Browsing by Subject "CYP2C19"
Now showing 1 - 9 of 9
Results Per Page
Sort Options
Item Clinical non-effectiveness of clopidogrel use for peripheral artery disease in patients with CYP2C19 polymorphisms: A systematic review(Springer, 2022) Huang, Shu; Yang, Seonkyeong; Ly, Shirly; Yoo, Ryan H.; Lo-Ciganic, Wei-Hsuan; Eadon, Michael T.; Schleyer, Titus; Whipple, Elizabeth; Nguyen, Khoa Anh; Medicine, School of MedicinePurpose: To conduct a systematic review to identify studies that assessed the association between CYP2C19 polymorphisms and clinical outcomes in peripheral artery disease (PAD) patients who took clopidogrel. Methods: We systematically searched Ovid EMBASE, PubMed, and Web of Science from November 1997 (inception) to September 2020. We included observational studies evaluating how CYP2C19 polymorphism is associated with clopidogrel's effectiveness and safety among patients with PAD. We extracted relevant information details from eligible studies (e.g., study type, patient population, study outcomes). We used the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) Tool to assess the risk of bias for included observational studies. Results: The outcomes of interest were the effectiveness and safety of clopidogrel. The effectiveness outcomes included clinical ineffectiveness (e.g., restenosis). The safety outcomes included bleeding and death related to the use of clopidogrel. We identified four observational studies with a sample size ranging from 50 to 278. Outcomes and comparison groups of the studies varied. Three studies (75%) had an overall low risk of bias. All included studies demonstrated that carrying CYP2C19 loss of function (LOF) alleles was significantly associated with reduced clinical effectiveness and safety of clopidogrel. Conclusions: Our systematic review showed an association between CYP2C19 LOF alleles and reduced functions of clopidogrel. The use of CYP2C19 testing in PAD patients prescribed clopidogrel may help improve the clinical outcomes. However, based on the limited evidence, there is a need for randomized clinical trials in PAD patients to test both the effectiveness and safety outcomes of clopidogrel.Item Clinical non-effectiveness of clopidogrel use for peripheral artery disease in patients with CYP2C19 polymorphisms: a systematic review.(Springer, 2022-06-03) Huang, Shu; Yang, Seonkyeong; Ly, Shirly; Yoo, Ryan H.; Lo-Ciganic, Wei-Hsuan; Eadon, Michael T.; Schleyer, Titus; Whipple, Elizabeth C.; Nguyen, Khoa AnhPurpose: To conduct a systematic review to identify studies that assessed the association between CYP2C19 polymorphisms and clinical outcomes in peripheral artery disease (PAD) patients who took clopidogrel. Methods: We systematically searched Ovid EMBASE, PubMed, and Web of Science from November 1997 (inception) to September 2020. We included observational studies evaluating how CYP2C19 polymorphism is associated with clopidogrel's effectiveness and safety among patients with PAD. We extracted relevant information details from eligible studies (e.g., study type, patient population, study outcomes). We used the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) Tool to assess the risk of bias for included observational studies. Results: The outcomes of interest were the effectiveness and safety of clopidogrel. The effectiveness outcomes included clinical ineffectiveness (e.g., restenosis). The safety outcomes included bleeding and death related to the use of clopidogrel. We identified four observational studies with a sample size ranging from 50 to 278. Outcomes and comparison groups of the studies varied. Three studies (75%) had an overall low risk of bias. All included studies demonstrated that carrying CYP2C19 loss of function (LOF) alleles was significantly associated with reduced clinical effectiveness and safety of clopidogrel. Conclusions: Our systematic review showed an association between CYP2C19 LOF alleles and reduced functions of clopidogrel. The use of CYP2C19 testing in PAD patients prescribed clopidogrel may help improve the clinical outcomes. However, based on the limited evidence, there is a need for randomized clinical trials in PAD patients to test both the effectiveness and safety outcomes of clopidogrel.Item Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update(Wiley, 2017-07) Hicks, J. Kevin; Sangkuhl, Katrin; Swen, Jesse J.; Ellingrod, Vicki L.; Müller, Daniel J.; Shimoda, Kazutaka; Bishop, Jeffrey R.; Kharasch, Evan D.; Skaar, Todd C.; Gaedigk, Andrea; Dunnenberger, Henry M.; Klein, Teri E.; Caudle, Kelly E.; Stingl, Julia C.; Medicine, School of MedicineCYP2D6 and CYP2C19 polymorphisms affect the exposure, efficacy and safety of tricyclic antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and desipramine) and others by both polymorphic enzymes (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). Evidence is presented for CYP2D6 and CYP2C19 genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants.Item Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype-dependent(Springer Nature, 2014) Michaud, Veronique; Kreutz, Yvonne; Skaar, Todd; Ogburn, Evan; Thong, Nancy; Flockhart, David A.; Desta, Zeruesenay; Medicine, School of MedicineEfavirenz increases CYP2C19- and CYP3A-mediated omeprazole metabolism. We hypothesized that CYP2C19 and CYP2B6 genetic polymorphisms influence the extent of induction of omeprazole metabolism by efavirenz. Healthy subjects (n=57) were administered a single 20mg oral dose of omeprazole with a single dose (600mg) or after multiple doses (600mg/day for 17 days) of efavirenz. DNA was genotyped for CYP2C19*2, *3 and *17 alleles and CYP2B6*6, *4 and *9 alleles using Taqman assays. Omeprazole, its enantiomers and metabolites were measured by LC/MS/MS. Our results showed that efavirenz increased omeprazole clearances in all CYP2C19 genotypes in non-stereoselective manner, but the magnitude of induction was genotype-dependent. Metabolic ratios of 5-hydroxylation of omeprazole were reduced in extensive and intermediate metabolizers of CYP2C19 (p<0.05). No significant associations were observed between CYP2B6 genotypes and induction by efavirenz on omeprazole metabolism. Our data indicate how interplays between drug interactions and CYP2C19 genetic variations may influence systemic exposure of CYP2C19 substrates.Item Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection(Nature, 2020-11) Beitelshees, Amber L.; Stevenson, James M.; El Rouby, Nihal; Dillon, Chrisly; Empey, Philip E.; Fielstein, Elliot M.; Johnson, Julie A.; Limdi, Nita A.; Ong, Henry H.; Franchi, Francesco; Angiolillo, Dominick P.; Peterson, Joshua F.; Rosenman, Marc B.; Skaar, Todd C.; Tuteja, Sony; Cavallari, Larisa H.; Medicine, School of MedicinePurpose 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 performing CYP2C19 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.Item Multi-site investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy(Wiley, 2018) Empey, Philip E.; Stevenson, James M.; Tuteja, Sony; Weitzel, Kristin W.; Angiolillo, Dominick J.; Beitelshees, Amber L.; Coons, James C.; Duarte, Julio D.; Franchi, Francesco; Jeng, Linda J. B.; Johnson, Julie A.; Kreutz, Rolf P.; Limdi, Nita A.; Maloney, Kristin A.; Obeng, Aniwaa Owusu; Peterson, Josh F.; Petry, Natasha; Pratt, Victoria M.; Rollini, Fabiana; Scott, Stuart A.; Skaar, Todd C.; Vesely, Mark R.; Stouffer, George A.; Wilke, Russell A.; Cavallari, Larisa H.; Lee, Craig R.; Medicine, School of MedicineCYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes which are both related to CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. This article is protected by copyright.Item Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention(Elsevier, 2018-01-22) Cavallari, Larisa H.; Lee, Craig R.; Beitelshees, Amber L.; Cooper-DeHoff, Rhonda M.; Duarte, Julio D.; Voora, Deepak; Kimmel, Stephen E.; McDonough, Caitrin W.; Gong, Yan; Dave, Chintan V.; Pratt, Victoria M.; Alestock, Tameka D.; Anderson, R. David; Alsip, Jorge; Ardati, Amer K.; Brott, Brigitta C.; Brown, Lawrence; Chumnumwat, Supatat; Clare-Salzler, Michael J.; Coons, James C.; Denny, Joshua C.; Dillon, Chrisly; Elsey, Amanda R.; Hamadeh, Issam; Harada, Shuko; Hillegass, William B.; Hines, Lindsay; Horenstein, Richard B.; Howell, Lucius A.; Jeng, Linda J.B.; Kelemen, Mark D.; Lee, Y.M.; Magvanjav, Oyunbileg; Montasser, May; Nelson, David R.; Nutescu, Edith A.; Nwaba, Devon C.; Pakyz, Ruth E.; Palmer, Kathleen; Peterson, Josh F.; Pollin, Toni I.; Quinn, Alison H.; Robinson, Shawn W.; Schub, Jamie; Skaar, Todd C.; Smith, Donald M.; Sriramoju, Vindhya B.; Starostik, Petr; Stys, Tomasz P.; Stevenson, James M.; Varunok, Nicholas; Vesely, Mark R.; Wake, Dyson T.; Weck, Karen E.; Weitzel, Kristin W.; Wilke, Russell A.; Willig, James; Zhao, Richard Y.; Kreutz, Rolf P.; Stouffer, George A.; Empey, Philip E.; Limdi, Nita A.; Shuldiner, Alan R.; Winterstein, Almut G.; Johnson, Julie A.; Medical and Molecular Genetics, School of MedicineOBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.Item Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy(Wiley, 2018-10) Empey, Philip E.; Stevenson, James M.; Tuteja, Sony; Weitzel, Kristin W.; Angiolillo, Dominick J.; Beitelshees, Amber L.; Coons, James C.; Duarte, Julio D.; Franchi, Francesco; Jeng, Linda J.B.; Johnson, Julie A.; Kreutz, Rolf P.; Limdi, Nita A.; Maloney, Kristin A.; Obeng, Aniwaa Owusu; Peterson, Josh F.; Petry, Natasha; Pratt, Victoria M.; Rollini, Fabiana; Scott, Stuart A.; Skaar, Todd C.; Vesely, Mark R.; Stouffer, George A.; Wilke, Russell A.; Cavallari, Larisa H.; Lee, Craig R.; IGNITE Network; Medicine, School of MedicineCYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutionsItem Patient understanding of pharmacogenomic test results in clinical care(Elsevier, 2023) Doyle, Tom A.; Schmidt, Karen K.; Halverson, Colin M. E.; Olivera, Jesus; Garcia, Abigail; Shugg, Tyler A.; Skaar, Todd C.; Schwartz, Peter H.; Medicine, School of MedicineObjective: Previous research has not objectively assessed patients' comprehension of their pharmacogenomic test results. In this study we assessed understanding of patients who had undergone cytochrome P450 2C19 (CYP2C19) pharmacogenomic testing. Methods: 31 semi-structured interviews with patients who underwent CYP2C19 testing after cardiac catheterization and had been sent a brochure, letter, and wallet card explaining their results. Answers to Likert and binary questions were summarized with descriptive statistics. Qualitative data were analyzed using a grounded theory approach, with particular focus on categorization. Results: No participants knew the name of the gene tested or their metabolizer status. Seven participants (23%) knew whether the testing identified any medications that would have lower effectiveness or increased adverse effects for them at standard doses ("Adequate Understanding"). Four participants (13%) read their results from the letter or wallet card they received but had no independent understanding ("Reliant on Written Materials"). Ten participants remembered receiving the written materials (32%). Conclusion: A majority of participants who had undergone CYP2C19 PGx testing did not understand their results at even a minimal level and would be unable to communicate them to future providers. Practice implications: Further research is necessary to improve patient understanding of PGx testing and their results, potentially through improving patient-provider communication.