Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update

Mary V Relling; Matthias Schwab; Michelle Whirl-Carrillo; Guilherme Suarez-Kurtz; Ching-Hon Pui; Charles M Stein; Ann M Moyer; William E Evans; Teri E Klein; Federico Guillermo Antillon-Klussmann; Kelly E Caudle; Motohiro Kato; Allen E J Yeoh; Kjeld Schmiegelow; Jun J Yang

doi:10.1002/cpt.1304

Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update

Clin Pharmacol Ther. 2019 May;105(5):1095-1105. doi: 10.1002/cpt.1304. Epub 2019 Jan 20.

Authors

Mary V Relling¹, Matthias Schwab^{2

3

4}, Michelle Whirl-Carrillo⁵, Guilherme Suarez-Kurtz⁶, Ching-Hon Pui⁷, Charles M Stein⁸, Ann M Moyer⁹, William E Evans¹, Teri E Klein⁴, Federico Guillermo Antillon-Klussmann^{10

11}, Kelly E Caudle¹, Motohiro Kato¹², Allen E J Yeoh^{13

14}, Kjeld Schmiegelow^{15

16}, Jun J Yang¹

Affiliations

¹ Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
² Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
³ Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tuebingen, Germany.
⁴ Department of Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany.
⁵ Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
⁶ Instituto Nacional de Câncer, Rio de Janeiro, Brazil Pharmacogenomics Network, Rio de Janeiro, Brazil.
⁷ Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁸ Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁰ National Pediatric Oncology Unit, Guatemala City, Guatemala.
¹¹ School of Medicine, Universidad Francisco Marroquin, Guatemala City, Guatemala.
¹² Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan.
¹³ National University Health System, National University Cancer Institute, Singapore.
¹⁴ Viva University Children's Cancer Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
¹⁵ Department of Paediatrics and Adolescent Medicine, Rigshospitalet University Hospital, Copenhagen, Denmark.
¹⁶ Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Abstract

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

Publication types

Practice Guideline
Research Support, N.I.H., Extramural

MeSH terms

Antimetabolites, Antineoplastic* / administration & dosage
Antimetabolites, Antineoplastic* / pharmacokinetics
Azathioprine* / administration & dosage
Azathioprine* / pharmacokinetics
Dose-Response Relationship, Drug
Drug Dosage Calculations
Humans
Inactivation, Metabolic / genetics
Mercaptopurine* / administration & dosage
Mercaptopurine* / pharmacokinetics
Methyltransferases / genetics*
Pharmacogenetics
Pharmacogenomic Testing
Pyrophosphatases / genetics*
Thioguanine* / administration & dosage
Thioguanine* / pharmacokinetics

Substances

Antimetabolites, Antineoplastic
Mercaptopurine
Methyltransferases
TPMT protein, human
NUDT15 protein, human
Pyrophosphatases
Thioguanine
Azathioprine

Abstract

Publication types

MeSH terms

Substances

Grants and funding