Thiopurine Therapeutic Drug Management Increased IBD Remission Rates

Therapeutic drug monitoring (TDM) could increase the efficacy of thiopurine treatment for patients with inflammatory bowel disease (IBD).

A team, led by Alex Barnes, IBD Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital Adelaide, assessed the long-term outcomes of patients with IBD treated with thiopurines following therapeutic drug monitoring.

What’s Known?

While thiopurines are commonly used to treat IBD, there is significant variation in the levels of toxic and therapeutic metabolites.

Current data show the benefits of therapeutic drug monitoring of in assessing azathioprine and 6-mercaptopurine. However, this was mainly done in small or short-term studies, as well as dose-dependent studies based on body weight.

“Prior to the introduction of metabolite measurement, ongoing active disease was commonly attributed to resistance and resulted in escalation of therapy to other agents,” the authors wrote. “Thiopurine metabolite measurement has since been demonstrated to facilitate clinical management by identifying other explanations for an apparent failure of thiopurines.”

However, current data shows azathioprine, a prodrug converted to 6-mercaptopurine and methyl-nitroimidazole in the liver, results in an overall maintenance remission rate of 71% (CI 95%, 0.64–0.77) in Crohn’s disease and 54% (CI 95% 0.54–0.86) in ulcerative colitis. Thiopurine maintenance therapy also has shown to reduce the requirement for corticosteroid use and is linked to reduced rates of surgery in patients with Crohn’s disease.

Pathways

6-mercaptopurine is metabolized through 3 competing pathways. In the first pathway, xanthine oxidase converts 6MP to 6-thiouric acid, an inactive metabolite.

In the second pathway, thiopurine methyltransferase (TPMT) converts 6MP to 6-methyl-mercaptopurine ribonucleotides (6-MMPR), a potentially hepatotoxic metabolite.

Finally, in the third pathway, a series of enzymatic steps exist wherein 6MP is converted to 6-thioguanine nucleotide (6-TGN). This is recognized as the therapeutic and potentially myelotoxic metabolite.

The Study

In the multicenter, retrospective, observational study, the investigators collected the demographics, disease characteristics, physician global assessment, IBD therapy at baseline therapeutic drug monitoring, and again at 12 months for 541 patients with IBD. Of the patients, only 39% had an appropriate dosing of thiopurines.

They then analyzed clinical outcomes according to TDM result and indication for TDM including proactive and other indications.

The results show azathioprine and 6-mercaptopurine therapeutic drug monitoring informed a management change in 61.9% of the patient population. The treatment also enabled 88.8% of the patients to continue treatment following therapeutic drug monitoring.

At the 12 month mark following therapeutic drug monitoring, 74.1% of the cohort remained on their medication.

For clinical remission, rates were higher at 12 months following thiopurines TDM compared to baseline (68% vs 37%), including proactive therapeutic drug monitoring. Post TDM, 13% of the cohort identified as shunters and continued on thiopurine-allopurinol co-therapy.

“Thiopurine TDM resulted in a change in management for the majority of patients,” the authors wrote. Post TDM significantly more patients were in remission. TDM allowed the identification of non-adherence and shunters who, without intervention, would not reach therapeutic drug levels. Proactive TDM allowed identification and management of inappropriate dosing and was associated with increased levels of clinical remission.”

The study, “Proactive Metabolite Testing in Patients on Thiopurine May Yield Long-Term Clinical Benefits in Inflammatory Bowel Disease,” was published online in Digestive Diseases and Sciences.