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Dr. Burrill B. Crohn Professor of Medicine
Chief of the Dr. Henry D. Janowitz Division of Gastroenterology
Mount Sinai Hospital
Chief, Division of Gastroenterology
Mount Sinai Health System
Director, Digestive Disease Institute
Icahn School of Medicine at Mount Sinai
New York, New York
Bruce E. Sands, MD, MS, has disclosed that he has received consulting fees from Abivax, Arena, AstraZeneca, Bacainn, Boehringer Ingelheim, Boston Pharmaceuticals, Celltrion, Genentech, Gilead Sciences, GlaxoSmithKline, Index, Inotrem, Ironwood, Janssen, Kallyope, Lilly, Pfizer, Prometheus Biosciences, Prometheus Therapeutics, Surrozen, Takeda, Target RWE, USWM Enterprises, and Viela Bio and funds for research support from Theravance.
Therapeutic drug monitoring (TDM) is an important part of personalizing biologic therapy for patients with inflammatory bowel disease (IBD). The aim of TDM is to inform decisions about whether and when to adjust dosing or consider switching drugs for patients who are not responding to therapy. An understanding of the target therapeutic ranges for each agent and how to interpret test results allows healthcare professionals to optimize outcomes for patients receiving biologic therapy. Of note, the practice of TDM for IBD management is currently limited to TNF-α inhibitors; it has not been fully worked out for other biologics.
Reactive TDM is an approach for patients who lose response to treatment. The American Gastroenterological Association has incorporated reactive TDM into the treatment algorithm for patients who are receiving TNF-α inhibitors, advising that patients with objective evidence of active IBD despite treatment should be evaluated to determine the trough drug concentration and evaluated for the presence of antidrug antibodies, which are a common cause of loss of response to TNF-α inhibitors. Drug-specific assays that measure the drug concentrations and antidrug antibodies from a single sample are commercially available from many manufacturers, although I recommend using a particular assay consistently, as results may not be comparable among manufacturers.
The first step of TDM is to compare the patient’s trough plasma drug concentrations with the established target range. The therapeutic ranges for infliximab, adalimumab, and certolizumab are well defined (those for golimumab are proposed). For patients with adequate trough concentrations, the implication is that they are no longer responding to TNF-α inhibition and should be switched to a different class of drugs. For patients with an inadequate trough drug concentrations, the next step is to assess whether antidrug antibodies are present. When antidrug antibodies are not present or are minimal, it is reasonable to optimize the dosage of the TNF-α inhibitor, either by increasing the dose, decreasing the dosing interval, or sometimes both. This patient likely has a high rate of drug turnover and requires an optimized dosage to achieve therapeutic targets.
On the other hand, when high levels of antidrug antibodies are present in the context of low trough drug concentrations, we should consider a switch to another therapy, either within the same class or a different class. However, I would caution that adding an immune modulator to the TNF-α inhibitor should be considered at this point, which could help prevent antibodies forming against the next drug. This is especially true if the next agent is another TNF-α inhibitor. Vedolizumab and ustekinumab are less likely to generate antidrug antibodies associated with loss of response, and therefore, the role of combination therapy with an immune modulator is less certain.
One practical consideration with reactive TDM is the time needed to receive the assay results. At my institution, these tests typically take a few days or a week. Because the optimal timing for sampling the trough drug concentrations is typically a day or two before the next infusion, it is difficult to have the assay results back in time to adjust the very next dose. My approach is to plan to obtain the sample 1 week before the next scheduled dose. I would not advise testing any earlier, as you would likely not be at the trough, and reliable tools to project trough concentrations from a static level drawn several weeks before the next dose are not widely available.
Proactive TDM is a more controversial approach that entails routine monitoring of drug concentrations and antidrug antibodies to achieve and maintain therapeutic concentrations and prevent disease flares. Because we do not yet have reliable methods for tailoring the initial loading dose, we are likely underdosing a fair number of patients who initiate biologic therapy. The rationale for proactive TDM is that checking levels early may afford the opportunity to correct the dosing before it becomes a problem. Indeed, some patients have detectable antidrug antibodies within weeks of their first dose of a TNF-α inhibitor.
To date, the evidence for this approach is lacking, as studies evaluating proactive TDM have failed to meet primary outcomes. However, several studies have found an association between higher trough concentrations of TNF-α inhibitors and improved clinical outcomes, including clinical remission and endoscopic remission. Yet without prospective studies demonstrating that proactive TDM leads to improved clinical outcomes, the approach remains controversial.
Nonetheless, proactive TDM may be appropriate when the stakes are high. For example, when a patient has severe disease with extensive inflammation and bowel involvement, or has had prior drug failures, that could warrant the use of proactive TDM.
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