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* = Presenting author

P415 Therapeutic drug monitoring of thiopurines in the management of Asian patients with inflammatory bowel disease

S. N. W. Chuah*1, P. Delord2, N. Sutiman3, W. F. Leong3, S. C. Kong1, B. Schwender1, P. W. Chan1, H. H. Shim1, E. Salazar1, E. H. Ong4, H. Y. Aw5, J. L. Hartono4, W. C. Lim6, C. Ong7, P. L. Ong8, K. L. Ling1, B. Chowbay2

1Singapore General Hospital, Department of Gastroenterology and Hepatology, Singapore, Singapore, 2National Cancer Centre, Clinical Pharmacology Laboratory, Singapore, Singapore, 3Singapore Health Services, Clinical Pharmacology, Singapore, Singapore, 4National University Hospital, Department of Gastroenterology and Hepatology, Singapore, Singapore, 5National University Hospital, Division of Paediatric Gastroenterology, Singapore, Singapore, 6Tan Tock Seng Hospital, Department of Gastroenterology and Hepatology, Singapore, Singapore, 7KK Women’s and Children’s Hospital, Department of Gastroenterology and Hepatology, Singapore, Singapore, 8Changi General Hospital, Department of Gastroenterology and Hepatology, Singapore, Singapore

Background

Thiopurines undergo complex metabolism that leads to the formation of the active and potentially myelotoxic metabolite,6-thioguanine (6-TGN), as well as inactive and potentially hepatotoxic metabolite 6-methyl mercaptopurine (6-MMPN).Therapeutic drug monitoring (TDM) of 6-TGN and 6-MMPN has been suggested to improve efficacy and safety, with thresholds proposed to be 235–450 and < 5 700 pmole/8x108 erythrocytes, respectively. We describe our experience with TDM of thiopurines in the management of Asian inflammatory bowel disease (IBD) patients.

Methods

IBD patients who have been on a stable thiopurine dose for at least 4 weeks were recruited. Clinical data of disease characteristics, treatment details, efficacy, and toxicity parameters were prospectively collected. Quantification of 6-TGN and 6-MMPN concentrations in erythrocytes was performed using a validated LC-MS/MS assay. Variables were compared between groups using non-parametric tests on GraphPad Prism v6.0.

Results

Of 105 patients, 7 (6.7%) had undetectable 6-TGN and 6-MMPN levels. They were identified to be non-compliant and excluded from further analysis. The majority of patients were Chinese (n = 65; 66.3%), followed by Malay (n = 8; 8.2%), Indian (n = 21; 21.4%), and others (n = 4; 4.1%). Most patients were male (n = 70, 71.4%), with median age of 44 years (range 17–81).The diagnosis was predominantly Crohn’s disease (n = 68; 69.4%). Further, 95 (96.9%) patients received azathioprine, and 3(3.1%) received 6-mercaptopurine. Concomitantly, 12 (12.2%) patients were on steroids; 68 (69.4%) were on 5-aminosalicylates/sulfasalazine; 21 (21.4%) were on anti-tumour necrosis factor, and 30 (30.6%) were not on any co-medication. Of the 98 patients, 41(41.8%) achieved therapeutic 6-TGN levels, and 41(41.8%) had sub-therapeutic 6-TGN levels. Moreover, 16 (16.3%) patients had supra-therapeutic 6-TGN levels, of which 6(37.5%) cases of leukopenia were identified. Nine (9.2%) patients had shunted metabolism towards the production of 6-MMPN. Six (6.1%) patients had supra-therapeutic 6-MMPN levels, but no significant associations were observed with hepatotoxicity. Of the 34 patients receiving weight-based AZA-equivalent doses of 2.0–2.5 mg/kg, only 15 (44.1%) patients achieved therapeutic 6-TGN levels. Patients on concurrent 5-aminosalicylates/sulfasalazine had significantly higher dose-normalised 6-TGN levels compared with those who were not (p = 0.024).

Conclusion

TDM of thiopurines is highly useful in optimising thiopurine therapy in Asian IBD patients, particularly in identifying non-compliance, shunted metabolism, and patients who may require dose adjustment or a switch of therapy to alternative immunomodulator or biologics. This helps improve the efficacy of thiopurine use before escalating to the costly biologic therapy.