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Adjustment of azathioprine dose should be based on a lower 6‐TGN target level to avoid leucopenia in NUDT15 intermediate metabolisers
Author(s) -
Kang Ben,
Kim Tae Jun,
Choi Jaeyoung,
Baek SunYoung,
Ahn Soohyun,
Choi Rihwa,
Lee SooYoun,
Choe Yon Ho
Publication year - 2020
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.15810
Subject(s) - thiopurine methyltransferase , azathioprine , medicine , gastroenterology , genotyping , inflammatory bowel disease , genotype , disease , chemistry , biochemistry , gene
Summary Background The association between NUDT15 polymorphisms and thiopurine‐induced leucopenia is well known. Aim To investigate the association between NUDT15 polymorphisms and time‐to‐leucopenia in paediatric patients with inflammatory bowel disease (IBD) receiving azathioprine and to determine the relationship between NUDT15 polymorphisms and 6‐thioguanine nucleotide (6‐TGN) levels. Methods This retrospective observational study included Korean paediatric patients with IBD who were treated with azathioprine and underwent NUDT15 and TPMT genotyping. Azathioprine doses were adjusted by regular thiopurine metabolite monitoring. Factors associated with time‐to‐leucopenia and the relationship between NUDT15 polymorphisms and 6‐TGN levels were analysed. Results Among the 167 patients included, leucopenia was observed in 16% (19/119), 44% (20/45) and 100% (3/3) of the NUDT15 normal, intermediate and poor metabolisers respectively ( P < 0.001). NUDT15 polymorphism was significantly associated with time‐to‐leucopenia (HR = 5.26, 95% CI = 2.74‐10.09, P < 0.001). There was a positive association between 6‐TGN levels and leucopenia among the NUDT15 intermediate/TPMT normal metabolisers (median 361.3 vs 263.8 pmol/8 × 10 8 RBC, P = 0.013). The most accurate 6‐TGN cut‐off level associated with leucopenia was 308.2 pmol/8 × 10 8 RBC (AUC = 0.742, 95% CI = 0.569‐0.915, sensitivity 80.0%, specificity 72.7%, P < 0.001) in this subgroup. When the specificity was set to <15%, the 6‐TGN cut‐off level was 167.1 pmol/8 × 10 8 RBC (sensitivity 93.3%, specificity 13.6%). Conclusions NUDT15 polymorphisms were associated with time‐to‐leucopenia during azathioprine treatment in Korean paediatric patients with IBD. In order to reduce the development of thiopurine‐induced leucopenia (<15%) in NUDT15 intermediate metabolisers, adjustment of azathioprine doses should be based on a lower 6‐TGN target level (<167.1 pmol/8 × 10 8 RBC).