Rediscovery of Thioguanine Treatment in Inflammatory Bowel Disease: Echoes of the Past

This thesis examines the safety, effectiveness, pharmacological monitoring, and future development of thiopurine therapy in inflammatory bowel disease (IBD), with a particular focus on thioguanine (TG). Although newer IBD treatments are increasingly available, there remains a need for well-tolerated, low-toxicity maintenance therapies. Conventional thiopurines such as azathioprine and mercaptopurine have been used for decades, but their use is limited by adverse effects, especially hepatotoxicity and myelotoxicity, largely related to methylated metabolites such as 6-MMPR. TG offers a potential advantage because it bypasses this metabolic pathway. Since 2022, TG has been registered in the Netherlands for IBD patients who fail conventional therapy due to intolerance or ineffectiveness. The first part of the thesis focuses on TG safety and effectiveness. A UK cohort of 193 IBD patients showed that TG was clinically effective in 65% at 12 months, with 54% continuing treatment until study end. Adverse events included elevated liver enzymes, myelotoxicity, rash, and rare cases of nodular regenerative hyperplasia or non-cirrhotic portal hypertension. A prospective real-world study of Thiosix® in 89 patients found it was generally well tolerated, with 83% remaining on treatment after 12 months and no new safety concerns. TG was also evaluated as first-line maintenance therapy in 114 IBD patients. At 12 months, 53% achieved clinical effectiveness and 86% continued therapy, while adverse events were mostly mild. No cases of nodular regenerative hyperplasia or portal hypertension were detected. In pediatric IBD, TG appeared to be a safe alternative for children who previously developed azathioprine-induced pancreatitis, although long-term data remain limited. The second part examines therapeutic drug monitoring and pharmacogenomics. A review of 22 international guidelines showed major variability in recommendations for thiopurine monitoring. While TPMT testing was commonly recommended, NUDT15 testing—important for predicting myelotoxicity, especially in Asian and Hispanic populations—was mentioned far less often. This highlights the need for more consistent international guidance. Another study found that TPMT variants were associated with higher 6-TGN levels in TG-treated IBD patients, supporting the relevance of genetic variation in thiopurine metabolism. The thesis also developed a population pharmacokinetic model for TG using 6-TGN trough concentrations. A one-compartment model with first-order absorption was established, identifying body weight and 5-ASA dose as significant covariates influencing TG clearance. This model may support more individualized dosing in the future. For patients who develop hypermethylation on conventional thiopurines, switching to either TG or low-dose thiopurine plus allopurinol improved metabolite profiles. However, TG appeared more favorable, with a higher proportion of patients achieving non-toxic 6-TGN levels and less residual 6-MMPR formation compared with low-dose thiopurine-allopurinol therapy. The thesis further explores future directions in thiopurine delivery and monitoring. Novel drug delivery systems may improve local intestinal exposure while reducing systemic toxicity, but clinical validation remains limited. A newly validated fecal metabolite assay showed that fecal 6-TGN metabolites were rarely detectable after oral thiopurine therapy, suggesting limited colonic exposure. This supports further research into targeted colonic or rectal thiopurine delivery. Finally, a systematic review and meta-analysis evaluated DNA-thioguanine as a biomarker. DNA-TG levels were significantly associated with leukopenia in IBD and may be more informative than conventional red blood cell 6-TGN monitoring, particularly in patients with relevant genetic variants such as NUDT15. Overall, the thesis supports TG as a promising, generally well-tolerated thiopurine option in IBD, while emphasizing the need for improved monitoring, individualized dosing, and innovative delivery strategies.