{
  "abstract": "Thiopurine remain essential maintenance therapy in paediatric inflammatory bowel disease (IBD), yet clinical implementation of pharmacogenetic testing and therapeutic drug monitoring (TDM) varies widely despite guideline recommendations. 1 2Whilst TPMT enzyme activity predicts myelotoxicity risk, the optimal integration of TPMT results with serial metabolite monitoring for dose optimisation remains incompletely defined.3 We evaluated our centre’s approach to TPMT-guided therapy initiation, metabolite-based dose optimisation, and clinical outcomes.We conducted retrospective analysis of paediatric IBD patients undergoing TPMT testing or receiving thiopurine therapy at a general centre between 2022-2025. We extracted TPMT activity levels, genotyping results, treatment data, serial monitoring, all 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) measurements with corresponding dose adjustments, and adverse events. Clinical response was assessed by steroid-free remission at six months and biochemical markers.One hundred seventy patients underwent TPMT testing. TPMT activity was normal in 129 patients (76%) whilst 41 (24%) demonstrated low or intermediate activity, notably higher than expected 10-11% heterozygote frequency.2 Six patients with low TPMT underwent formal genotyping revealing *1/*3A (n=4), *1/*3C (n=1), and other heterozygous variants (n=1). Of tested patients, 100 subsequently received thiopurine therapy. Azathioprine (n=81) was initiated at median 1.5 mg/kg/day (range 0.5-2.5), while 6-mercaptopurine (n=19) at median 1.0 mg/kg/day (range 1.0-1.5). TPMT-guided dose reduction was systematically employed in 23 patients (23%). Combination therapy rates were high: 77% received 5-aminosalicylic acid, 52% anti-tumour necrosis factor biologics, and 67% concurrent corticosteroids at initiation.Metabolite monitoring was performed in our cohort with mean 5.3 measurements per patient. Initial 6-TGN levels were subtherapeutic (<230 pmol/8×108 RBC) in 46%, therapeutic (230-450) in 52%, and supratherapeutic in 2%.4 6 Metabolite results influenced clinical management in 33% of episodes, leading to dose escalation, reduction, or identification of preferential shunting.5 Haematological monitoring completion was excellent early (84-93% at weeks 4-12) but declined to 67% by month 12.Sixty Seven patients (67%) achieved steroid-free remission at six months, of which 35 patients were on concomitant biologics. Adverse event rate was 12%. Specific events included myelosuppression (6%), pancreatitis (4%), and rash (4%). Importantly, analysis of TPMT status in patients experiencing adverse events revealed that the majority (67%) had normal TPMT activity, emphasizing that normal TPMT does not eliminate toxicity risk and metabolite monitoring remains essential for all patients.3 Three patients developed severe neutropenia requiring temporary cessation but successfully resumed therapy. Treatment was permanently discontinued in six patients (6%), considerably lower than literature-reported rates of 10-28% mainly due to patient preferences.Our data demonstrate that systematic pre-treatment TPMT testing combined with genotype-guided dosing, proactive metabolite monitoring, and responsive dose optimisation achieves superior clinical outcomes with lower adverse event rates. The high rate of low TPMT activity (24%) in our tested population warrants investigation and may reflect appropriate risk-stratified testing practices.2 The substantial proportion requiring dose adjustment based on metabolites (33%) validates routine TDM utility beyond TPMT testing alone.5 Our findings support integrated pharmacogenetic and metabolite-guided thiopurine therapy in paediatric IBD.References Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019;105:1095–105.Kennedy AM, Griffiths AM, Muise AM, et al. Landscape of TPMT and NUDT15 pharmacogenetic variation in a cohort of Canadian pediatric inflammatory bowel disease patients. Inflamm Bowel Dis. 2024;30:2418–27.Coelho T, Andreoletti G, Ashton J, et al. Genes implicated in thiopurine-induced toxicity: comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort. Sci Rep. 2016;6:34658.Spencer E, Norris E, William C, et al. The impact of thiopurine metabolite monitoring on the durability of thiopurine monotherapy in pediatric IBD. Inflamm Bowel Dis. 2019;25:142–9.Deben DS, Winkens B, van Moorsel SAW, et al. Early therapeutic drug monitoring helps to identify inflammatory bowel disease patients with a high risk to fail thiopurine treatment. Br J Clin Pharmacol. 2024;90:3296–307.Ooi CY, Bohane TD, Lee D, et al. Thiopurine metabolite monitoring in paediatric inflammatory bowel disease. 2007;25:941–7.",
  "authors": [
    {
      "affiliations": [
        "Royal Manchester Children’s hospital"
      ],
      "name": "Rose Alhaleem"
    },
    {
      "affiliations": [
        "Royal Manchester Children’s hospital"
      ],
      "name": "Sian Copley"
    }
  ],
  "title": "OC79 Real-world implementation of TPMT testing and metabolite-guided thiopurine therapy in paediatric inflammatory bowel disease: a contemporary single-centre analysis",
  "uid": "5506e3ba-0d1d-5f51-a2f9-c5412b1aaff7"
}