Thiopurine dose in intermediate and normal metabolizers of thiopurine methyltransferase may differ three-fold.
OBJECTIVE
Patients with inflammatory bowel disease (IBD) may have different thiopurine dose requirements in relation to thiopurine methyltransferase (TPMT) genotype and/or phenotype. The purpose of this study was to determine thiopurine dose requirements in intermediate versus normal TPMT metabolism status.


METHODS
Consecutive patients starting azathioprine or 6-mercaptopurine for IBD were followed up for 9 months. The thiopurine dose was individualized using 6-thioguanine nucleotide (6-TGN) concentrations (range, 235-450 pmol/8 x 10(8) red blood cells [RBCs]) and clinical status. Additional assessments undertaken every three months included measures of disease activity.


RESULTS
Eight (10%) of 77 participants were withdrawn because of protocol violation. Fifty-two (75%) of the remaining 69 subjects ( approximately 90% and 10% with the TPMT*1/*1 and *1/*3 genotypes, respectively) completed follow-up on azathioprine (n = 46) or 6-mercaptopurine (n = 6). The mean initial dose (as azathioprine equivalents) was similar ( approximately 1 mg/kg/d) for the 2 TPMT genotypes, but after 9 months the dose was 50% lower in the TPMT*1/*3 group (0.9 vs 1.8 mg/kg/d, P < .0001). Despite dose adjustment, median 6-TGN concentrations still were 2-fold higher in the TPMT*1/*3 group at the end of the follow-up period (505 vs 273 pmol/8 x 10(8) RBCs, P = .02). This difference was 3-fold when the concentration was adjusted for dose (578 vs 183 pmol/8 x 10(8) per mg/kg/d, P = .0007). Results were similar if TPMT phenotype was used instead of genotype. Clinical outcomes did not differ between groups.


CONCLUSIONS
Initial target doses to attain therapeutic 6-TGN concentrations (>235 pmol/8 x 10(8) RBCs) in patients with IBD might be 1 and 3 mg/kg/d in intermediate and normal metabolizers, respectively.
Gardiner
Sharon J
SJ
Department of Medicine, Christchurch Hospital and Christchurch School of Medicine, Christchurch, New Zealand. sharon.gardiner@cdhb.govt.nz
Gearry
Richard B
RB
Begg
Evan J
EJ
Zhang
Mei
M
Barclay
Murray L
ML
D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011446:Prospective Studies; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine