Early therapeutic drug monitoring helps to identify inflammatory bowel disease patients with a high risk to fail thiopurine treatment.

Abstract

Conventional thiopurines (azathioprine and mercaptopurine) remain standard therapy to maintain steroid sparing remission in inflammatory bowel disease (IBD), but are regularly discontinued due to adverse drug reactions (ADRs). Measurement of the metabolites 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine ribonucleotides (6-MMPR) and the 6-MMPR/6-TGN ratio, may predict the development of these ADRs. Our aim was to evaluate whether early thiopurine metabolite measurements were associated with clinical outcomes. A post-hoc analysis was conducted of a multicentre, prospective, observational study on thiopurine-induced hepatotoxicity. IBD patients who initiated thiopurine therapy were included and thiopurine metabolite concentrations were assessed after 7days (±1) (T1). Patients were monitored for 12 weeks to document the occurrence of ADRs, early treatment discontinuation and effectiveness. In total, 181 patients were evaluated. At T1, 6-MMPR concentrations and 6-TGN/6-MMPR ratios were independently related to treatment discontinuation within 12 weeks after correction for sex, age and body mass index (BMI) (P= .034 and .002, respectively). The largest effects were observed for 6-MMPR ≥3000pmol/8 × 108 RBC and 6-TGN/6-MMPR ratio ≥17. Furthermore, 6-MMPR concentrations and 6-TGN/6-MMPR ratios at T1 were independently related to skewed metabolism at steady state (Week 8, 6-MMPR/-6TGN ratio ≥11 and ≥20) (both P< .001). The occurrence of ADRs and effectiveness were not independently related to T1 thiopurine metabolite concentrations. Thiopurine metabolite concentrations at T1 were related to early treatment discontinuation and skewed metabolism at steady state, but not to effectiveness, helping to identify patients with a high risk of thiopurine treatment failure.