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      Clinical Pharmacogenetics Implementation Consortium Guideline for Cytochrome P450 ( CYP ) 2D6 Genotype and Atomoxetine Therapy

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          Abstract

          Atomoxetine is a nonstimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). Cytochrome P450 (CYP)2D6 polymorphisms influence the metabolism of atomoxetine thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for atomoxetine based on CYP2D6 genotype (updates at www.cpicpgx.org).

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          Most cited references 33

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          Pharmacogenomics knowledge for personalized medicine.

           C Thorn,  J M Hébert,  L Gong (2012)
          The Pharmacogenomics Knowledgebase (PharmGKB) is a resource that collects, curates, and disseminates information about the impact of human genetic variation on drug responses. It provides clinically relevant information, including dosing guidelines, annotated drug labels, and potentially actionable gene-drug associations and genotype-phenotype relationships. Curators assign levels of evidence to variant-drug associations using well-defined criteria based on careful literature review. Thus, PharmGKB is a useful source of high-quality information supporting personalized medicine-implementation projects.
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            The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype.

            Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an "activity score" (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations.
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              Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors.

              Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).
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                Author and article information

                Journal
                Clinical Pharmacology & Therapeutics
                Clin. Pharmacol. Ther.
                Wiley
                0009-9236
                1532-6535
                April 13 2019
                April 13 2019
                Affiliations
                [1 ]Department of Pharmacy Practice and Pharmaceutical SciencesUniversity of Minnesota College of Pharmacy Duluth Minnesota USA
                [2 ]Department of Experimental and Clinical PharmacologyCollege of PharmacyDepartment of PsychiatryMedical SchoolUniversity of Minnesota Minneapolis Minnesota USA
                [3 ]Department of Biomedical Data ScienceStanford University Stanford California USA
                [4 ]Division of Child and Adolescent PsychiatryDepartment of Psychiatry and Biobehavioral SciencesUniversity of California Los Angeles California USA
                [5 ]Campbell Family Mental Health Research InstituteCentre for Addiction and Mental Health Toronto Ontario Canada
                [6 ]Department of PsychiatryUniversity of Toronto Toronto Ontario Canada
                [7 ]Division of Clinical Pharmacology, Toxicology & Therapeutic InnovationDepartment of PediatricsChildren's Mercy Kansas City Kansas City Missouri USA
                [8 ]School of MedicineUniversity of Missouri‐Kansas City Kansas City Missouri USA
                [9 ]Department of Pharmaceutical SciencesSt. Jude Children's Research Hospital Memphis Tennessee USA
                [10 ]University of Kentucky Mental Health Research CenterEastern State Hospital Lexington Kentucky USA
                Article
                10.1002/cpt.1409
                6612570
                30801677
                © 2019

                http://doi.wiley.com/10.1002/tdm_license_1.1

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