An Open-Label Pilot Study Using Thioguanine as a Therapeutic Alternative in Crohn's Disease Patients Resistant to 6-Mercaptopurine Therapy

• Published in: Inflammatory bowel diseases 2001-08, Vol.7 (3), p.181-189
• Main Authors: Dubinsky, Marla C., Hassard, Philip V., Seidman, Ernest G., Kam, Lori Y., Abreu, Maria T., Targan, Stephan R., Vasiliauskas, Eric A.
• Format: Article
• Language: English
• Subjects: 6‐Mercaptopurine; 6‐Mercaptopurine metabolites; 6‐Methylmercaptopurine ribonucleotides; 6‐Thioguanine nucleotides; Adult; Antimetabolites - administration & dosage; Antimetabolites - adverse effects; Antimetabolites - therapeutic use; Azathioprine - therapeutic use; Child; Crohn Disease - drug therapy; Crohn's disease; Drug Resistance; Female; Humans; Male; Maximum Tolerated Dose; Mercaptopurine - therapeutic use; Middle Aged; Pilot Projects; Thioguanine; Thioguanine - administration & dosage; Thioguanine - therapeutic use; Thiopurine methyltransferase; Treatment Outcome
• ISSN: 1078-0998; 1536-4844
• DOI: 10.1097/00054725-200108000-00001

SummaryBackground and AimsA substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy.MethodsTen CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities.ResultsSeventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity.Conclusions6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short-and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.