Therapeutic Drug Monitoring in IBD

Biologic medications are often used to treat inflammatory bowel disease (IBD), especially when the seriousness of the condition is considered to be moderate to severe. These drugs are often effective in treating symptoms and/or inducing remission in Crohn’s disease or ulcerative colitis. However, there is the potential for these therapies to not have an effect at all or to work for a time but then stop being as effective. This might happen for various reasons in anywhere from one-third to one-half of people who live with IBD.

This problem of loss of response has prompted clinicians to start looking for ways to prevent it before it leads to a worsening of symptoms, or loss of remission. One way that a loss of response can be predicted is with therapeutic drug monitoring (TDM). The idea is that a loss of response might be predicted by checking how much of the drug is in the blood at a specific time after the last dose was taken.

The use of therapeutic drug monitoring is not completely agreed upon by all gastroenterologists or IBD specialists. There are questions about when it is appropriate, which patients should be tested, and what the results of the tests might mean. This article will define the different types of loss of response, how and when drug monitoring is usually done, and how much it might cost.

Loss of Response

With any of these medications, there are patients who will not initially respond. In fact, a quarter of patients fall into this category, according to the most recent large study performed on the treatment of Crohn's disease.

It’s not specific to biologics, either—loss of response can happen with other classes of drugs used to treat IBD. It is also common for patients to have a partial response. Measuring levels of the drug can be an important strategy for patients who have lost response or are losing response. When therapeutic drug monitoring is considered, it may be in order to determine if a patient is experiencing one of the two different types of loss of response: primary non-response and secondary loss of response.

Primary Non-Response

Biologic drugs are usually started with an induction dose, which is a dose that is larger than the maintenance dose (given at regular intervals). This could be given as one infusion via IV, or it could be a series of infusions or injections given over a period of weeks. Every biologic has a different loading dose and timeframe in which it is given. When a patient doesn’t respond (meaning have any improvement in symptoms) or is only having a partial response to this initial loading dose of the drug, it’s called a primary non-response.

Many biologics take time to begin working, so it’s not usually known if a patient is a non-responder until anywhere from about eight to 14 weeks after the induction. However, there’s no agreement among researchers about how to define a loss of response.

For the anti-tumor necrosis factor (TNF) medications, primary non-response has been shown to happen in anywhere from up to 20 percent of patients in real-world experience and 40 percent of patients in clinical trials. The patients who most often have primary non-response are those who have had IBD for a long time, who smoke, and who may have certain genetic mutations. However, primary non-response is not always class-dependent. That is to say, using another drug in the same class (such as another anti-TNF drug) doesn’t always result in another lack of response.

Secondary Loss of Response

In secondary loss of response, the patient does better at first, then after a period of time the medication seems to stop working. This is during the maintenance period, when the medication is given according to guidelines at regular intervals. Patients might experience a return of symptoms again after the initial induction period.

The rate of secondary loss of response after 12 months with anti-TNF treatments has been shown to be anywhere from approximately 20 percent to 40 percent. The loss of response might result in deciding to increase the dosage, add another medication to the regimen (a co-therapy), or try another therapy altogether. Or, in some cases, it might be decided to take an approach of watching and waiting, because the loss of response might not continue.

Therapeutic Drug Monitoring

Therapeutic drug monitoring is the process of measuring drug levels in the blood, which is also called the serum drug concentration. Drug monitoring is done with a blood test. The blood is drawn during a specific time period, usually a few days prior to the next dose of the drug being given. It’s then sent to a lab that can complete the analysis.

The level of a drug in the body takes a certain course, which varies based on the drug. Drug levels increase to a certain point and then decrease again, which usually means it is time for the next dose. The time between doses is decided based on the results of clinical trials, in order to keep as steady a level of the drug as possible in the body. This is in order to prevent inflammation and the symptoms of IBD from returning.

However, while drug levels might take a somewhat predictable course, it’s not the same for every patient. That’s where drug monitoring has a role. The lowest concentration of a drug in the body is called the trough level or trough concentration. When the trough level is reached, it is time to give the next dose of the drug to increase the levels again. The trough level is individualized and varies based on a number of different factors that can include gender, disease severity, and the patient’s own individual ability to clear the drug from the body.

If it is thought that the trough level might not be what is expected, such as because symptoms are returning, a blood test might be done. The blood test can be used to determine the level of drug in the body and if it is lower—or higher—than what is expected and/or needed.

When Drug Monitoring Might Be Used

When and how often to use therapeutic drug monitoring, and how useful it is in guiding treatment decisions, is an active area of debate. Some studies have shown that a serum level of a drug being low or even too low to measure is associated with a loss of response. Drug monitoring is often used to measure levels of the anti-TNF medications (such as Cimzia, Humira, Remicade, Simponi, and their biosimilars). It may also be used for other types of biologics as well, such as Vedolizumab and Stelara.

A blood serum test to measure drug levels might be used after the induction period to ensure that the drug is reaching the appropriate level. After that, trough levels might be measured at other times, which is up to the discretion of the healthcare providers. There is debate on whether monitoring should be done routinely or only when there appears to be a reason to do so, such as when the symptoms of IBD return.

Some published studies recommend that drug monitoring be done at these times:

• When there is primary non-response
• When there is a secondary loss of response
• At some point during the first year of maintenance therapy
• When re-initiating therapy with a drug after discontinuing it for a time

When the Results Come Back

Not only is there a lack of consensus about when to use drug monitoring, there is also a continuing debate about how the results should be interpreted and when it should lead to a change in therapy. A change could mean giving the drug more often, adding a helper drug (a co-therapy), or moving to a different drug. It could also be decided to do nothing for one or more treatment cycles and measure again.

These decisions should be made by taking all the available information into account and talking to the healthcare team. Clinicians may consult consensus statements from expert panels or colleagues or rely on their own experience to make recommendations.

The Twist: Drug Antibodies

With certain biologics, especially the anti-TNF medications, some people can develop antibodies to the drug. This is an immune response to the drug. It could have some bearing on how treatment is continued or changed. Having antibodies to a drug could mean that the drug is working less effectively to treat the disease. It could also mean that an adverse event may occur when taking the drug, such as an allergic reaction. In some cases these adverse events may be serious.

When there are antibodies but the trough level is good, there might not be any reason to make a change. However, if anti-drug antibody levels are found to be high, there might be a reason to reconsider the medication because it might also be associated with a loss of response.

Cost-Effectiveness of Drug Monitoring

One argument about the use of drug monitoring is the associated cost. Monitoring drug levels sounds like a good idea, and because it’s a blood test it's something that can be done quickly and easily for most patients. However, it may or may not be cost-effective to monitor drug levels proactively—that is, outside of the times when it's considered most useful or necessary (such as after induction).

On the one hand, monitoring drug levels and antibodies closely might help predict when a loss of response could be likely. Acting to make a change to therapy before it stops working could save the costs associated with a flare-up, such as hospitalizations or even surgery. On the other hand, monitoring could be expensive for patients and insurance companies. Repeated testing during remission might not yield any answers and yet still incur the same cost.

The American Gastroenterological Association (AGA) does have guidelines on therapeutic drug monitoring in patients with IBD. However, many large insurance companies do not follow these guidelines or have a policy in place regarding drug monitoring. That means in some cases the insurance company might refuse to cover the cost of the test. There are several different factors that could affect the cost of the test, but in many cases it could be between $200 and $300 in the United States.

It may be necessary for the healthcare team to file paperwork and make phone calls in order to get the test covered by insurance. When discussing the test with an insurance company, it may be helpful to reference the AGA guidelines. It may also be helpful for healthcare providers to address the many studies that have shown therapeutic drug monitoring to be cost-effective.

Even after putting these measures into place, it may still be that patients are responsible for part of the cost of the test. Calling the insurance company’s phone number (which is found on the back of the insurance card) will help in getting more information about policies in regards to drug monitoring.

A Word From Verywell

If therapeutic drug monitoring seems confusing, that’s because it is. Even prominent IBD specialists disagree on how it should be used, in which patients, and what the results mean. However, there is evidence that drug monitoring can be a cost-saving measure, especially in the long term. Those with IBD will want to ask their healthcare providers about drug monitoring, how often it’s needed, and how and where it might be done. The insurance company may have a preferred provider for drug monitoring tests, which means that it could be necessary to work with that lab to get the blood drawn and sent out to the appropriate lab.

In some cases, it may take persistence on the part of the healthcare team to ensure that insurance covers the cost, or part of the cost, of the test. However, it may be worth the time and energy to work with the insurance company because drug monitoring may prove helpful in making therapy choices.