Therapeutic Drug Monitoring of Thiopurines in Patients With Inflammatory Bowel Disease: Observations From Daily Practice.

Abstract

Background: Patients with inflammatory bowel disease (IBD) to be treated with thiopurines should undergo preemptive genotyping for reduced-function thiopurine methyltransferase ( TPMT ) polymorphisms. Therapeutic drug monitoring (TDM) is recommended in cases of toxicity or a lack of efficacy. The relationship between TPMT genotype and 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) concentrations in the early steady state was assessed.

Methods: Consecutive adults with IBD to be treated with azathioprine underwent preemptive TPMT genotyping and were dosed accordingly. All patients underwent TDM after 4-6 weeks of treatment and occasionally thereafter.

Results: Of the 235 included patients, 45 were not genotyped for various reasons (45 samples at first TDM, 66 overall). Of the 190 patients who were genotyped, 19 (10%) were heterozygous (*1/*3) (19 samples at first TDM, 32 overall) and 171 (90%) were wild-type (171 samples at first TDM, 280 overall). At first TDM, 7 patients were hypermethylators, and 6 were identified at later TDMs. Compared with patients with a wild-type genotype or those who were not genotyped, those who were heterozygous consistently had markedly higher 6-TGN (2-fold, 3.7-fold if dose-adjusted) and lower 6-MMP (75%-90%, 30%-50% if dose-adjusted) concentrations (pmol/8 × 10 8 red blood cells). Based on the 6-TGN/6-MMP profiles, they were 2-3 times less likely to be classified as receiving "too low of a dose" (6-TGN <235 and 6-MMP <5700 pmol/8 × 10 8 red blood cells), and 4-20 times more likely to be classified as receiving "too high of a dose" (6-TGN >450).

Conclusions: These data support the importance of TPMT genotyping and suggest that thiopurine TDM generates supplementary information and should be performed for all patients.