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Clin Pharmacol Ther. Apr 2013; 93(4): 324–325.
Published online Feb 20, 2013. Prepublished online Jan 17, 2013. doi:  10.1038/clpt.2013.4
PMCID: PMC3604643
Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing: 2013 Update
M V Relling,1* E E Gardner,2 W J Sandborn,3 K Schmiegelow,4,5 C-H Pui,6 S W Yee,7 C M Stein,8 M Carrillo,9 W E Evans,1 J K Hicks,1 M Schwab,10,11 and T E Klein9
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
3Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
4Institute of Gynaecology, Obstetrics and Paediatrics, University of Copenhagen, Copenhagen, Denmark
5Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
6Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
7Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
8Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
9Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
10Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
11Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tuebingen, Germany
*(cpic/at/pharmgkb.org)
Received November 12, 2012; Accepted January 3, 2013.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly.
The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current.
Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations.
Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online).
Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
CPIC's guidelines reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision making, as well as to identify questions and settings for further research. New evidence may have emerged since the time a guideline was submitted for publication, which may or may not affect that guideline. The health-care provider is responsible to check for updates to guidelines or subsequently published data. Guidelines are limited in scope and are not applicable to interventions or diseases not specifically identified. Guidelines do not account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the complete responsibility of the health-care provider to determine the best course of treatment for the patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be solely made by the clinician and the informed and consenting patient. CPIC assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of CPIC's guidelines, or for any errors or omissions.
Notes
M.V.R. and W.E.E. receive income from St. Jude for licensing patent rights for TPMT and GGH polymorphisms. They also receive funding for investigator-initiated research on the pharmacology of asparaginase from Sigma-Tau Pharmaceuticals.
Footnotes
SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/cpt
Supplementary Material
Supplementary Table S1
Supplementary Table S2
Supplementary Table S3
Supplementary Table S4
Supplementary Table S5
Supplementary Figure S1
Supplementary Data
  • Relling M.V., Klein T.E. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clin. Pharmacol. Ther. 2011;89:464–467. [PMC free article] [PubMed]
  • Relling M.V., et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin. Pharmacol. Ther. 2011;89:387–391. [PMC free article] [PubMed]
  • Krynetski E., Evans W.E. Drug methylation in cancer therapy: lessons from the TPMT polymorphism. Oncogene. 2003;22:7403–7413. [PubMed]
  • González-Lama Y., et al. Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients. Aliment. Pharmacol. Ther. 2011;34:544–554. [PubMed]
  • Adam de Beaumais T., et al. Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy. Br J Clin Pharmacol. 2011;71:575–584. [PubMed]
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