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

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).

Figure 1:

Metabolism of azathioprine, thioguanine, and mercaptopurine (41). Permission has been given by PharmGKB and Stanford to use figure (https://www.pharmgkb.org/pathway/PA2040). Pathway images and data are available under a Creative Commons BY-SA 4.0 license.

Figure 2.

Recommended Starting Doses of Thiopurines by TPMT and NUDT15 phenotype ^aWhether a dose reduction is recommended from the starting dose depends on the level of the standard starting dose; for example, if the standard starting dose of mercaptopurine is 75 mg/m²/day or higher, then a lower starting dose may be considered in intermediate metabolizers and would be recommended in poor metabolizers, whereas if the starting dose is 50 mg/m²/day or lower, a reduced starting dose may not be necessary in intermediate metabolizers. ^bSee Table 2 for recommendation. ^cFor patients who are IM for both TPMT and NUDT15, further dose reduction might be needed compared to those who are only IM with respect to one gene (TPMT or NUDT15).