P565 Real-world use of azathioprine metabolites changes clinical management of inflammatory bowel disease
Bibliographic record
Abstract
With ongoing sub-optimal efficacy of current therapies in achieving intestinal healing in IBD, the thiopurines, 6-mercaptopurine (6MP) and azathioprine (AZA), continue to have a role in IBD treatment. However, their complex metabolism results in inter-individual differences in clinical efficacy and risk of drug toxicity, making conventional weight-based dosing both inaccurate and potentially unsafe. Therapeutic drug monitoring (TDM) of thiopurine metabolites improves clinical outcomes through optimisation of dosing and monitoring for toxicity (Haines et al., 2011). Despite evidence for thiopurine TDM, there remain significant disparities in use, due in part to test availability. We recently described implementation of a novel thiopurine metabolite assay (Yang et al. poster, AACC, 2017). This study aims to determine the impact of thiopurine metabolite levels on physician decision-making and clinical management. Patients who had undergone thiopurine TDM as part of their outpatient care were identified and prospective and retrospective chart reviews performed to measure the impact of TDM on clinical management. Additional data were gathered from patient charts including demographics, dosing, clinical disease activity, concurrent medication use, and frequency of adverse effects. A second physician reviewed clinical scenarios with blinding of TDM results and original clinical management, and provided an opinion on clinical decision-making before and after unblinding of TDM results. A total of 92 IBD patients (63% CD, 37% UC) with available metabolite levels were included, of which 64% had active disease, and 43% were on combination therapy with a biologic. Levels of the active metabolite 6TG were sub-therapeutic in 52%, therapeutic in 29% and supra-therapeutic in 14%. High 6MMP: 6TG ratios were found in 26% of patients. Weight-based AZA doses accounted for only 5% of the variation in 6TG levels (r2 = 0.057, p = 0.02). TDM resulted in a change in clinical management in 64% of the cases. In 44% of those dosing was decreased, 19% dosing increased, and in 8% AZA discontinued. Allopurinol was added to the drug regimen in 12%. TDM also informed biologic management, with the addition of a biologic in 24%, optimisation of biologic in 7%, and change of biologic in 5%. Adverse reactions were observed in 28% of patients after weight-based dosing alone. The use of thiopurine TDM results informed IBD clinical decision-making in over two-thirds of patients. Additionally, therapeutic 6TG levels were seen in only 29% of patients. The demonstrated poor efficacy of weight-based dosing and significant impact of metabolite levels on clinical management highlights the need for greater availability and uptake of thiopurine TDM.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.007 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".