Thiopurine Dose in Intermediate and Normal Metabolizers of Thiopurine Methyltransferase May Differ Three-Fold

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Abstract

Background & Aims:

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 × 108 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Eight (10%) of 77 participants were withdrawn because of protocol violation.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 (∼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 (∼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 × 108 RBCs, P = .02). This difference was 3-fold when the concentration was adjusted for dose (578 vs 183 pmol/8 × 108 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 × 108 RBCs) in patients with IBD might be 1 and 3 mg/kg/d in intermediate and normal metabolizers, respectively.

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