Browsing by Subject "Pharmacogenetics"

Now showing 1 - 10 of 70
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    A Cohort Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms: Results from ECOG-ACRIN E1Z11
    (American Association for Cancer Research, 2024) Stearns, Vered; Jegede, Opeyemi A.; Chang, Victor T-S; Skaar, Todd C.; Berenberg, Jeffrey L.; Nand, Ranveer; Shafqat, Atif; Jacobs, Nisha L.; Luginbuhl, William; Gilman, Paul; Benson, Al B., III; Goodman, Judie R.; Buchschacher, Gary L., Jr.; Henry, N. Lynn; Loprinzi, Charles L.; Flynn, Patrick J.; Mitchell, Edith P.; Fisch, Michael J.; Sparano, Joseph A.; Wagner, Lynne I.; Pharmacology and Toxicology, School of Medicine
    Purpose: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. Patients and methods: Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). Results: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. Conclusions: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.
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    Animal models for medications development targeting alcohol abuse using selectively bred rat lines: Neurobiological and pharmacological validity
    (Elsevier, 2012) Bell, Richard L.; Sable, Helen J. K.; Colombo, Giancarlo; Hyytia, Petri; Rodd, Zachary A.; Lumeng, Lawrence; Psychiatry, School of Medicine
    The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence.
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    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 Medicine
    Pharmacogenetic 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.
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    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 Medicine
    Pharmacogenomic 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.
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    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 Medicine
    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.
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    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 Medicine
    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.
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    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.
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    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.
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    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 Medicine
    Proton 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.
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    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 Medicine
    Phenytoin 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).