Azathioprine dosing and metabolite measurement in pediatric inflammatory bowel disease: does one size fit all?

Abstract

Background Azathioprine is widely used for the maintenance of remission in children with inflammatory bowel disease (IBD). Measuring thiopurine metabolites 6-thioguanine (6-TGN) and 6-methyl-mercaptopurine (6-MMP) can aid in optimizing treatment and preventing toxicity. We report a proactive approach combining early metabolite measurements with IBD activity index to achieve optimal azathioprine dosing. Methods The reporting of azathioprine dosing, IBD activity indexes and thiopurine metabolites was evaluated retrospectively in 40 children with IBD. Additional treatments and the effect of azathioprine on blood counts were also examined. Results Forty children (40% female) with IBD (26 Crohn’s disease, 12 ulcerative colitis, and 2 unclassified IBD), mean age 12.2±3.4 years, were included in the study. The mean azathioprine dose was 1.3±0.4 mg/kg; mean 6-TGN level was 280±151 pmol/8 × 10 8 red blood cells (RBC) and mean 6-MMP level 1022±1007 pmol/8 × 10 8 RBC. Disease activity index (Crohn’s and ulcerative colitis, pediatric specific) at the time of metabolite measurement was 6.5±8. Twenty-eight children did not require azathioprine dose adjustment, while it was increased in 12. Data from children with azathioprine monotherapy were analyzed separately and the results were similar. Conclusion Timely measurement of thiopurine metabolites and clinical assessment can provide a powerful tool to optimize azathioprine dosing and reduce serious adverse effects in children with IBD.

Usefulness of Measuring Thiopurine Metabolites in Children with Inflammatory Bowel Disease and Autoimmunological Hepatitis, Treated with Azathioprine

“…None of the children developed azathioprine toxicity, as defined by abnormal liver function tests. That observation was similar to that in another study [ 26 ]. On the contrary, Pavlovska et al reported a higher percentage of adverse effects [ 24 ].…”

“…As in some other studies, we did not find any correlation between thiopurine dose and 6-TGN levels; therefore, increasing the drug dose may not be sufficient to reach the desired 6-TGN target [ 24 , 26 ]. This may be explained by an increased methylation of intermediate 6-MP metabolites by inherited high levels of TPMT activity [ 5 ].…”

“…Hibi et al revealed the same observation in adults [ 31 ]. Walker et al [ 26 ] also showed that, in the paediatric IBD children, the AZA dose, sufficient to maintain remission, was 1.3 ± 0.4 mg/kg; after excluding children on biologics, the effective azathioprine dose was 1.4 ± 0.5 mg/kg. Apart from receiving low AZA doses, 75% of IBD patients in our study were in remission.…”

Pharmacologic Management of Monogenic and Very Early Onset Inflammatory Bowel Diseases

“…Out of 41 pediatric patients evaluated in one retrospective study conducted in England, 12 patients required dose increases to achieve clinical remission. A total of 28 patients did not require AZA dose adjustments and achieved [ 142 ].…”