CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of ...CYP2D6-guided opioid prescribing on pain control.
Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (n = 235) or usual care (n = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS
measures.
On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (n = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P = 0.540).
These data support the potential benefits of CYP2D6-guided pain management.
The US Food and Drug Administration (FDA) lists 22 medications as clinical inhibitors of cytochrome P450 2D6 isoenzyme, with classifications of strong, moderate, and weak. It is accepted that strong ...inhibitors result in nearly null enzymatic activity, but reduction caused by moderate and weak inhibitors is less well characterized. The objective was to identify if the classification of currently listed FDA moderate and weak inhibitors is supported by publicly available primary literature. We conducted a literature search and reviewed product labels for area under the plasma concentration‐time curve (AUC) fold‐changes caused by inhibitors in humans and identified 89 inhibitor–substrate pairs. Observed AUC fold‐change of the substrate was used to create an observed inhibitor classification per FDA‐defined AUC fold‐change thresholds. We then compared the observed inhibitor classification with the classification listed in the FDA Table of Inhibitors. We found 62% of the inhibitors within the pairs matched the listed FDA classification. We explored reasons for discordance and suggest modifications to the FDA table of clinical inhibitors for cimetidine, desvenlafaxine, and fluvoxamine.
Pharmacogenetic testing can help identify primary care patients at increased risk for medication toxicity, poor response or treatment failure and inform drug therapy. While testing availability is ...increasing, providers are unprepared to routinely use pharmacogenetic testing for clinical decision-making. Practice-based resources are needed to overcome implementation barriers for pharmacogenetic testing in primary care.The NHGRI's IGNITE I Network (Implementing GeNomics In pracTicE; www.ignite-genomics.org) explored practice models, challenges and implementation barriers for clinical pharmacogenomics. Based on these experiences, we present a stepwise approach pharmacogenetic testing in primary care: patient identification; pharmacogenetic test ordering; interpretation and application of test results, and patient education. We present clinical factors to consider, test-ordering processes and resources, and provide guidance to apply test results and counsel patients. Practice-based resources such as this stepwise approach to clinical decision-making are important resources to equip primary care providers to use pharmacogenetic testing.
Nearly all clinically used antibiotics have been (1) discovered from microorganisms (2) using phenotype screens to identify inhibitors of bacterial growth. The effectiveness of these antibiotics is ...attributed to their endogenous roles as bacterial warfare agents against competing microorganisms. Unfortunately, every class of clinically used antibiotic has been met with drug resistant bacteria. In fact, the emergence of resistant bacterial infections coupled to the dismal pipeline of new antibacterial agents has resulted in a global health care crisis. There is an urgent need for innovative antibacterial strategies and treatment options to effectively combat drug resistant bacterial pathogens. Here, we describe the implementation of a Pseudomonas competition strategy, using redox-active phenazines, to identify novel antibacterial leads against Staphylococcus aureus and Staphylococcus epidermidis. In this report, we describe the chemical synthesis and evaluation of a diverse 27-membered phenazine library. Using this microbial warfare inspired approach, we have identified several bromophenazines with potent antibacterial activities against S. aureus and S. epidermidis. The most potent bromophenazine analogue from this focused library demonstrated a minimum inhibitory concentration (MIC) of 0.78-1.56 μM, or 0.31-0.62 μg mL(-1), against S. aureus and S. epidermidis and proved to be 32- to 64-fold more potent than the phenazine antibiotic pyocyanin in head-to-head MIC experiments. In addition to the discovery of potent antibacterial agents against S. aureus and S. epidermidis, we also report a detailed structure-activity relationship for this class of bromophenazine small molecules.
A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both ...early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers.
We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.
Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability.
There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. ...Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear.
In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates.
We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low.
These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.
The risk of severe adverse events related to thiopurine therapy can be reduced by personalizing dosing based on TPMT and NUDT15 genetic polymorphisms. However, the optimal genetic testing platform ...has not yet been established. In this study, we report on the TPMT and NUDT15 genotypes and phenotypes generated from 320 patients from a multicenter pediatric healthcare system using both Sanger sequencing and polymerase chain reaction genotyping (hereafter: genotyping) methods to determine the appropriateness of genotyping in our patient population. Sanger sequencing identified variant TPMT alleles including *3A (8, 3.2% of alleles), *3C (4, 1.6%), and *2 (1, 0.4%), and NUDT15 alleles including *2 (5, 3.6%) and *3 (1, 0.7%). For genotyped patients, variants identified in TPMT included *3A (12, 3.1%), *3C (4, 1%), *2 (2, 0.5%), and *8 (1, 0.25%), whereas NUDT15 included *4 (2, 1.9%) and *2 or *3 (1, 1%). Between Sanger sequencing and genotyping, no significant difference in allele, genotype, or phenotype frequency was identified for either TPMT or NUDT15. All patients who were tested using Sanger sequencing would have been accurately phenotyped for either TPMT (124/124), NUDT15 (69/69), or both genes (68/68) if they were assayed using the genotyping method. Considering 193 total TPMT and NUDT15 Sanger Sequencing tests reviewed, all tests would have resulted in an appropriate clinical recommendation if the test had instead been conducted using the comparison genotyping platforms. These results suggest that, in this study population, genotyping would be sufficient to provide accurate phenotype calls and clinical recommendations.
Pharmacogenetic testing (PGT) is increasingly being used as a tool to guide clinical decisions. This article describes the development of an outpatient, pharmacist-led, pharmacogenetics consult ...clinic within internal medicine, its workflow, and early results, along with successes and challenges. A pharmacogenetics-trained pharmacist encouraged primary care physicians (PCPs) to refer patients who were experiencing side effects/ineffectiveness from certain antidepressants, opioids, and/or proton pump inhibitors. In clinic, the pharmacist confirmed the need for and ordered
and/or
testing, provided evidence-based pharmacogenetic recommendations to PCPs, and educated PCPs and patients on the results. Operational and clinical metrics were analyzed. In two years, 91 referred patients were seen in clinic (mean age 57, 67% women, 91% European-American). Of patients who received PGT, 77% had at least one CYP2C19 and/or CYP2D6 phenotype that would make conventional prescribing unfavorable. Recommendations suggested that physicians change a medication/dose for 59% of patients; excluding two patients lost to follow-up, 87% of recommendations were accepted. Challenges included PGT reimbursement and referral maintenance. High frequency of actionable results suggests physician education on who to refer was successful and illustrates the potential to reduce trial-and-error prescribing. High recommendation acceptance rate demonstrates the pharmacist's effectiveness in providing genotype-guided recommendations, emphasizing a successful pharmacist-physician collaboration.
Junctional ectopic tachycardia (JET) is a potentially life‐threatening postoperative arrhythmia in children with specific congenital heart defects and can contribute significantly to postoperative ...morbidity for at‐risk populations. In adults, β1‐adrenergic receptor (ADRB1) and β2‐adrenergic receptor (ADRB2) genotypes have been associated with increased risk for arrhythmias. However, their association with arrhythmia risk in children is unknown. We aimed to test associations between ADRB1 and ADRB2 genotypes and postoperative JET in patients with congenital heart defects. Children who underwent cardiac surgery were genotyped for the ADRB1 p.Ser49Gly (rs1801252; c.145A>G), p.Arg389Gly (rs1801253; c.1165C>G), ADRB2 p.Arg16Gly (rs1042713; c.46A>G), and p.Glu27Gln (rs1042714; c.79G>C) polymorphisms. The occurrence of postoperative JET was assessed via cardiologist‐interpreted electrocardiograms. Genotype associations with JET were analyzed via logistic regression, adjusted for clinical variables associated with JET, with separate analysis in patients not on a β‐blocker. Of the 343 children included (median age 8 months, 53% boys, 69% European ancestry), 45 (13%) developed JET. The Arg389Arg genotype was not significantly associated with JET in the overall population (odds ratio OR = 1.96, 95% confidence interval CI = 0.96–4.03, p = 0.064), but was nominally associated in patients not taking a β‐blocker (n = 324, OR = 2.25, 95% CI = 1.05–4.80. p = 0.034). None of the other variants were associated with JET. These data suggest that the ADRB1 Arg389Arg genotype may predict risk for JET following cardiac surgery in pediatric patients in the absence of β‐blockade. Whether treatment with a β‐blocker ameliorates this association requires further research.
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