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      Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT 15 Genotypes: 2018 Update

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          Abstract

          TPMT activity exhibits a monogenic co-dominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmalogic effecs of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduces the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting dosesof azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org ).

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          NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.

          Takaya Moriyama, Rina Nishii, Virginia Pérez-Andreu … (2016)
          Widely used as anticancer and immunosuppressive agents, thiopurines have narrow therapeutic indices owing to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and the clinical implications of this pharmacogenetic association remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore and Japan, we identified four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile and p.Val18_Val19insGlyVal) that resulted in 74.4-100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across the three cohorts (P = 0.021, 2.1 × 10(-5) and 0.0054, respectively; meta-analysis P = 4.45 × 10(-8), allelic effect size = -11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased thiopurine cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive levels of thiopurine active metabolites and toxicity. Taken together, these results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.
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            Inheritance and drug response.

            Richard Weinshilboum (2003)
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              American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease.

              Maria T. Abreu, , William Tremaine … (2006)
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                Author and article information

                Journal
                Title: Clinical Pharmacology & Therapeutics
                Abbreviated Title: Clin. Pharmacol. Ther.
                Publisher: Wiley
                ISSN (Print): 0009-9236
                ISSN (Electronic): 1532-6535
                Publication date Created: April 15 2019
                Publication date Created: May 2019
                Publication date (Electronic): January 20 2019
                Publication date (Print): May 2019
                Volume: 105
                Issue: 5
                Pages: 1095-1105
                Affiliations
                [1 ]Department of Pharmaceutical SciencesSt. Jude Children's Research Hospital Memphis Tennessee USA
                [2 ]Dr. Margarete Fischer‐Bosch Institute of Clinical Pharmacology Stuttgart Germany
                [3 ]Department of Clinical PharmacologyInstitute of Experimental and Clinical Pharmacology and ToxicologyUniversity Hospital Tuebingen Germany
                [4 ]Department of Pharmacy and BiochemistryUniversity of Tuebingen Tuebingen Germany
                [5 ]Department of Biomedical Data ScienceStanford University Stanford California USA
                [6 ]Instituto Nacional de Câncer, Rio de JaneiroBrazil Pharmacogenomics Network Rio de Janeiro Brazil
                [7 ]Department of OncologySt. Jude Children's Research Hospital Memphis Tennessee USA
                [8 ]Division of Clinical PharmacologyVanderbilt University School of Medicine Nashville Tennessee USA
                [9 ]Department of Laboratory Medicine and PathologyMayo Clinic Rochester Minnesota USA
                [10 ]National Pediatric Oncology Unit Guatemala City Guatemala
                [11 ]School of MedicineUniversidad Francisco Marroquin Guatemala City Guatemala
                [12 ]Department of Pediatric Hematology and Oncology ResearchNational Center for Child Health and Development Tokyo Japan
                [13 ]National University Health SystemNational University Cancer Institute Singapore
                [14 ]Viva University Children's Cancer CentreYong Loo Lin School of MedicineNational University of Singapore Singapore
                [15 ]Department of Paediatrics and Adolescent MedicineRigshospitalet University Hospital Copenhagen Denmark
                [16 ]Institute of Clinical MedicineUniversity of Copenhagen Copenhagen Denmark
                Article
                DOI: 10.1002/cpt.1304
                PMC ID: 6576267
                PubMed ID: 30447069
                SO-VID: c881060a-3f4a-4643-8704-5c93e16c5d8b
                Copyright © © 2019
                License:

                http://onlinelibrary.wiley.com/termsAndConditions#vor

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

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