Abstract Background Thiopurines remain essential maintenance therapy in paediatric inflammatory bowel disease (IBD), yet implementation of pharmacogenetic testing and therapeutic drug monitoring (TDM) varies widely despite guidelines. Whilst TPMT enzyme activity predicts myelotoxicity risk, optimal integration of TPMT with serial metabolite monitoring for dose optimisation remains incompletely defined. We evaluated systematic TPMT-guided therapy initiation, metabolite-based dose optimisation, and clinical outcomes. Methods Retrospective analysis of paediatric IBD patients at a tertiary hospital (2022-2025). We extracted TPMT activity, genotyping, serial 6-TGN and 6-MMP measurements with dose adjustments, and adverse events. Clinical response was assessed by steroid free remission at six months and biochemical markers. Results One hundred seventy patients underwent TPMT testing: 129 (76%) normal, 41 (24%) low/intermediate (exceeding expected 10-11%). Six underwent genotyping: *1/*3A (n = 4), *1/*3C (n = 1), other (n = 1). One hundred received thiopurines: azathioprine (n = 81, median 1.5 mg/kg/day) and 6-mercaptopurine (n = 19, median 1.0 mg/kg/day). TPMT-guided reduction in 23 (23%). Concomitant therapy: 77% 5-ASA, 52% anti-TNF, 67% corticosteroids. Metabolite monitoring in 79 (79%), mean 5.3 measurements/patient. Initial 6-TGN: 46% subtherapeutic, 52% therapeutic, 2% supratherapeutic. Metabolites influenced management in 33%. Monitoring completion: 84-93% weeks 4-12, declining to 67%by month 12. Sixty-seven (67%) achieved steroid-free remission, of which 35% were on concomitant biologics. Adverse events 12%. Specific events included myelosuppression 6%, pancreatitis 4%, rash 4%. Importantly, majority occurred in normal TPMT patients, emphasising metabolite monitoring essential for all. Three developed severe neutropenia 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. Conclusion Systematic TPMT testing combined with genotype-guided dosing, proactive metabolite monitoring, and responsive optimisation achieves superior outcomes with lower adverse events. Critically, most adverse events occurred in normal TPMT patients, validating routine metabolite monitoring for all regardless of TPMT status. Thirty-three percent required metabolite-based dose adjustment, validating TDM utility beyond TPMT testing alone. Findings support integrated pharmacogenetic and metabolite-guided thiopurine therapy in paediatric IBD. References: 1. 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. 2. 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. 3. 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. 4. 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. Conflict of interest: Dr. Alhaleem, Rose: No conflict of interest Foulkes, Rebecca: No conflict of interest Chatzidaki, Virginia: No conflict of interest Lee, Chai Leng: No conflict of interest Kala, adnaan: No conflict of interest Jago, Loveday: No conflict of interest Lawson, Maureen: No conflict of interest Fagbemi, Andrew: No conflict of interest Copley, Sian: No conflict of interest
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