title: Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.
abstract: Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. mary.relling@stjude.org
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
authors.forename: E E
authors.initials: EE
authors.lastname: Gardner
authors.forename: W J
authors.initials: WJ
authors.lastname: Sandborn
authors.forename: K
authors.initials: K
authors.lastname: Schmiegelow
authors.forename: C-H
authors.initials: CH
authors.lastname: Pui
authors.forename: S W
authors.initials: SW
authors.lastname: Yee
authors.forename: C M
authors.initials: CM
authors.lastname: Stein
authors.forename: M
authors.initials: M
authors.lastname: Carrillo
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.forename: T E
authors.initials: TE
authors.lastname: Klein
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D001379:Azathioprine / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D013866:Thioguanine / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine