Publications by authors named "Philip E Empey"

73 Publications

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

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

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

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

Pharmacists Leading the Way to Precision Medicine: Updates to the Core Pharmacist Competencies in Genomics.

Am J Pharm Educ 2021 Jul 22:8634. Epub 2021 Jul 22.

American Association of Colleges of Pharmacy Pharmacogenomics Special Interest Group, Arlington, Virginia.

Genomics is increasingly becoming an important part of health care, and pharmacists are well-positioned to be practice-based leaders in pharmacogenomics and precision medicine. Competencies available through the Genetics/Genomics Competency Center provide a framework for pharmacogenomics instruction in both pharmacy school curricula and continuing education programs. Given the significant advancements in pharmacogenomics over the past decade, the 2019-2020 American Association of Colleges of Pharmacy Pharmacogenomics Special Interest Group updated the pharmacist competencies. The process used a systematic approach which included mapping pharmacogenomics-specific competencies to the Entrustable Professional Activities for pharmacists and seeking consensus from key stakeholders. The final result is an expansion to 30 competencies that reflect the contemporary roles pharmacists play in the application of pharmacogenomics in clinical practice. When implemented into curricula, these competencies will ensure that learners are "practice-ready" to integrate pharmacogenomics into patient care. Additional post-graduate training is needed for advanced roles in pharmacogenomics implementation, education, and research.
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http://dx.doi.org/10.5688/ajpe8634DOI Listing
July 2021

Advanced Pharmacy Practice Experiences in Pharmacogenomics Offered by US Pharmacy Programs.

Am J Pharm Educ 2020 12 2;84(12):ajpe8031. Epub 2020 Oct 2.

University of Pittsburgh, School of Pharmacy, Pittsburgh, Pennsylvania.

To characterize advanced pharmacy practice experiences (APPEs) with a primary focus in pharmacogenomics at schools and colleges of pharmacy in the United States. This was a cross-sectional, multicenter, observational study of pharmacogenomics APPEs at US pharmacy schools. Directors of experiential education at 146 accredited schools of pharmacy were contacted by phone and asked if their school offered a pharmacogenomics APPE. The preceptors of pharmacogenomics APPEs identified by this phone screen were sent an email with a link to an online survey that asked about their APPE offerings. Of the 142 schools of pharmacy that were successfully reached via phone, 40 (28%) offered an APPE with a primary focus in pharmacogenomics. Thirty unique APPEs with pharmacogenomics as a primary focus were identified. The total number of preceptors involved in the pharmacogenomics APPEs was 33: 19 (58%) faculty preceptors and 14 (42%) non-faculty preceptors. Twenty-three of the 30 pharmacogenomics APPEs completed the survey (77% response rate). The APPE sites were diverse and included academic medical centers, community health systems, pharmacogenomic testing laboratories, and schools of pharmacy. Each pharmacogenomics APPE accommodated an average of six students per year. The APPE activities varied across sites. Only a small number of US pharmacy schools offer an APPE with a primary focus in pharmacogenomics. These rotations are diverse in scope and precepted by faculty or non-faculty pharmacists. The Academy should pursue opportunities to increase experiential education in pharmacogenomics.
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http://dx.doi.org/10.5688/ajpe8031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779881PMC
December 2020

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

Genet Med 2021 Jul 19. Epub 2021 Jul 19.

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

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

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

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

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

A pilot study of oral treprostinil pharmacogenomics and treatment persistence in patients with pulmonary arterial hypertension.

Ther Adv Respir Dis 2021 Jan-Dec;15:17534666211013688

Pharmacogenomics Center of Excellence, Institute for Personalized Medicine, Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences and the Clinical and Translational Science Institute, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.

Background And Aims: Treprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing.

Methods: Patients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in , , and . A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher's exact test was used for categorical data and Kruskal-Wallis test or Wilcoxon rank sum were used for continuous data.

Results: A total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91;  = 0.04]. Genetic variants were not significantly associated with dosing.

Conclusion: Genetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing was not associated with genetic variants in metabolizing enzymes for treprostinil. Our findings suggest significant variability in treatment persistence to oral treprostinil, with pharmacogenomics being a potentially important contributor.
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http://dx.doi.org/10.1177/17534666211013688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111525PMC
April 2021

Kollidon VA64 Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

J Neurotrauma 2021 Sep 14;38(17):2454-2472. Epub 2021 May 14.

Department of Neurological Surgery, Brain Trauma Research Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Loss of plasmalemmal integrity may mediate cell death after traumatic brain injury (TBI). Prior studies in controlled cortical impact (CCI) indicated that the membrane resealing agent Kollidon VA64 improved histopathological and functional outcomes. Kollidon VA64 was therefore selected as the seventh therapy tested by the Operation Brain Trauma Therapy consortium, across three pre-clinical TBI rat models: parasagittal fluid percussion injury (FPI), CCI, and penetrating ballistic-like brain injury (PBBI). In each model, rats were randomized to one of four exposures (7-15/group): (1) sham; (2) TBI+vehicle; (3) TBI+Kollidon VA64 low-dose (0.4 g/kg); and (4) TBI+Kollidon VA64 high-dose (0.8 g/kg). A single intravenous VA64 bolus was given 15 min post-injury. Behavioral, histopathological, and serum biomarker outcomes were assessed over 21 days generating a 22-point scoring matrix per model. In FPI, low-dose VA64 produced zero points across behavior and histopathology. High-dose VA64 worsened motor performance compared with TBI-vehicle, producing -2.5 points. In CCI, low-dose VA64 produced intermediate benefit on beam balance and the Morris water maze (MWM), generating +3.5 points, whereas high-dose VA64 showed no effects on behavior or histopathology. In PBBI, neither dose altered behavior or histopathology. Regarding biomarkers, significant increases in glial fibrillary acidic protein (GFAP) levels were seen in TBI versus sham at 4 h and 24 h across models. Benefit of low-dose VA64 on GFAP was seen at 24 h only in FPI. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) was increased in TBI compared with vehicle across models at 4 h but not at 24 h, without treatment effects. Overall, low dose VA64 generated +4.5 points (+3.5 in CCI) whereas high dose generated -2.0 points. The modest/inconsistent benefit observed reduced enthusiasm to pursue further testing.
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http://dx.doi.org/10.1089/neu.2021.0089DOI Listing
September 2021

Expanding evidence leads to new pharmacogenomics payer coverage.

Genet Med 2021 05 24;23(5):830-832. Epub 2021 Feb 24.

Department of Biomedical Data Science and Medicine, Stanford University, Stanford, CA, USA.

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http://dx.doi.org/10.1038/s41436-021-01117-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222707PMC
May 2021

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

J Neurotrauma 2021 03 18;38(5):628-645. Epub 2020 Dec 18.

Safar Center for Resuscitation Research, Department of Critical Care Medicine, Anesthesiology, and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Glibenclamide (GLY) is the sixth drug tested by the Operation Brain Trauma Therapy (OBTT) consortium based on substantial pre-clinical evidence of benefit in traumatic brain injury (TBI). Adult Sprague-Dawley rats underwent fluid percussion injury (FPI;  = 45), controlled cortical impact (CCI;  = 30), or penetrating ballistic-like brain injury (PBBI;  = 36). Efficacy of GLY treatment (10-μg/kg intraperitoneal loading dose at 10 min post-injury, followed by a continuous 7-day subcutaneous infusion [0.2 μg/h]) on motor, cognitive, neuropathological, and biomarker outcomes was assessed across models. GLY improved motor outcome versus vehicle in FPI (cylinder task,  < 0.05) and CCI (beam balance,  < 0.05; beam walk,  < 0.05). In FPI, GLY did not benefit any other outcome, whereas in CCI, it reduced 21-day lesion volume versus vehicle ( < 0.05). On Morris water maze testing in CCI, GLY worsened performance on hidden platform latency testing versus sham ( < 0.05), but not versus TBI vehicle. In PBBI, GLY did not improve any outcome. Blood levels of glial fibrillary acidic protein and ubiquitin carboxyl terminal hydrolase-1 at 24 h did not show significant treatment-induced changes. In summary, GLY showed the greatest benefit in CCI, with positive effects on motor and neuropathological outcomes. GLY is the second-highest-scoring agent overall tested by OBTT and the only drug to reduce lesion volume after CCI. Our findings suggest that leveraging the use of a TBI model-based phenotype to guide treatment (i.e., GLY in contusion) might represent a strategic choice to accelerate drug development in clinical trials and, ultimately, achieve precision medicine in TBI.
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http://dx.doi.org/10.1089/neu.2020.7421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418525PMC
March 2021

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

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

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

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

Correction: Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

Genet Med 2020 Nov;22(11):1919

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0931-1DOI Listing
November 2020

Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

Genet Med 2020 11 17;22(11):1898-1902. Epub 2020 Jul 17.

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

Purpose: Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19.

Methods: We assembled a cohort of patients from eight sites performingCYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug-genotype interaction and time to receiving a CYP2C19 substrate.

Results: Nine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68 ± 3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug-genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days.

Conclusions: More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient's lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.
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http://dx.doi.org/10.1038/s41436-020-0894-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606808PMC
November 2020

Cost-effectiveness of CYP2C19-guided antiplatelet therapy in patients with acute coronary syndrome and percutaneous coronary intervention informed by real-world data.

Pharmacogenomics J 2020 10 11;20(5):724-735. Epub 2020 Feb 11.

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

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 traditionally grounded in clinical trial data. We conduct a CEA using real-world data using a 1-year decision-analytic model comparing primary strategies: universal empiric clopidogrel (base case), universal ticagrelor, and genotype-guided escalation. We also explore secondary strategies commonly implemented in practice, wherein all patients are prescribed ticagrelor for 30 days post PCI. After 30 days, all patients are switched to clopidogrel irrespective of genotype (nonguided de-escalation) or to clopidogrel only if patients do not harbor an LOF allele (genotype-guided de-escalation). Compared with universal clopidogrel, both universal ticagrelor and genotype-guided escalation were superior with improvement in quality-adjusted life years (QALY's). Only genotype-guided escalation was cost-effective ($42,365/QALY) and demonstrated the highest probability of being cost-effective across conventional willingness-to-pay thresholds. In the secondary analysis, compared with the nonguided de-escalation strategy, although genotype-guided de-escalation and universal ticagrelor were more effective, with ICER of $188,680/QALY and $678,215/QALY, respectively, they were not cost-effective. CYP2C19 genotype-guided antiplatelet prescribing is cost-effective compared with either universal clopidogrel or universal ticagrelor using real-world implementation data. The secondary analysis suggests genotype-guided and nonguided de-escalation may be viable strategies, needing further evaluation.
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http://dx.doi.org/10.1038/s41397-020-0162-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417282PMC
October 2020

Affiliate network members as force amplifiers of genomic medicine research.

Per Med 2019 11 11;16(6):431-433. Epub 2019 Nov 11.

University of Pittsburgh Medical Center (UPMC) Institute of Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15213 USA.

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http://dx.doi.org/10.2217/pme-2019-0077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807288PMC
November 2019

Nitrite pharmacokinetics, safety and efficacy after experimental ventricular fibrillation cardiac arrest.

Nitric Oxide 2019 12 14;93:71-77. Epub 2019 Sep 14.

Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, PA, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Introduction: Besides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA. However, little is known about brain penetration or pharmacokinetics (PK). Therefore, to define the optimal use of this agent, studies on the PK of nitrite in experimental ventricular fibrillation (VF) are needed. We tested the hypothesis that nitrite administered after resuscitation from VF is detectable in cerebrospinal fluid (CSF), brain and other organ tissues, produces no adverse hemodynamic effects, and improves neurologic outcome in rats.

Methods: After return of spontaneous circulation (ROSC) of 5 min untreated VF, adult male Sprague-Dawley rats were given intravenous nitrite (8 μM, 0.13 mg/kg) or placebo as a 5 min infusion beginning at 5 min after CA. Additionally, sham groups with and without nitrite treatment were also studied. Whole blood nitrite levels were serially measured. After 15 min, CSF, brain, heart and liver tissue were collected. In a second series, using a randomized and blinded treatment protocol, rats were treated with nitrite or placebo after arrest. Neurological deficit scoring (NDS) was performed daily and eight days after resuscitation, fear conditioning testing (FCT) and brain histology were assessed.

Results: In an initial series of experiments, rats (n = 21) were randomized to 4 groups: VF-CPR and nitrite therapy (n = 6), VF-CPR and placebo therapy (n = 5), sham (n = 5), or sham plus nitrite therapy (n = 5). Whole blood nitrite levels increased during drug infusion to 57.14 ± 10.82 μM at 11 min post-resuscitation time (1 min after dose completion) in the VF nitrite group vs. 0.94 ± 0.58 μM in the VF placebo group (p < 0.001). There was a significant difference between the treatment and placebo groups in nitrite levels in blood between 7.5 and 15 min after CPR start and between groups with respect to nitrite levels in CSF, brain, heart and liver. In a second series (n = 25 including 5 shams), 19 out of 20 animals survived until day 8. However, NDS, FCT and brain histology did not show any statistically significant difference between groups.

Conclusions: Nitrite, administered early after ROSC from VF, was shown to cross the blood brain barrier after a 5 min VF cardiac arrest. We characterized the PK of intravenous nitrite administration after VF and were able to demonstrate nitrite safety in this feasibility study.
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http://dx.doi.org/10.1016/j.niox.2019.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957908PMC
December 2019

Engaging and Empowering Stakeholders to Advance Pharmacogenomics.

Clin Pharmacol Ther 2019 08 26;106(2):305-308. Epub 2019 Jun 26.

Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

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http://dx.doi.org/10.1002/cpt.1470DOI Listing
August 2019

Factors Contributing to Fentanyl Pharmacokinetic Variability Among Diagnostically Diverse Critically Ill Children.

Clin Pharmacokinet 2019 12;58(12):1567-1576

Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.

Objective: The objective of this study was to characterize the population pharmacokinetics of fentanyl and identify factors that contribute to exposure variability in critically ill pediatric patients.

Methods: We conducted a single-center, retrospective cohort study using electronic record data and remnant blood samples in the setting of a mixed medical/surgical intensive care unit (ICU) at a quaternary children's hospital. Children with a predicted ICU length of stay of at least 3 days and presence of an indwelling central venous or arterial line were included. Serum fentanyl measurements were performed for 278 unique remnant samples from 66 patients. Both one- and two-compartment models were evaluated to describe fentanyl disposition. Covariates were introduced into the model in a forward/backward, stepwise approach and included age, sex, race, weight, cytochrome P450 (CYP) 3A5 genotype, and the presence of CYP3A4 or CYP3A5 inducers or inhibitors. Simulations were performed using the successful model to depict the influence of inducers on fentanyl concentrations.

Results: A two-compartment base model best described the data. There was good agreement between observed and predicted concentrations in the final model. The typical fentanyl clearance for 70 kg (reference weight) and 20.1 kg (median weight) patients were 34.6 and 13.6 L/h, respectively. The magnitude of the unexplained random inter-individual variability was high for both clearance (60.7%) and apparent volume of the central compartment (V) (107.2%). Coadministration of the known CYP3A4/5 inducers fosphenytoin and/or phenobarbital was associated with significantly increased fentanyl clearance. Simulations demonstrate that the effect of inducer administration was most pronounced following discontinuation of a fentanyl infusion.

Conclusions: In this study we show the feasibility and utility of using electronic record data and remnant blood samples to successfully construct population pharmacokinetic models for a heterogeneous cohort of critically ill children. A clinically relevant effect of concomitant CYP3A4/5 inducers was identified. Scaling this population pharmacokinetic approach is necessary to craft precision approaches to fentanyl administration for critically ill children.
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http://dx.doi.org/10.1007/s40262-019-00773-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122686PMC
December 2019

Confirmation of Selected Synergistic Cancer Drug Combinations Identified in an HTS Campaign and Exploration of Drug Efflux Transporter Contributions to the Mode of Synergy.

SLAS Discov 2019 07 30;24(6):653-668. Epub 2019 Apr 30.

1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.

Systematic unbiased high-throughput screening (HTS) of drug combinations (DCs) in well-characterized tumor cell lines is a data-driven strategy to identify novel DCs with potential to be developed into effective therapies. Four DCs from a DC HTS campaign were selected for confirmation; only one appears in clinicaltrials.gov and limited preclinical in vitro data indicates that the drug pairs interact synergistically. Nineteen DC-tumor cell line sets were confirmed to interact synergistically in three pharmacological interaction models. We developed an imaging assay to quantify accumulation of the ABCG2 efflux transporter substrate Hoechst. Gefitinib and raloxifene enhanced Hoechst accumulation in ABCG2 (BCRP)-expressing cells, consistent with inhibition of ABCG2 efflux. Both drugs also inhibit ABCB1 efflux. Mitoxantrone, daunorubicin, and vinorelbine are substrates of one or more of the ABCG2, ABCB1, or ABCC1 efflux transporters expressed to varying extents in the selected cell lines. Interactions between ABC drug efflux transporter inhibitors and substrates may have contributed to the observed synergy; however, other mechanisms may be involved. Novel synergistic DCs identified by HTS were confirmed in vitro, and plausible mechanisms of action studied. Similar approaches may justify the testing of novel HTS-derived DCs in mouse xenograft human cancer models and support the clinical evaluation of effective in vivo DCs in patients.
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http://dx.doi.org/10.1177/2472555219844566DOI Listing
July 2019

Community pharmacists' educational needs for implementing clinical pharmacogenomic services.

J Am Pharm Assoc (2003) 2019 Jul - Aug;59(4):539-544. Epub 2019 Apr 19.

Objectives: Pharmacist leadership and knowledge of pharmacogenomics is critical to the acceleration and enhancement of clinical pharmacogenomic services. This study aims for a qualitative description of community pharmacists' pharmacogenomic educational needs when implementing clinical pharmacogenomic services at community pharmacies.

Methods: Pharmacists practicing at Rite Aid Pharmacy locations in the Greater Pittsburgh Area were recruited to participate in this qualitative analysis. Pharmacists from pharmacy locations offering pharmacogenomic testing and robust patient care services were eligible to participate in a semistructured, audio-recorded interview. The semistructured interview covered 4 domains crafted by the investigative team: (1) previous knowledge of pharmacogenomics; (2) implementation resources; (3) workflow adaptation; and (4) learning preferences. Interviews were transcribed verbatim and independently coded by 2 researchers. A thematic analysis by the investigative team followed. Supporting quotes were selected to illustrate each theme.

Results: Eleven pharmacists from 9 unique pharmacy locations participated in this study. The average length of practice as a community pharmacist was 12 years (range, 1.5-31 years). Pharmacist's pharmacogenomic educational needs were categorized into 5 key themes: (1) enriched pharmacogenomic education and training; (2) active learning to build confidence in using pharmacogenomic data in practice; (3) robust and reputable clinical resources to effectively implement pharmacogenomic services; (4) team-based approach throughout implementation; (5) readily accessible network of pharmacogenomic experts.

Conclusion: This study describes the educational needs and preferences of community pharmacists for the successful provision of clinical pharmacogenomic services in community pharmacies. Pharmacists recognized their needs for enriched knowledge and instruction, practice applying pharmacogenomic principles with team-based approaches, robust clinical resources, and access to pharmacogenomic experts. This deeper understanding of pharmacist needs for pharmacogenomic education could help to accelerate and enhance the clinical implementation of pharmacogenomic services led by community pharmacists.
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http://dx.doi.org/10.1016/j.japh.2019.03.005DOI Listing
July 2020

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.

Genet Med 2019 10 21;21(10):2255-2263. Epub 2019 Mar 21.

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

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1038/s41436-019-0484-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754805PMC
October 2019

Membrane transporters in traumatic brain injury: Pathological, pharmacotherapeutic, and developmental implications.

Exp Neurol 2019 07 21;317:10-21. Epub 2019 Feb 21.

Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, PA, United States of America; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States of America. Electronic address:

Membrane transporters regulate the trafficking of endogenous and exogenous molecules across biological barriers and within the neurovascular unit. In traumatic brain injury (TBI), they moderate the dynamic movement of therapeutic drugs and injury mediators among neurons, endothelial cells and glial cells, thereby becoming important determinants of pathogenesis and effective pharmacotherapy after TBI. There are three ways transporters may impact outcomes in TBI. First, transporters likely play a key role in the clearance of injury mediators. Second, genetic association studies suggest transporters may be important in the transition of TBI from acute brain injury to a chronic neurological disease. Third, transporters dynamically control the brain penetration and efflux of many drugs and their distribution within and elimination from the brain, contributing to pharmacoresistance and possibly in some cases pharmacosensitivity. Understanding the nature of drugs or candidate drugs in development with respect to whether they are a transporter substrate or inhibitor is relevant to understand whether they distribute to their target in sufficient concentrations. Emerging data provide evidence of altered expression and function of transporters in humans after TBI. Genetic variability in expression and/or function of key transporters adds an additional dynamic, as shown in recent clinical studies. In this review, evidence supporting the role of individual membrane transporters in TBI are discussed as well as novel strategies for their modulation as possible therapeutic targets. Since data specifically targeting pediatric TBI are sparse, this review relies mainly on experimental studies using adult animals and clinical studies in adult patients.
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http://dx.doi.org/10.1016/j.expneurol.2019.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544476PMC
July 2019

Design and testing of Medivate, a mobile app to achieve medication list portability via Fast Healthcare Interoperability Resources.

J Am Pharm Assoc (2003) 2019 Mar - Apr;59(2S):S78-S85.e2. Epub 2019 Feb 5.

Objectives: To describe the architecture, design, and testing of an innovative mobile application (Medivate) that facilities accurate sharing of medication lists with linked education.

Setting: The deployment and testing of this app occurred in both the community and hospital settings in Pittsburgh, PA.

Practice Innovation: Medivate is an iOS smartphone application and cloud architecture for patients and providers to keep medication and vaccine lists accurate by providing a method and tool to easily exchange these data. Medications are added directly to the app from the electronic health record (EHR) or by the patient manually. Quick response (QR) code technology is used to trigger the secure transfer and sharing of medications on demand via HL-7 Fast Healthcare Interoperability Resources-based data transfer. An iterative user-centered design process involving patients and student pharmacists practicing in community settings was used to develop and refine functionality.

Practice Description: Adults with an iPhone were approached for participation in the design and evaluation of Medivate. Its functionality and integration into clinical workflow at hospital discharge or vaccine administration in the community were determined.

Evaluation: In the community setting, interviews of pharmacists were conducted. In the hospital, metrics of study participation and experience with app deployment were determined.

Results: The app was deployed in the community for patients that received vaccinations. Interviews provided insight into barriers and logistics for successful engagement. The app was integrated into hospital workflow and demonstrated interoperability with the inpatient EHR. Thirteen patients were provided the app before discharge. Engagement with the app was evident through medication list shares, education access, and changes to medication lists. Patients noted strong agreement with usefulness of the app to learn more about the purposes and adverse effects of medications prescribed.

Conclusion: A mobile app to achieve medication and vaccine list portability was successfully designed and integrated into the inpatient and community settings.
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http://dx.doi.org/10.1016/j.japh.2019.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411446PMC
June 2020

Paths to Successful Translation of New Therapies for Severe Traumatic Brain Injury in the Golden Age of Traumatic Brain Injury Research: A Pittsburgh Vision.

J Neurotrauma 2020 11 1;37(22):2353-2371. Epub 2019 Feb 1.

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

New neuroprotective therapies for severe traumatic brain injury (TBI) have not translated from pre-clinical to clinical success. Numerous explanations have been suggested in both the pre-clinical and clinical arenas. Coverage of TBI in the lay press has reinvigorated interest, creating a golden age of TBI research with innovative strategies to circumvent roadblocks. We discuss the need for more robust therapies. We present concepts for traditional and novel approaches to defining therapeutic targets. We review lessons learned from the ongoing work of the pre-clinical drug and biomarker screening consortium Operation Brain Trauma Therapy and suggest ways to further enhance pre-clinical consortia. Biomarkers have emerged that empower choice and assessment of target engagement by candidate therapies. Drug combinations may be needed, and it may require moving beyond conventional drug therapies. Precision medicine may also link the right therapy to the right patient, including new approaches to TBI classification beyond the Glasgow Coma Scale or anatomical phenotyping-incorporating new genetic and physiologic approaches. Therapeutic breakthroughs may also come from alternative approaches in clinical investigation (comparative effectiveness, adaptive trial design, use of the electronic medical record, and big data). The full continuum of care must also be represented in translational studies, given the important clinical role of pre-hospital events, extracerebral insults in the intensive care unit, and rehabilitation. TBI research from concussion to coma can cross-pollinate and further advancement of new therapies. Misconceptions can stifle/misdirect TBI research and deserve special attention. Finally, we synthesize an approach to deliver therapeutic breakthroughs in this golden age of TBI research.
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http://dx.doi.org/10.1089/neu.2018.6203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698994PMC
November 2020

Therapeutic Hypothermia in Cardiac Arrest.

Ther Hypothermia Temp Manag 2018 12 9;8(4):195-198. Epub 2018 Nov 9.

4 Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1089/ther.2018.29051.mjnDOI Listing
December 2018

Usefulness of Intravenous Sodium Nitrite During Resuscitation for the Treatment of Out-of-Hospital Cardiac Arrest.

Am J Cardiol 2018 08 20;122(4):554-559. Epub 2018 Jun 20.

Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington; Department of Emergency Medicine, Harborview Medical Center, University of Washington, Seattle, Washington.

It is hypothesized that intravenous (IV) sodium nitrite given during resuscitation of out-of-hospital cardiac arrest (OHCA) will improve survival. We performed a phase 1 open-label study of IV sodium nitrite given during resuscitation of 120 patents with OHCA from ventricular fibrillation or nonventricular fibrillation initial rhythms by Seattle Fire Department paramedics. A total of 59 patients received 25 mg (low) and 61 patients received 60 mg (high) of sodium nitrite during resuscitation from OHCA. Treatment effects were compared between high- and low-dose nitrite groups, and all patients in a concurrent local Emergency Medical Services registry of OHCA. Whole blood nitrite levels were measured in 97 patients. The rate of return of spontaneous circulation (48% vs 49%), rearrest in the field (15% vs 25%), use of norepinephrine (12% vs 12%), first systolic blood pressure (124 ± 32 vs 125 ± 38 mm Hg), survival to discharge (23.7% vs 16.4%), and neurologically favorable survival (18.6% vs 11.5%) were not significantly different in the low and high nitrite groups. There were no significant differences in these outcomes among patients who received IV nitrite compared with concurrent registry controls. We estimate that 60 mg achieves whole blood nitrite levels of 22 to 38 μM 10 minutes after administration, whereas 25 mg achieves a level of 9 to 16 μM 10 minutes after delivery. In conclusion, administration of IV nitrite is feasible and appears to be safe in patients with OHCA, permitting subsequent evaluation of the effectiveness of IV nitrite for the treatment of OHCA.
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http://dx.doi.org/10.1016/j.amjcard.2018.04.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515919PMC
August 2018

Multi-Center Pre-clinical Consortia to Enhance Translation of Therapies and Biomarkers for Traumatic Brain Injury: Operation Brain Trauma Therapy and Beyond.

Front Neurol 2018 7;9:640. Epub 2018 Aug 7.

Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, United States.

Current approaches have failed to yield success in the translation of neuroprotective therapies from the pre-clinical to the clinical arena for traumatic brain injury (TBI). Numerous explanations have been put forth in both the pre-clinical and clinical arenas. Operation Brain Trauma Therapy (OBTT), a pre-clinical therapy and biomarker screening consortium has, to date, evaluated 10 therapies and assessed three serum biomarkers in nearly 1,500 animals across three rat models and a micro pig model of TBI. OBTT provides a unique platform to exploit heterogeneity of TBI and execute the research needed to identify effective injury specific therapies toward precision medicine. It also represents one of the first multi-center pre-clinical consortia for TBI, and through its work has yielded insight into the challenges and opportunities of this approach. In this review, important concepts related to consortium infrastructure, modeling, therapy selection, dosing and target engagement, outcomes, analytical approaches, reproducibility, and standardization will be discussed, with a focus on strategies to embellish and improve the chances for future success. We also address issues spanning the continuum of care. Linking the findings of optimized pre-clinical consortia to novel clinical trial designs has great potential to help address the barriers in translation and produce successes in both therapy and biomarker development across the field of TBI and beyond.
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http://dx.doi.org/10.3389/fneur.2018.00640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090020PMC
August 2018

Clinical Pharmacogenomics: Applications in Nephrology.

Clin J Am Soc Nephrol 2018 10 23;13(10):1561-1571. Epub 2018 May 23.

Department of Pharmacy and Therapeutics, School of Pharmacy, and

Pharmacogenomics is a tool for practitioners to provide precision pharmacotherapy using genomics. All providers are likely to encounter genomic data in practice with the expectation that they are able to successfully apply it to patient care. Pharmacogenomics tests for genetic variations in genes that are responsible for drug metabolism, transport, and targets of drug action. Variations can increase the risk for drug toxicity or poor efficacy. Pharmacogenomics can, therefore, be used to help select the best medication or aid in dosing. Nephrologists routinely treat cardiovascular disease and manage patients after kidney transplantation, two situations for which there are several high-evidence clinical recommendations for commonly used anticoagulants, antiplatelets, statins, and transplant medications. Successful use of pharmacogenomics in practice requires that providers are familiar with how to access and use pharmacogenomics resources. Similarly, clinical decision making related to whether to use existing data, whether to order testing, and if data should be used in practice is needed to deliver precision medicine. Pharmacogenomics is applicable to virtually every medical specialty, and nephrologists are well positioned to be implementation leaders.
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http://dx.doi.org/10.2215/CJN.02730218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218819PMC
October 2018

Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury.

Crit Care Med 2018 09;46(9):1471-1479

Clinical and Translational Science Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Objectives: To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment.

Design: Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board-approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009).

Setting: Thirty-six-bed PICU in a university-affiliated children's hospital.

Patients And Subjects: Twelve children 2-18 years old after severe traumatic brain injury and five age-matched control subjects.

Intervention: Probenecid (25 mg/kg) and N-acetylcysteine (140 mg/kg) or placebo administered via naso/orogastric tube.

Measurements And Main Results: The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation.

Conclusions: This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children.
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http://dx.doi.org/10.1097/CCM.0000000000003203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095742PMC
September 2018
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