals' SIRE with > 96% accuracy, and accordingly, GA provides only a marginal increase in resolution for PGx risk stratification. In light of the concordance between SIRE and GA, taken together with the fact that information on SIRE is readily available to clinicians, we evaluated PGx variation between SIRE groups to explore the potential clinical utility of race and ethnicity. PGx variants are highly diverged compared to the genomic background; 82 variants show significant frequency differences among SIRE groups, and genome-wide patterns of PGx variation are almost entirely concordant with SIRE. The vast majority of PGx variation is found within rather than between groups, a well-established fact for almost all genetic variants, which is often taken to argue against the clinical utility of population stratification. Nevertheless, analysis of highly differentiated PGx variants illustrates how SIRE partitions PGx variation based on groups' characteristic ancestry patterns. These cases underscore the extent to which SIRE carries clinically valuable information for stratifying PGx risk among populations, albeit with less utility for predicting individual-level PGx alleles (genotypes), supporting the concept of population pharmacogenomics. Conclusions: Perhaps most interestingly, we show that individuals who identify as Black or Hispanic stand to gain far more from the consideration of race/ethnicity in treatment decisions than individuals from the majority White population. [ABSTRACT FROM AUTHOR]

Background: Genetic variants in the BCHE (butyrylcholinesterase) gene are associated with reduced BChE enzyme activity and prolonged post-succinylcholine neuromuscular blockade, which can lead to postanesthetic apnea and respiratory depression. Testing for BChE deficiency is usually performed by biochemical methods and is generally only offered to patients who have a personal or family history of prolonged post-succinylcholine neuromuscular blockade. Purpose: Using a clinical test, we investigated the frequencies of BCHE genotypes that are associated with increased risk for prolonged post-succinylcholine neuromuscular blockade. Materials and Methods: Five BCHE variants, including the A (atypical, rs1799807), K (Kalow, rs1803274), F1 (fluoride-1, rs28933389), F2 (fluoride-2, rs28933390), and S1 (silent-1, rs398124632), were genotyped in a large (n = 13,301), multi-ethnic cohort in the United States. Subjects were recipients of pharmacogenetic testing ordered by their physicians as part of routine care. Results: The minor allele frequencies of A, K, F1, F2, and S1 were 1.60%, 19.93%, 0.08%, 0.47%, and 0.04%, respectively, in this cohort. Based on a review of biochemical and clinical data of these variants, we grouped BCHE genotypes into four phenotypic categories to stratify the risk for prolonged post-succinylcholine neuromuscular blockade. Approximately 0.06% of patients were predicted to have severe BChE deficiency, 8% were predicted to have moderate BChE deficiency, and 29% were predicted to have mild BChE deficiency. Compared to other ethnic groups, Caucasians were predicted to have the highest frequency of BChE deficiency. Conclusion: While severe BChE deficiency is rare in the United States, approximately 8% of Americans are at moderate risk of prolonged post-succinylcholine neuromuscular blockade, suggesting that a sizable percentage of patients may benefit from preoperative genetic testing of BCHE. [ABSTRACT FROM AUTHOR]

Introduction: This descriptive study aimed to evaluate the depth, extent, and perception of pharmacogenomics instruction in schools and colleges of medicine in the United States. Changes in medical pharmacogenomics instruction over the past decade were also assessed by comparing our results with those of a previous study. Methods: An electronic survey was emailed to all accredited allopathic and osteopathic medical schools across the US using Qualtrics online survey software. Multiple email reminders were sent to increase the response rate. Results: Of 151 targeted eligible medical schools across the United States, 22 responded to the survey. One invalid response was excluded, resulting in a response rate of 13.9%. Of responding schools, 85.7% cover pharmacogenomics in their curriculum, mainly in the second year, however, none teach pharmacogenomics as a stand-alone course. The depth and the extent of pharmacogenomics coverage varied among responding programs. Although 66.7% of respondents believe that neither physicians nor other health care professionals possess appropriate knowledge in pharmacogenomics, only 23.8% plan to increase pharmacogenomics instruction in their curricula in the near future. Conclusions: Most medical schools surveyed include some pharmacogenomics instruction in their curricula, although the depth and the extent of the instruction varies. Most respondents believe that physicians and other health care professionals today do not possess an appropriate level of knowledge in pharmacogenomics; however, few institutions report short-term plans to increase pharmacogenomics instruction. Pharmacogenomics plays a significant role in personalized medicine; greater efforts by medical school decision-makers are needed to improve the level of pharmacogenomics instruction in medical curricula. [ABSTRACT FROM AUTHOR]

Introduction: Colchicine is currently approved for the treatment of gout and familial Mediterranean fever, among other conditions. Clarithromycin, a strong inhibitor of CYP3A4 and P-glycoprotein, dramatically increases colchicine's half-life, augmenting the risk of a life-threatening adverse reaction when used inadvertently with colchicine.Objectives: The aim of this study was to examine the evidence and clinical implications of concomitant use of colchicine and clarithromycin.Methods: Case reports of colchicine-clarithromycin co-administration were searched using the FDA's Adverse Event Reporting System (FAERS) database. PubMed, EMBASE, and Web of Science electronic databases were also searched from January 2005 through November 2019 for articles reporting colchicine-clarithromycin concomitant use. Individual reports were reviewed to identify consequences of coadministration, dose, days to onset of interaction, symptoms, evidence of renal disease, time to resolution of symptoms, and Drug Interaction Probability Scale (DIPS) rating.Results: The FAERS search identified 58 reported cases, nearly 53% of which were from patients aged between 65 and 85 years. Of 30 reported deaths, 11 occurred in males, and 19 in females. Other frequent complications reported in FAERS included diarrhea (31%), pancytopenia (22%), bone marrow failure (14%), and vomiting (14%). From published literature, we identified 20 case reports of concomitant exposure, 19 of which were rated 'probable' and one 'possible' according to DIPS rating. Of these cases, four 'probable' patients expired. The documented onset of colchicine toxicity occurred within 5 days of starting clarithromycin, and death within 2 weeks of concomitant exposure.Conclusion: Clinical manifestations of colchicine-clarithromycin interaction may resemble other systemic diseases and may be life threatening. Understanding this clinically meaningful interaction can help clinicians avoid unsafe medication combinations. [ABSTRACT FROM AUTHOR]

Background. Sleep is one of the most essential processes required to maintain a healthy human life, and patients experiencing psychiatric illness often experience an inability to sleep. The aim of this study is to test the hypothesis that antidepressant compounds with strong binding affinities for the serotonin 5-HT2C receptor, histamine H1 receptors, or norepinephrine transporter (NET) will be associated with the highest odds of somnolence. Methods. Post-marketing cases of patient adverse drug reactions were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) during the reporting window of January 2004 to September 2019. Disproportionality analyses of antidepressants reporting somnolence were calculated using the case/non-case method. The reporting odds-ratios (ROR) and corresponding 95% confidence interval (95% CI) were computed and all computations and graphing conducted in R. Results. There were a total of 69,196 reported cases of somnolence out of a total of 7,366,864 cases reported from January 2004 to September 2019. Among the 30 antidepressants assessed, amoxapine (n=16) reporting odds-ratio (ROR) = 7.1 (95% confidence interval [CI] [4.3-11.7]), atomoxetine (n = 1,079) ROR = 6.6 (95% CI [6.2-7.1]), a compound generally approved for attention deficit hyperactivity disorder (ADHD), and maprotiline (n = 18) ROR = 6.3 (95% CI, 3.9-10.1) were the top three compounds ranked with the highest reporting odds of somnolence. In contrast, vortioxetine (n=52) ROR = 1.3 (95% CI [1.0-1.8]), milnacipran (n=58) ROR = 2.1 (95% CI [1.7-2.8]), and bupropion (n=1,048) ROR=2.2 (95% CI [2.1-2.4]) are least significantly associated with somnolence. Moreover, levomilnacipran (n=1) ROR = 0.4 (95% CI [0.1-2.9]) was not associated with somnolence. Conclusion. Among the thirty tested antidepressants, consistent with the original hypothesis, amoxepine has strongest 5-HT2C receptor binding affinity and has the highest reporting odds of somnolence. Atomoxetine, ranked second in reporting odds of somnolence overall, binds to the NET with with the strongest binding affinity among the thirty compounds. Mirtazapine, a tetracyclic antidepressant, was ranked 11th in reporting odds of somnolence and had the strongest H1 receptor binding affinity. This study provides an informative ranking of somnolence among thirty antidepressant compounds with an already wide array of clinical indications as well as provides insight into potential drug repurposing in psychopharmacology. [ABSTRACT FROM AUTHOR]

Elderly critical care patients are one of the largest growing patient population groups according to Medicare data. More than 51% of elderly patients are discharged on inappropriate medications that have the potential to cause harm or interact adversely with other medications. Precision health has the potential to prevent adverse drug events and prescription of inappropriate medications. The purpose of this literature review was to define the concept of precision health and determine the state of science regarding interprofessional models of precision health for assessment of caregiver impact on polypharmacy in elderly intensive care unit patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Opioid use in the United States has steadily risen since the 1990s, along with staggering increases in addiction and overdose fatalities. With this surge in prescription and illicit opioid abuse, it is paramount to understand the genetic risk factors and neuropsychological effects of opioid use disorder (OUD). Polymorphisms disrupting the opioid and dopamine systems have been associated with increased risk for developing substance use disorders. Molecular imaging studies have revealed how these polymorphisms impact the brain and contribute to cognitive and behavioral differences across individuals. Here, we review the current molecular imaging literature to assess how genetic variations in the opioid and dopamine systems affect function in the brain's reward, cognition, and stress pathways, potentially resulting in vulnerabilities to OUD. Continued research of the functional consequences of genetic variants and corresponding alterations in neural mechanisms will inform prevention and treatment of OUD. [ABSTRACT FROM AUTHOR]

Health disparities exist among minorities in the United States, with differences seen in disease prevalence, mortality, and responses to medications. These differences are multifactorial with genetic variation explaining a portion of this variability. Pharmacogenomics aims to find the effect of genetic variations on drug response, with the goal of optimizing drug therapy and development. Although genome‐wide association studies have been useful in unbiasedly surveying the genome for genetic drivers of clinically relevant phenotypes, most of these studies have been conducted in mainly participants of European and Asian descent, contributing to a growing health disparity in precision medicine. Diversity is important to pharmacogenomic studies, and there may be real advantages to the use of these complex genomes in pharmacogenomics. In this review we will outline some of the advantages and confounders of pharmacogenomics in minorities, describe the role of genetic variation in pharmacologic pathways, and highlight a number of population‐specific findings. [ABSTRACT FROM AUTHOR]

Purpose To evaluate final-year pharmacy students' perceptions toward pharmacogenomics education, their attitudes on its clinical relevance, and their readiness to use such knowledge in practice. Methods A 19-question survey was developed and modified from prior studies and was pretested on a small group of pharmacogenomics faculty and pharmacy students. The final survey was administered to 978 final-year pharmacy students in 8 school/colleges of pharmacy in New York and New Jersey between January and May 2017. The survey targeted 3 main themes: perceptions toward pharmacogenomics education, attitudes toward the clinical relevance of this education, and the students' readiness to use knowledge of pharmacogenomics in practice. Results With a 35% response rate, the majority (81%) of the 339 student participants believed that pharmacogenomics was a useful clinical tool for pharmacists, yet only 40% felt that it had been a relevant part of their training. Almost half (46%) received only 1–3 lectures on pharmacogenomics and the majority were not ready to use it in practice. Survey results pointed toward practice-based trainings such as pharmacogenomics rotations as the most helpful in preparing students for practice. Conclusions Final-year student pharmacists reported varying exposure to pharmacogenomics content in their pharmacy training and had positive attitudes toward the clinical relevance of the discipline, yet they expressed low confidence in their readiness to use this information in practice. [ABSTRACT FROM AUTHOR]

Objective: To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure.Design: Prospective pharmacokinetic-pharmacogenomic observational study.Setting: Thirteen PICUs across the United States.Patients: Pediatric subjects (n = 66) mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions.Interventions: Serial blood sampling for drug quantification and a single blood collection for genomic evaluation.Measurements and Main Results: Concentrations of morphine, the two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were quantified by high-performance liquid chromatography tandem mass spectrometry/mass spectroscopy. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed-effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. A two-compartment model with linear elimination and two individual compartments for metabolites best describe morphine disposition in this population. Our analysis demonstrates that body weight and postmenstrual age are relevant predictors of pharmacokinetic parameters of morphine and its metabolites. Furthermore, our research shows that a duration of mechanical ventilation greater than or equal to 10 days reduces metabolite formation and elimination upwards of 30%. However, due to the small sample size and relative heterogeneity of the population, no heritable factors associated with uridine diphosphate glucuronyl transferase 2B7 metabolism of morphine were identified.Conclusions: The results provide a better understanding of the disposition of morphine and its metabolites in critically ill children with acute respiratory failure requiring mechanical ventilation due to nonheritable factors. It also provides the groundwork for developing additional studies to investigate the role of heritable factors. [ABSTRACT FROM AUTHOR]

Despite monumental advances in genomics, relatively few health care provider organizations in the United States offer personalized or precision medicine as part of the routine clinical workflow. The gaps between research and applied genomic medicine may be a result of a cultural gap across various stakeholders representing scientists, clinicians, patients, policy makers, and third party payers. Scientists are trained to assess the health care value of genomics by either quantifying population-scale effects, or through the narrow lens of clinical trials where the standard of care is compared with the predictive power of a single or handful of genetic variants. While these metrics are an essential first step in assessing and documenting the clinical utility of genomics, they are rarely followed up with other assessments of health care value that are critical to stakeholders who use different measures to define value. The limited value assessment in both the research and implementation science of precision medicine is likely due to necessary logistical constraints of these teams; engaging bioethicists, health care economists, and individual patient belief systems is incredibly daunting for geneticists and informaticians conducting research. In this narrative review, we concisely describe several definitions of value through various stakeholder viewpoints. We highlight the existing gaps that prevent clinical translation of scientific findings generally as well as more specifically using two present-day, extreme scenarios: (1) genetically guided warfarin dosing representing a handful of genetic markers and more than 10 years of basic and translational research, and (2) next-generation sequencing representing genome-dense data lacking substantial evidence for implementation. These contemporary scenarios highlight the need for various stakeholders to broadly adopt frameworks designed to define and collect multiple value measures across different disciplines to ultimately impact more universal acceptance of and reimbursement for genomic medicine. [ABSTRACT FROM AUTHOR]

Race and ancestry have long been associated with differential risk and outcomes to disease as well as responses to medications. These differences in drug response are multifactorial with some portion associated with genomic variation. The field of pharmacogenomics aims to predict drug response in patients prior to medication administration and to uncover the biological underpinnings of drug response. The field of human genetics has long recognized that genetic variation differs in frequency between ancestral populations, with some single nucleotide polymorphisms found solely in one population. Thus far, most pharmacogenomic studies have focused on individuals of European and East Asian ancestry, resulting in a substantial disparity in the clinical utility of genetic prediction for drug response in US minority populations. In this review, we discuss the genetic factors that underlie variability to drug response and known pharmacogenomic associations and how these differ between populations, with an emphasis on the current knowledge in cardiovascular pharmacogenomics. [ABSTRACT FROM AUTHOR]

Summary: What is known and objectives: Many drug labels contain information on pharmacogenomic biomarkers (PGBMs), but the information is not necessarily actionable. Pharmacogenomics Knowledgebase (PharmGKB) aims to clarify the level of action for PGBMs (PGx levels) implied in each label as issued by the US Food and Drug Administration. We wished to evaluate the association between the PGx level for US and Japanese drug labels and the insurance coverage for PGBM testing or approval for in vitro diagnostics (IVDs) in each country. Methods: We investigated the information on PGBMs in US and Japanese drug labels with PGx levels, insurance coverage of PGBM tests and IVD approval in the US and Japan. We analysed the relationship of PGx levels with insurance coverage. Results: A total of 243 labels were listed by PharmGKB, and 215 (88%) had PGx levels for US labels and 52 (21%) for Japanese labels. Of the 215 US labels, 54 were designated as “Testing Required” in PGx levels. PGx levels in US labels were strongly associated with coverage of PGBM testing. Tests in 52 (96%) of the 54 labels with Testing Required had insurance coverage, 2 (50%) of 4 in “Testing Recommended,” 38 (38%) of 100 in “Actionable PGx,” 11 (19%) of 57 in “Informative PGx” and 3 (11%) of 28 in “No Level.” In Japanese labels, only 14 of 52 were listed as Testing Required, and all were covered by the National Health Insurance in Japan. What is new and conclusion: The PGx level given in drug labels provides information on availability of PGBM testing. Higher PGx levels, based on better evidence of usefulness of PGBM testing, provide a route to broader test coverage. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Clinically validated pharmacogenomic information useful for patient selection and/or dose adjustment is included in drug labels. However, the label information may differ among countries. This commentary summarizes the pharmacogenomic information on drug labels in different countries. Comment: We selected six drugs, namely, clopidogrel, atomoxetine, irinotecan, mercaptopurine, abacavir and carbamazepine and compared the pharmacogenomic information in the “Warning” section of these drug labels in the United States and 5 other countries/regions. What is new and conclusion: The pharmacogenomic information in drug labels is not well harmonized across countries/regions, possibly due to differences in population characteristics such as relevant allele frequencies, variable genetic test availability and differences in insurance coverage. Further and periodical investigations of this issue would be useful. [ABSTRACT FROM AUTHOR]

Pharmacogenetic (PGx) testing involves the analysis of genes known to affect response to medications. The field has been projected as a leading application of personalized or precision medicine, but the use of PGx tests has been stymied, in part, by the lack of clinical evidence of utility and reported low provider awareness. Another factor is the availability of testing. The range and types of PGx tests available have not been assessed to date. In the period September 2017-January 2018 we analyzed the numbers and types of PGx tests offered by clinical testing laboratories in the US. Of the 111 such labs that we identified, we confirmed that 76 offered PGx testing services. Of these, 31 offered only tests for single genes; 30 offered only tests for multiple genes; and 15 offered both types of tests. Collectively, 45 laboratories offered 114 multigene panel tests covering 295 genes. The majority of these tests did not have any clinical guidelines. PGx tests vary in type and makeup, which presents challenges in appropriate test evaluation and selection for providers, insurers, health systems, and patients alike. [ABSTRACT FROM AUTHOR]

Perpetual debate regarding the delicate balance between access and innovation and the protection of the public health and safety dominate discussions of the United States Food and Drug Administration ("FDA"). Established chiefly as a command and control federal administrative agency, iterative changes in legislation have shaped the FDA's activity in drug, biologic, and medical device regulation over the course of the last one hundred plus years. The most recent fundamental reframing of the agency's authority and directive presented itself in the 21st Century Cures Act, reflecting an important role for patient perspectives in the regulatory process. This Article explores recent developments in patient-focused product development efforts at the FDA and offers modest insights on the increasing role of patients, and patient advocacy groups, in agency decision-making. The Article terms this era "21st century citizen pharma." [ABSTRACT FROM AUTHOR]

Billions of US dollars are invested every year by the pharmaceutical industry in drug development, with the aim of introducing new drugs that are effective and have minimal side effects. Thirty percent of in-pipeline drugs are excluded in an early phase of preclinical and clinical screening owing to cardiovascular safety concerns, and several lead molecules that pass the early safety screening make it to market but are later withdrawn owing to severe cardiac side effects. Although the current drug safety screening methodologies can identify some cardiotoxic drug candidates, they cannot accurately represent the human heart in many aspects, including genomics, transcriptomics, and patient- or population-specific cardiotoxicity. Despite some limitations, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful and evolving technology that has been shown to recapitulate many attributes of human cardiomyocytes and their drug responses. In this review, we discuss the potential impact of the inclusion of the hiPSC-CM platform in premarket candidate drug screening [ABSTRACT FROM AUTHOR]

Background: The response to therapeutics varies widely in patients with depression and anxiety, making selection of an optimal treatment choice challenging. IDgenetix®, a novel pharmacogenomic test, has been shown to improve outcomes by predicting the likelihood of response to different psychotherapeutic medications.Objective: The objective of this study was to estimate the cost effectiveness of implementing a novel pharmacogenomic test (IDgenetix®) to guide treatment choices in patients with depression and/or anxiety compared with treatment as usual from the US societal perspective.Methods: We developed a discrete event simulation to compare clinical events, quality-adjusted life-years, and costs of the two treatment strategies. Target patients had a Hamilton Rating Scale for Depression Score ≥ 20 and/or a Hamilton Rating Scale for Anxiety score ≥ 18 at baseline. Remission, response, and no response were simulated based on the observed rates in the IDgenetix® randomized controlled trial. Quality-adjusted life-years and direct and indirect costs attributable to depression and anxiety were estimated and compared over a 3-year time horizon. We conducted extensive deterministic and probabilistic sensitivity analyses to assess the robustness of the results.Results: The model predicted cumulative remission rates of 78 and 66% in IDgenetix® and treatment as usual groups, respectively. Estimated discounted quality-adjusted life-years were 2.09 and 1.94 per patient for IDgenetix® and treatment as usual, respectively, which resulted in 0.15 incremental quality-adjusted life-years (95% credible interval 0.04-0.28). The total costs after accounting for a US$2000 test cost were US$14,124 for IDgenetix® compared with US$14,659 for treatment as usual, suggesting a US$535 (95% credible interval - 2902 to 1692) cost saving per patient in the IDgenetix® group. Incremental quality-adjusted life-year gain (0.49) and cost savings (US$6800) were substantially larger in patients with severe depression (Hamilton Rating Scale for Depression score ≥ 25).Conclusion: Using the IDgenetix® test to guide the treatment of patients with depression and anxiety may be a dominant strategy, as it improves quality-adjusted life-years and decreases overall costs over a 3-year time horizon. [ABSTRACT FROM AUTHOR]

Concerns about the ethical and social implications of genetics persist as more applications of genetic and genomic technology have become available. Pediatric testing for genetic influences on response to opioids like codeine is one area of application. We interviewed parents of children enrolled in a mixed-methods study following the communication of actual or hypothetical results forCYP2D6, which impacts opioid response. Forty-one parents of children naive to opioids and 42 parents of children previously exposed to opioids participated in qualitative interviews. Findings did not differ by the child’s opioid exposure or by actual versus hypothetical results. Parents’ responses centered on the experience of the parent(s) and the potential impact of that information on the parent, rather than the result’s impact on the child. Parents also emphasized that the results did not impact their perceptions of the child, reaffirming that the child was still “normal” regardless of test result. When asked about the impact of receiving secondary results, parents’ responses emphasized how the results would impact their ability to advocate for the child or impact their state of mind. While the answers reflect parents’ role as surrogate decision maker for their child, they also reinforced concerns that health care decisions might be influenced by secondary parental concerns as much as by the best interests of the child. Emphasis on the child’s “normality” challenges concerns about the impact of genetic essentialism, but further research is required to see whether the type of testing done or the way results were communicated shaped this response. [ABSTRACT FROM PUBLISHER]

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs. [ABSTRACT FROM AUTHOR]