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Item Characterization of Reference Materials with an Association for Molecular Pathology Pharmacogenetics Working Group Tier 2 Status: CYP2C9, CYP2C19, VKORC1, CYP2C Cluster Variant, and GGCX: A GeT-RM Collaborative Project(Elsevier, 2021) Pratt, Victoria M.; Turner, Amy; Broeckel, Ulrich; Dawson, D. Brian; Gaedigk, Andrea; Lynnes, Ty C.; Medeiros, Elizabeth B.; Moyer, Ann M.; Requesens, Deborah; Vetrini, Francesco; Kalman, Lisa V.; Medical and Molecular Genetics, School of MedicinePharmacogenetic testing is increasingly available from clinical and research laboratories. However, only a limited number of quality control and other reference materials are currently available for many of the variants that are tested. The Association for Molecular Pathology Pharmacogenetic Work Group has published a series of papers recommending alleles for inclusion in clinical testing. Several of the alleles were not considered for tier 1 because of a lack of reference materials. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention-based Genetic Testing Reference Material (GeT-RM) program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 18 DNA samples derived from Coriell cell lines. DNA samples were distributed to five volunteer testing laboratories for genotyping using three commercially available and laboratory developed tests. Several tier 2 variants, including CYP2C9∗13, CYP2C19∗35, the CYP2C cluster variant (rs12777823), two variants in VKORC1 (rs61742245 and rs72547529) related to warfarin resistance, and two variants in GGCX (rs12714145 and rs11676382) related to clotting factor activation, were identified among these samples. These publicly available materials complement the pharmacogenetic reference materials previously characterized by the GeT-RM program and will support the quality assurance and quality control programs of clinical laboratories that perform pharmacogenetic testing.Item Clinical and educational impact of pharmacogenomics testing: a case series from the INGENIOUS trial(Future Medicine, 2017-06) Pierson, Rebecca C.; Gufford, Brandon T.; Desta, Zeruesenay; Eadon, Michael T.; Medicine, School of MedicinePharmacogenomic testing has become increasingly widespread. However, there remains a need to bridge the gap between test results and providers lacking the expertise required to interpret these results. The Indiana Genomics Implementation trial is underway at our institution to examine total healthcare cost and patient outcomes after genotyping in a safety-net healthcare system. As part of the study, trial investigators and clinical pharmacology fellows interpret genotype results, review patient histories and medication lists and evaluate potential drug-drug interactions. We present a case series of patients in whom pharmacogenomic consultations aided providers in appropriately applying pharmacogenomic results within the clinical context. Formal consultations not only provide valuable patient care information but educational opportunities for the fellows to cement pharmacogenomic concepts.Item Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers(American Society of Clinical Oncology, 2022) Shugg, Tyler; Ly, Reynold C.; Rowe, Elizabeth J.; Philips, Santosh; Hyder, Mustafa A.; Radovich, Milan; Rosenman, Marc B.; Pratt, Victoria M.; Callaghan, John T.; Desta, Zeruesenay; Schneider, Bryan P.; Skaar, Todd C.; Medicine, School of MedicinePurpose: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. Methods: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. Results: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. Conclusion: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.Item Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers(ASCO, 2022) Shugg, Tyler; Ly, Reynold C.; Rowe, Elizabeth J.; Philips, Santosh; Hyder, Mustafa A.; Radovich, Milan; Rosenman, Marc B.; Pratt, Victoria M.; Callaghan, John T.; Desta, Zeruesenay; Schneider, Bryan P.; Skaar, Todd C.; Medicine, School of MedicinePURPOSE: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. METHODS: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. RESULTS: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. CONCLUSION: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.Item Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers.(American Society of Clinical Oncology, 2022-02) Shugg, Tyler; Ly, Reynold C.; Rowe, Elizabeth J.; Philips, Santosh; Hyder, Mustafa A.; Radovich, Milan; Rosenman, Marc B.; Pratt, Victoria M.; Callaghan, John T.; Desta, Zeruesenay; Schneider, Bryan P.; Skaar, Todd C.PURPOSE: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. METHODS: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. RESULTS: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. CONCLUSION: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.Item Clinical Pharmacogenetics From a Nursing Perspective: Personalizing Drug Therapy(Sigma International Nursing Research Congress, 2019) Fulton, Cathy R.Precision medicine is the approach to patient care that is focused on finding the most appropriate medication based on the interplay between genetic, environmental, and lifestyle factors to improve patient outcomes. With sufficient knowledge and experience, all nurses will become more confident in applying pharmacogenetic results within the clinical context.Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing(Wiley, 2021) Lima, John J.; Thomas, Cameron D.; Barbarino, Julia; Desta, Zeruesenay; Van Driest, Sara L.; El Rouby, Nihal; Johnson, Julie A.; Cavallari, Larisa H.; Shakhnovich, Valentina; Thacker, David L.; Scott, Stuart A.; Schwab, Matthias; Uppugunduri, Chakradhara Rao S.; Formea, Christine M.; Franciosi, James P.; Sangkuhl, Katrin; Gaedigk, Andrea; Klein, Teri E.; Gammal, Roseann S.; Furuta, Takahisa; Medicine, School of MedicineProton pump inhibitors (PPIs) are widely used for acid suppression in the treatment and prevention of many conditions, including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, Helicobacter pylori infection, and pathological hypersecretory conditions. Most PPIs are metabolized primarily by cytochrome P450 2C19 (CYP2C19) into inactive metabolites, and CYP2C19 genotype has been linked to PPI exposure, efficacy, and adverse effects. We summarize the evidence from the literature and provide therapeutic recommendations for PPI prescribing based on CYP2C19 genotype (updates at www.cpicpgx.org). The potential benefits of using CYP2C19 genotype data to guide PPI therapy include (i) identifying patients with genotypes predictive of lower plasma exposure and prescribing them a higher dose that will increase the likelihood of efficacy, and (ii) identifying patients on chronic therapy with genotypes predictive of higher plasma exposure and prescribing them a decreased dose to minimize the risk of toxicity that is associated with long-term PPI use, particularly at higher plasma concentrations.Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update(Wiley, 2021) Karnes, Jason H.; Rettie, Allan E.; Somogyi, Andrew A.; Huddart, Rachel; Fohner, Alison E.; Formea, Christine M.; Lee, Ming Ta Michael; Llerena, Adrian; Whirl-Carrillo, Michelle; Klein, Teri E.; Phillips, Elizabeth J.; Mintzer, Scott; Gaedigk, Andrea; Caudle, Kelly E.; Callaghan, John T.; Medicine, School of MedicinePhenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (updates on cpicpgx.org).Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P450 2D6 (CYP2D6) Genotype(Wiley, 2012-02) Crews, K.R.; Gaedigk, A.; Dunnenberger, H.M.; Klein, T.E.; Shen, D.D.; Callaghan, J.T.; Kharasch, E.D.; Skaar, Todd C.Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing(Wiley, 2015-07) Birdwell, Kelly A.; Decker, Brian; Barbarino, Julia M.; Peterson, Josh F.; Stein, C. Michael; Sadee, Wolfgang; Wang, Danxin; Vinks, Alexander A.; He, Yijing; Swen, Jesse J.; Leeder, J. Steven; van Schaik, RHN; Thummel, Kenneth E.; Klein, Teri E.; Caudle, Kelly E.; MacPhee, Iain A.M.; Department of Medicine, IU School of MedicineTacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).