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Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing

Mary V. Relling, E E Gardner, William J. Sandborn, Kjeld Schmiegelow, C-H Pui, Sook Wah Yee, C. Michael Stein, William E. Evans, Teri E. Klein

Clinical Pharmacology & Therapeutics · 2011 · 573 citations · 37 references

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TL;DR

TPMT activity follows a monogenic co‑dominant inheritance pattern with ethnic variation, and homozygous nonfunctional alleles cause severe myelosuppression, heterozygotes moderate toxicity, while wild‑type individuals have lower active metabolite levels and reduced myelosuppression. The guideline provides dosing recommendations for azathioprine, mercaptopurine, and thioguanine based on TPMT genotype. The guideline, updated online at http://www.pharmgkb.org, uses TPMT genotype to tailor dosing of these thiopurines. Published in Clinical Pharmacology & Therapeutics 2011, 89(3):387–391, doi:10.1038/clpt.2010.320.

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. Clinical Pharmacology & Therapeutics (2011) 89 3, 387–391. doi:10.1038/clpt.2010.320