Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease.
BACKGROUND
Circulating concentrations of 6-thioguanine nucleotide (6-TGN) and 6-methyl mercaptopurine (6-MMP) are associated with thiopurine efficacy and may predict toxicity. This study aimed to examine retrospectively the utility of measuring metabolite concentrations in patients with inflammatory bowel disease (IBD) who had continuing symptoms despite stable thiopurine treatment.


METHODS
Concentrations of 6-TGN and 6-MMP were measured in lysates of washed red cells by high-performance liquid chromatography in peripheral blood drawn from 63 symptomatic patients with IBD (63% men, mean age 37, range 14-74 years, 67% Crohn's disease, 33% ulcerative colitis) treated with azathioprine or 6-mercaptopurine. Short-term clinical outcomes were examined.


RESULTS
6-TGN concentrations weakly correlated with the thiopurine dose (r = 0.28, P = 0.08). On weight-based criteria, 50% of patients were underdosed. However, metabolite patterns suggested 7 (11%) patients were noncompliant, 18 (29%) were being underdosed, 33 (52%) were refractory to treatment with either appropriate (41%) or elevated (11%) metabolite concentrations, and 6 (10%) had a raised 6-MMP:6-TGN ratio consistent with aberrant thiopurine metabolism. The clinical outcome improved in 40 of 46 (87%) of patients in whom the course of action taken was as recommended by a metabolite-directed algorithm, while 3 of 17 patients (18%) improved where discordant actions were taken (P = 0.0001; Fisher's exact test). Fifteen patients (24%) avoided inappropriate escalation of therapy.


CONCLUSIONS
Dose-optimization or toxicity-avoidance strategies frequently result from metabolite testing in patients with inadequate efficacy from thiopurines, with evidence of better outcomes. Thiopurine metabolite testing is a potentially powerful tool for optimizing thiopurine usage in IBD.
Haines
Melissa L
ML
Department of Medicine, Eastern Health, Monash University, Victoria, Australia.
Ajlouni
Yousef
Y
Irving
Peter M
PM
Sparrow
Miles P
MP
Rose
Rosemary
R
Gearry
Richard B
RB
Gibson
Peter R
PR
D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003093:Colitis, Ulcerative / Q000097:blood / Q000188:drug therapy; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D008875:Middle Aged; D013866:Thioguanine / Q000097:blood*; D017211:Treatment Failure; D055815:Young Adult
D007166:Immunosuppressive Agents; C010240:6-methylthiopurine; D015122:Mercaptopurine; D013866:Thioguanine; D001379:Azathioprine