Relationship Between Azathioprine Dosage, 6-Thioguanine Nucleotide Levels, and Therapeutic Response in Pediatric Patients with IBD Treated with Azathioprine

Background:Azathioprine (AZA) is commonly used to treat IBD either alone or in combination with mesalazine. However, there are relatively few studies concerning the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in pediatric patients treated with both AZA and mesalazine.Methods:We retrospectively investigated the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in 137 pediatric patients with IBD treated with AZA using multilevel analysis. Additional factors affecting metabolite levels and therapeutic response were also analyzed.Results:A positive correlation was observed between AZA dosage and 6-thioguanine nucleotide (6-TGN) level (P < 0.0001). Variant TPMT genotype (P < 0.001) and concomitant use of mesalazine (P < 0.001) were predictors of higher 6-TGN levels. Leukopenia (P = 0.025) and lymphopenia (P = 0.045) were associated with higher levels of 6-TGN. Poor AZA compliance affected median 6-TGN levels (P < 0.001). The frequency of patients with median 6-TGN levels >235 pmol per 8 x 10(8) red blood cells was the highest in the sustained therapeutic response group (P = 0.015). Age, sex, IBD type, and duration of AZA therapy did not influence 6-TGN levels or therapeutic effect.Conclusions:AZA dosage is positively correlated with 6-TGN level. Higher 6-TGN levels are related to leukopenia, lymphopenia, and concurrent use of mesalazine. These results provide the rationale for monitoring metabolites to optimize drug dosing and minimize drug-related toxicity. In addition, maintenance of 6-TGN levels within a beneficial therapeutic range by direct monitoring should be helpful in attaining therapeutic efficacy, although this possibility should be verified in prospective studies.