Australian study backs proactive thiopurine TDM

Proactive therapeutic drug monitoring (TDM) should be routine with thiopurine treatment because it identifies many patients who are inappropriately dosed and allows treatment to be adjusted to produce better outcomes, an Australian study has shown.

Conducted at four IBD centres in three states, the study involving 541 patients with Crohn’s disease or ulcerative colitis also showed that TDM enabled most patients to stay on thiopurine treatment and avoid switching or escalating treatment to manage their IBD.

Led by Dr Alex Barnes and colleagues at the Flinders Medical Centre Department of Gastroenterology, Adelaide, the observational cohort study showed that TDM led to over half of patients having changes to their therapy, and also helped identify patients with adverse drug reactions to thiopurines and those who had ‘shunting’ who required addition of allopurinol.

The study involved patients with a median age of 40 years of whom 70% had Crohn’s disease, and 28% ulcerative colitis, with median IBD disease duration of 10 years, taking immunomodulators azathioprine and 6-mercaptopurine.

Testing for the thiopurine metabolites 6-TGN (6-thioguanine nucleotide) and 6-MMPR (6-methyl-mercaptopurine ribonucleotides) showed that at baseline only 39.7% had levels consistent with appropriate dosing.

For the 60% of patients with active disease, TDM showed that around 30 were under-dosed or non-compliant, 14% overdosed, 17% had levels  consistent with MMP-6 shunting.

The TDM results informed a management change in 62% of patients, and at 12 months repeat TDM showed that 56% of patients had therapeutic 6-TGN levels.

Overall, TGM enabled 89% of the patient cohort to continue thiopurines. At 12 months following TDM, only 23% of patients still had active disease and 68% had achieved clinical remissions.

Most of the patient who achieved a clinical response (73%) were able to do so while remaining on azathioprine without the need to escalate to other therapies. Escalation to biologic medication occurred in 7.3% of patients at 12 months, and four patients required surgical treatment.

Identification of shunting led to the proportion of patients on allopurinol and thiopurine therapy increasing from 3% to 13% by 12 months.

Of the 9% of patients who underwent metabolite measurement for suspected adverse drugs reactions, half were  judged to have unexplained symptoms/reactions unrelated to thiopurines, 30% to have idiosyncratic reactions and 19% to have dose-dependent adverse drug reactions.

Lymphopenia was present in 23% of the cohort, while most patients with adverse reactions were able to remain on thiopurines at 12 months.

The investigators said their findings confirmed those from smaller studies of the benefits of TDM for thiopurines in IBD. Without TDM a significant proportion of patients may have been labelled thiopurine refractory,” they said

“Rather than appropriately adjusting/augmenting the thiopurine dose, they may then have been subjected to escalation of therapy, such as blind AZA/6MP dose escalation, long-term corticosteroids, switching treatment to methotrexate, escalation to biologic agents or surgery,” they wrote.

With TDM only 8% of patients with active disease were judged truly thiopurine refractory, they said, and TDM-guided management changes such as dose optimisation reduced the proportion with active disease significantly, they noted.

The results therefore endorsed the use of routine proactive TDM, they concluded.

The findings are published in Digestive Diseases and Sciences.

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