Safety and Efficacy of Split-Dose Thiopurine vs Low-Dose Thiopurine-Allopurinol Cotherapy in Pediatric Inflammatory Bowel Disease

INTRODUCTION: Split-dose thiopurine and allopurinol-thiopurine cotherapy strategies have been suggested as rescue therapeutic options for children with inflammatory bowel disease (IBD) and impaired thiopurine metabolism. We compared the efficacy and safety of these regimens in patients who previously failed conventional thiopurine treatment. METHODS: Children with IBD treated with split-dose thiopurine or low-dose thiopurine-allopurinol cotherapy were retrospectively identified. Medical records were reviewed for demographics, treatment regimen, reason for thiopurine failure, side effects, and discontinuation of treatment. Laboratory findings were evaluated at different time points. RESULTS: After prior therapeutic failure, 42 patients were on split-dose regimen (group A) and 20 patients were on thiopurine-allopurinol cotherapy (group B). Twelve patients crossed from group A to group B because of treatment failure, 1 patient was lost at follow-up, and 1 patient discontinued the treatment. The final cotherapy group comprised 29 children (group C), while the split-dose group (group D) included 31 children. Intention-to-treat analysis showed significant differences between split-dose regimen and thiopurine-allopurinol cotherapy for 6-thioguanine nucleotide (6-TGN)/6-methyl mercaptopurine (6-MeMP) ratio (P < 0.001), 6-TGN (P < 0.05), and 6-MeMP (P < 0.001) at 1–3 months. As per protocol analysis, there was a significant difference between group C and group D at 6 months for 6-MeMP (P < 0.05) and 6-TGN/6-MeMP ratio (P < 0.05) and at 12 months for 6-MeMP (P < 0.05) and 6-TGN/6-MeMP ratio (P < 0.001). Side effects were more frequent in allopurinol-thiopurine cotherapy (P < 0.05). DISCUSSION: In children with IBD and impaired thiopurine metabolism, split-dose thiopurine and low-dose thiopurine-allopurinol cotherapy are both effective therapeutic strategies. The latter shows higher efficacy but a higher side effect rate, suggesting the use of split-dose regimen as the first-line approach.

[1]  A. Griffiths,et al.  The Medical Management of Paediatric Crohn's Disease: an ECCO-ESPGHAN Guideline Update. , 2020, Journal of Crohn's & colitis.

[2]  F. Hoentjen,et al.  A comparative analysis of tioguanine versus low‐dose thiopurines combined with allopurinol in inflammatory bowel disease patients , 2020, Alimentary pharmacology & therapeutics.

[3]  A. Griffiths,et al.  Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care—An Evidence-based Guideline From European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition , 2018, Journal of pediatric gastroenterology and nutrition.

[4]  G. Peters,et al.  High inter-individual variability of serum xanthine oxidoreductase activity in IBD patients , 2018, Nucleosides, nucleotides & nucleic acids.

[5]  S. Hanauer,et al.  Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study) , 2018, Alimentary pharmacology & therapeutics.

[6]  A. Griffiths,et al.  Infliximab Is Not Associated With Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric Patients With Inflammatory Bowel Disease. , 2017, Gastroenterology.

[7]  J. Duley,et al.  Long-term Safety and Efficacy of Low-dose Azathioprine and Allopurinol Cotherapy in Inflammatory Bowel Disease: A Large Observational Study , 2016, Inflammatory bowel diseases.

[8]  J. Sanderson,et al.  The impact of introducing thioguanine nucleotide monitoring into an inflammatory bowel disease clinic , 2013, International journal of clinical practice.

[9]  J. Sanderson,et al.  Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. , 2012, Journal of Crohn's & colitis.

[10]  S. Targan,et al.  Split‐dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6‐MMP metabolism , 2012, Alimentary pharmacology & therapeutics.

[11]  D. Shih,et al.  Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease. , 2011, World journal of gastroenterology.

[12]  Mary C. Henthorn,et al.  A prospective evaluation of the impact of allopurinol in pediatric and adult IBD patients with preferential metabolism of 6-mercaptopurine to 6-methylmercaptopurine. , 2010, Journal of Crohn's & colitis.

[13]  C. Lees,et al.  Tolerability and safety of mercaptopurine in azathioprine‐intolerant patients with inflammatory bowel disease , 2007, Alimentary pharmacology & therapeutics.

[14]  P. Söderkvist,et al.  Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease , 2006, Gut.

[15]  S. Hanauer,et al.  Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine , 2005, Alimentary pharmacology & therapeutics.

[16]  S. Targan,et al.  Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. , 2000, Gastroenterology.

[17]  R. Weinshilboum,et al.  Thiopurine pharmacogenetics in leukemia: Correlation of erythrocyte thiopurine methyltransferase activity and 6‐thioguanine nucleotide concentrations , 1987, Clinical pharmacology and therapeutics.