Increased dosing requirements for 6-mercaptopurine and azathioprine in inflammatory bowel disease patients six years and younger

Background: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are effective for the induction and maintenance of remission and reduction of corticosteroid exposure for pediatric inflammatory bowel disease (IBD). The standard dose of 6-MP is 1.0-1.5 mg/ka/day and for AZA is 2.0-2.5 mg/kg/day. The aim of this study was to determine whether 1131) patients 6 years of age and younger require higher than standard doses of 6-MP/AZA to achieve clinical remission. Methods: Clinical data was collected retrospectively for all 1131) patients 6 years of age or younger treated with 6-MP/AZA at The Children's Hospital of Philadelphia. Results: Thirty patients met the inclusion criteria. IBD was diagnosed at a median age of 3.3 years (25-75th %ile 2.3-4.6 years) and 6-MP/AZA was initiated at a median age of 3.9 years (range 0.8-6.8 years). After dose escalation, the median AZA-equivalent dose was 3.1 mg/kg/day (25-75th %ile 2.5-3.5, max. dose 5.1 mg/kg/day). At the final recorded dose, 8/13 (62%) patients receiving AZA >3.0 mg/kg/day achieved clinical remission, compared to 2/12 (17%) receiving 2-3 mg/kg/day (P = 0.02). The risk of having active disease was on average 85% lower if the AZA-equivalent dose was >3.0 mg/kg/day (95% confidence interval [CI] 72%-93%). Adverse events were experienced by 4/30 patients (hepatitis, n = 2; leukopenia, n = 2). No patients had to discontinue 6-MP/AZA, and all laboratory abnormalities improved spontaneously or with dose reduction. Conclusions: The standard dose of 6-MP/AZA may not be adequate for IBD patients 6 years of age and younger. Closely monitored dose escalation beyond the standard dosing range is effective and well-tolerated.