Tumour necrosis factor-α (TNF-α) antagonists constitute critically valuable therapy for patients with inflammatory bowel disease (IBD), but only three have been approved in Canada. Thus, it is essential to optimize treatment before switching to another TNF-α antagonist or other biologic therapy. Measuring drug trough levels and antidrug antibodies (ADAs) can inform decisions around loss of response. As not all studies have produced consistent results, TDM does not replace clinical evaluation of the patient, careful confirmation of active disease, and exclusion of disease complications.(1) While the broad principles underlying interpretation of TDM have been agreed upon, optimal TDM measurement methods and cut-offs remain controversial.
A retrospective analysis of infliximab trough levels and ADA levels in 90 patients, 53 of whom had ADAs and 37 of whom had no ADAs, found that high ADA levels (>9.1 U/mL) at loss of response were associated with persistent ADAs and unsuccessful dose optimization. Of note, ADA proved to be transient in 28% of patients.(2)
A retrospective study of 76 patients with IBD, who had lost response to infliximab, evaluated the clinical responses to different therapeutic approaches in relation to infliximab trough levels and the presence of ADAs.(3) The study found 27 patients (69% of those who received infliximab intensification), responded to an increased dose, including 6 of 10 patients who were positive for ADAs. In addition, ADAs decreased in 5 patients after infliximab intensification. As a result, clinicians should not rely solely on trough or ADA levels when making a decision about treatment optimization.
When patients develop secondary loss of response to biologic therapy, therapeutic algorithms can be informed by TDM results for trough levels and ADAs. However, it is important to first confirm the presence of active inflammation. One such algorithm recommends the following strategies:(4)
● Low trough levels and low or absent ADA titres: Biologic dose intensification
● Low trough levels and high ADA titres: Switch to another TNF-α antagonist
● High trough levels and low ADA levels: Change to a treatment with a different mechanism of action
● High trough levels and high ADA levels: Rare scenario with management unclear.
Several potential future uses of TDM are currently being evaluated, but insufficient data currently exist to recommend these applications in clinical practice.
Performing TDM soon after starting biologic therapy could help to predict subsequent response. Post-hoc analyses of data from 728 patients from the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) demonstrated that patients with ulcerative colitis (UC) with clinical response and remission and mucosal healing had significantly higher median infliximab concentrations at weeks 8, 30, and/or 54 than patients without response, remission or mucosal healing.(5) In addition, the analysis indicated that trough levels at week 14 may predict response during maintenance, with an infliximab concentration ≥5.1 μg/mL at week 14 associated with clinical response at week 30. Infliximab levels of 41 μg/mL at week 8 of induction and 3.7 μg/mL during maintenance were associated with optimal outcomes.
TDM might help predict the efficacy and safety of reintroducing biologics after a drug holiday. A study of reinitiating infliximab in patients, who had previously received episodic therapy, lost response, or experienced infusion reactions, used TDM to identify factors associated with success and safety of restarting infliximab.(6). An infliximab trough level >2 μg/mL and undetectable ADAs soon after reinitiation predicted response, and measuring these levels allowed early treatment optimization. Concomitant immunomodulator therapy was found to be critical to long-term response in patients with low infliximab levels soon after reinitiation. Undetectable ADAs early in treatment were associated with lack of infusion reactions. Early evaluation of trough levels and ADAs allowed reliable prediction of long-term efficacy and safety.
A retrospective analysis of infliximab trough levels and ADA titres in 90 patients with IBD found that low trough levels (<2.2 μg/mL) at week 14 were associated with ADA formation, hypersensitivity reactions, and infliximab discontinuation.(2) Therefore, measurement of trough levels and ADAs at week 14 may be useful, as determination of ADAs in patients with low or undetectable trough levels may allow appropriate intervention, such as initiation of immunomodulator therapy or dose optimization.
Routine monitoring of trough levels and ADAs in patients in remission does not appear to be necessary, but research is needed to determine wither proactive adjustment of drug dosing can help prevent future sensitization and loss of response.(5-7)
Special Edition IBD Dialogue: Therapeutic Drug Monitoring in Clinical Practice 2014·Volume 01 is made possible by an unrestricted educational grant from…