Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease.
BACKGROUND
Thiopurines are a mainstay of immunomodulator therapy in inflammatory bowel disease (IBD). Despite their efficacy, some patients may have a poor response due to inability to achieve adequate levels of the active metabolite, 6-thioguanine (6-TGN). Others experience hepatotoxicity, which correlates with excessive 6-methylmercaptopurine (6-MMP) levels. Two adult studies have demonstrated successful manipulation of thiopurine metabolism with allopurinol, a xanthine oxidase inhibitor, to achieve more optimal thiopurine levels. The aim was to retrospectively characterize the utility of allopurinol to optimize thiopurine metabolite levels in pediatric IBD patients.


METHODS
Thirteen patients received allopurinol daily (100 mg in patients >or=30 kg and 50 mg <30 kg), and their thiopurine dose was simultaneously reduced to 25%-50% of the previous maintenance dose. Metabolite levels and other screening labs were checked 2-4 weeks later.


RESULTS
The mean azathioprine dose was decreased from 148.1 to 59.6 mg daily (60% of the mean original dose). The mean 6-TGN level increased from 173 to 303 pmol/8 x 10(8) red blood cell count (RBC) (P = 0.03), and the mean 6-MMP level decreased from 7888 to 2315 pmol/8 x 10(8) RBC (P < 0.001). Elevated transaminase levels improved or resolved in all patients. Two patients experienced reversible neutropenia. At the conclusion of the study 9 patients (69%) remained on combination therapy with a mean duration of follow-up of 162.8 +/- 119.2 days.


CONCLUSIONS
Combination therapy successfully shunted thiopurine metabolites to a more favorable pattern. Reversible neutropenia was the most common side effect (2 patients). Long-term prospective studies are needed in this patient population.
Division of Pediatric Gastroenterology, Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA. riadrahhal@uiowa.edu
Riad M
RM
Rahhal
Warren P
WP
Bishop
D000293:Adolescent; D000493:Allopurinol / Q000627:therapeutic use*; D000963:Antimetabolites / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000097:blood / Q000188:drug therapy*; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011379:Prognosis; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome
D000963:Antimetabolites; D000493:Allopurinol; C010240:6-methylthiopurine; D015122:Mercaptopurine