5 Questions About Therapeutic Drug Monitoring for IBD

Therapeutic drug monitoring (TDM) is a process by which specific drug levels in the blood are measured over time with the goal of maintaining constant medication concentration in the blood. This process is widely used for patients with inflammatory bowel disease (IBD) and may be more cost-effective for patients taking biologics.

To answer our burning questions about TDM for IBD, Gastroenterology Consultant reached out to Bincy P. Abraham, MD, MS, who is the Fondren Distinguished Professor in Inflammatory Bowel Disease in the Department of Medicine, an associate professor of clinical medicine in the Academic Division of Gastroenterology and Hepatology, and an associate clinical member of the Research Institute at Houston Methodist – Weill Cornell in Houston, Texas.

GASTRO CON: How has the understanding of TDM changed over time?

Bincy Abraham: In the beginning, when TDM was just coming out, we were looking at figuring out, “How do we use this in clinical practice? What do these numbers mean? What does the drug levels mean?” It is easy when you order the test and get results back that say a patient has antibodies. We know that we most likely will not be able to use this medication. We need to move on. When we get drug levels back, how low is too low? How good is good enough? That is what we did not know initially.

Now, with more data, we have a better understanding when we get back drug levels of a certain drug, with the most evidence with the anti-TNFs. We know, “Okay, this is actually pretty low. We need to move forward with increasing dosing or the frequency of the medication.” However, if the drug levels are good or very high and the patient is not doing well, then we need to move on to something else, meaning a different mechanism-of-action agent.

We do not have as much data with the newer medical therapies, like vedolizumab or ustekinumab. However, it is still important that we get a general idea of where the patient’s drug levels are and make some clinical decisions based on those findings. We will be better able to utilize this information as more studies are done with the newer medical therapies as well.

One thing we do know is that adding an immunomodulator improves the drug levels of the anti-TNFs. However, with the newer medical therapies such as ustekinumab and vedolizumab, this is not the case: addition of immunomodulators do not improve drug levels. Based on data from clinical trials on trough-level monitoring, we have found that one can use these newer agents as monotherapy, due to much lower risk of immunogenicity. This is also helpful since immunomodulators have a higher potential for increased risk of adverse events, especially when using them in combination with biologics rather than just monotherapy.

GASTRO CON: Why else is TDM effective and important?

BA: TDM is really effective for making appropriate medical decisions for patients. The most benefit is seen among patients who are losing response, essentially utilizing reactive drug monitoring where patients have been doing well on medical therapy and then they lose response over time. We can use TDM to figure out why that is.

When we order drug levels and check for antibodies, we will know that if the patient has developed high levels of antibodies, that is the reason for his or her loss of response. Now we can make the decision to move them to a different medication, but they can stay on the same class of drug; they just need to go to a different brand of that same class.

Let's say you have a patient who has low drug levels but no anti-drug antibodies. You can then increase his or her drug dose or drug frequency—based on the type of drug or insurance coverage. Many studies show that increasing a patient’s dose or the frequency of patients who have subtherapeutic drug levels can capture them back into remission.

On the other hand, if you have a patient who is losing response but he or she has great drug levels, then continuing that same drug or increasing the dose or frequency is not going to improve the patient’s response, because they already have good drug levels. In this case, you would need to move on to a different class-of-action agent. We think that occurs because patients’ immune systems’ inflammatory pathway has changed somehow to a different process where that drug is no longer helping them by blocking the old pathway.

GASTRO CON: Are there any challenges associated with therapeutic drug monitoring?

BA: There are a few challenges regarding therapeutic drug monitoring. First and foremost would be access and insurance coverage. I think that has changed over the years, with several assays that insurances are covering, which has been great.

Secondly, we are not completely sure what should be the adequate trough level for every single patient, as we know inflammatory bowel disease is so heterogenous that no patient is the same. For those with very severe disease, we need to make sure that their trough levels are much higher than patients who have mild to moderate disease. We cannot go by one number and say, “Oh, this patient achieved this number. It should be working.” With severe disease, we may need to aim for higher trough levels. For example, take someone with perianal fistulizing disease compared with someone with isolated mild to moderate ileal disease.

Another drawback is that it also takes some time to get those results back; it takes typically 3 to 5 working days. Often, we have to wait for our patients’ dosing schedules to get to their trough before ordering the test, and once we order the test, we wait to get the results back before making a decision on next steps. Not having a point of care testing is another challenging part of TDM.

GASTRO CON: Can you give a specific example of a challenging IBD patient you had been monitoring?

BA: I had a patient who was on one biologic and was doing well for years in clinical and endoscopic remission. All of a sudden, she called me saying that she was having obstructive symptoms. Of course, I worried, “Is she having fibrostenotic disease, or is this inflammatory stenosis? What is causing this?” When I evaluated her, sure enough, she had an ileal narrowing that looked fibrostenotic at that time. Her last colonoscopy was a couple years prior to that examination, but she was doing well at the time.

First of all, I was surprised that she had symptoms and secondly that she had fibrotic disease. She had been on the same biologic for years, so there were no changes in her therapy, and she was adhering to her medication. I checked her drug levels and found that she did not have drug levels, but she had positive antibodies. That is what caused her to lose response to that biologic over time when she had been doing well on it for years. I had switched her to a different agent; I knew if I had kept her on the drug, she most likely would have developed an infusion reaction. This patient ended up needing surgery despite a few sessions of endoscopic dilation.

Usually, when patients have anti-drug antibodies, they tend to lose response, but they also develop infusion reactions or injection site reactions with subsequent doses. Surprisingly, in this patient’s case, she had not developed any infusion reactions to suggest that I would have needed to stop the medication. She continued the drug perhaps longer than she should have because she remained asymptomatic until the acute obstructive symptoms occurred.

GASTRO CON: What is the key take-home message for your peers about TDM for patients with IBD?

BA: The key takeaway about TDM in IBD is that I believe it to be useful, but we have to personalize it to individual patients based on their disease activity and severity.