6-TGN monitoring for azathioprine dose modification in IBD (V1.0)
Research type
Research Study
Full title
A retrospective observational study to determine the real world effectiveness of the azathioprine metabolite-monitoring (i.e. 6-TGN) based dosing strategy in patients with inflammatory bowel disease
IRAS ID
286477
Contact name
Bu'Hussain Hayee
Contact email
Sponsor organisation
King's College Hospital NHS Foundation Trust
Clinicaltrials.gov Identifier
286477, REC Submission
Duration of Study in the UK
0 years, 8 months, 1 days
Research summary
Research Summary
Inflammatory bowel disease (IBD) is non-infectious chronic inflammatory disease of the gastrointestinal (GI) tract. It is commonly differentiated by pattern of inflammation, where Crohn's disease can affect any segment of the GI tract from mouth to anus, and Ulcerative Colitis is limited to the colon. Approximately 7 million people have IBD globally, which results in over 1 million years lost to disability annually. Treatment of inflammatory bowel disease is split into two major therapeutic aims: 1) stopping the inflammatory process (known as inducing remission), and; 2) maintaining this inactive state (known as maintaining remission). There are an array of different drugs that can be used to achieve either, or both aims simultaneously. In this study we concern ourselves only with the objective of maintaining remission, and the use of one specific drug, i.e. azathioprine, which is the most commonly utilised drug in the management of IBD. Previous research has focused on weight-based dosing, however, there is an alternative approach based on measuring the quantity of specific end-products of the breakdown of azathioprine to decide if a dose is sufficient. The evidence for the latter approach is based on a series of studies which have suggested that it allows clinicians to identify the lowest possible dose that a patient requires to maintain remission, which is ideal given that many patients are unable to tolerate the side effects of azathioprine. However, may of these studies are based on a very small number of patents. In this study, we seek to contribute to the evidence base by reviewing the notes of every patient with IBD at our large specialist centre where we employ this alternative approach, to determine their outcomes. This study will not impact the care of the patients whose data we access, and we expect no additional inconvenience or burden on patients as a consequence of the study.
Summary of Results
Inflammatory bowel disease (IBD) is a global health issue, and maintaining remission in IBD patients is crucial. Thiopurines, like azathioprine and 6-mercaptopurine, are important for maintaining remission, but determining the best dose of the drug for an individual patient is challenging. Traditional weight-based dosing often leads to side effects, making it necessary to understand thiopurine metabolism.
The enzyme Thiopurine Methlytransferase (TPMT) plays a key role in thiopurine metabolism, and genetic variations in TPMT result in diverse responses to thiopurines. Failure to account for these variations can lead to suboptimal doses or increased toxicity. To address this, clinicians use metabolite-based dose optimization, focusing on 6-thioguanine nucleotide (6-TGN) levels. While observational studies suggest a link between 6-TGN concentrations and remission maintenance, they don't establish a predictive relationship.
This study used predictive modelling and real-world data to evaluate the effectiveness of 6-TGN-guided dosing. The findings indicate that predicting 6-TGN concentrations from azathioprine dosage alone is challenging. However, incorporating historical dose-response information improves predictions significantly.
Regarding predicting treatment outcomes, the study suggests that using azathioprine dose and metabolite data doesn't reliably predict time to treatment failure better than a guess. Complex machine learning methods didn't significantly improve performance, questioning the current practice of using 6-TGN biomarkers for dose optimization.
In essence, the study suggests that relying solely on clinician-led interpretation of 6-TGN results with protocolized adjustments may not be the best approach. The study recommends prioritizing a prediction-model-based approach for individualized dose modification over generic adjustments made by clinicians, and emphasizes the need for a robust randomised controlled trial to compare this approach to the current standard of care.
REC name
West of Scotland REC 3
REC reference
21/WS/0103
Date of REC Opinion
6 Oct 2021
REC opinion
Further Information Favourable Opinion