6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment.
OBJECTIVE
6-Mercaptopurine (6-MP) and azathioprine (AZA) have proven efficacy in the treatment of inflammatory bowel disease (IBD). However, adverse events leading to discontinuation may occur in 10-20% of patients. The efficacy of AZA and 6-MP is based on formation of their active metabolites, the 6-thioguaninenucleotides (6-TGNs). Therefore, 6-thioguanine (6-TG), an agent leading more directly to the formation of 6-TGNs and until recently used only in patients suffering from leukaemia, may be an alternative in AZA or 6-MP intolerance. The purpose of our study was to assess the short-term safety of 6-TG.


METHODS
Thirty-two IBD patients with previously established AZA or 6-MP intolerance were treated with 6-TG in doses of 20 mg (n = 19) or 40 mg (n = 13) once daily. Safety parameters were obtained at 0, 1, 2, 4 and 8 weeks after start of medication. Primary outcome measures were the ability to tolerate 6-TG and the occurrence of adverse events. Secondary outcome definitions included laboratory parameters.


RESULTS
Twenty-six (81%) patients were able to tolerate 6-TG during the first 8 weeks. In three of six patients, side effects leading to discontinuation were probably (n = 2) or obviously (n = 1) related to 6-TG. No clinically relevant haematological events or hepatotoxicity occurred in the observed period. Steady-state 6-TG levels were significantly higher with 40 mg once daily (1621 +/- 828 picomol/8 x 10(8) red blood cells (RBC)) than with 20 mg once daily (937 +/- 325 picomol/8 x 10(8) RBC; n = 0.001).


CONCLUSIONS
6-TG treatment seems promising in AZA- or 6-MP-intolerant IBD patients. However, long-term safety and efficacy have yet to be determined.
Derijks
Luc J J
LJ
Department of Clinical Pharmacy, Maasland Hospital, Sittard, the Netherlands. lderijks@orbisconcern.nl
de Jong
Dirk J
DJ
Gilissen
Lennard P L
LP
Engels
Leopold G J B
LG
Hooymans
Piet M
PM
Jansen
Jan B M J
JB
Mulder
Chris J J
CJ
D000328:Adult; D001379:Azathioprine / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects* / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000097:blood; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood; D008875:Middle Aged; D011446:Prospective Studies; D013866:Thioguanine / Q000009:adverse effects* / Q000097:blood
D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; C010240:6-methylthiopurine; D015122:Mercaptopurine; D013866:Thioguanine; D001379:Azathioprine