Proactive Therapeutic Drug Monitoring in IBD: What’s Stopping You?
Despite the wealth of benefits that can come from the use of proactive therapeutic drug monitoring (TDM) in treating inflammatory bowel disease (IBD), only a few gastroenterologists turn to this approach, according to Adam Cheifetz, MD.
Dr Cheifetz, who is the director of the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center and associate professor of medicine at Harvard Medical School in Boston, Massachusetts, recently discussed TDM use at the Interdisciplinary Autoimmune Summit (IAS) 2018 in Boston, Massachusetts.
Proactive TDM with drug titration to a target concentration may increase drug durability and decrease IBD-related surgeries and hospitalizations, as well as serious infusion reactions and antibodies to infliximab.1
However, many physicians are hesitant to put this approach into practice due to a number of potential barriers, even though this approach is commonly used in other medical settings with other medications like tacrolimus and cyclosporine, Dr Cheifetz said.
In a recent study that he co-authored, Dr Cheifetz and colleagues surveyed 403 gastroenterologists from 42 US states to further investigate these barriers to TDM.2
Among this sample of respondents, 90.1% used TDM. However, most respondents used TDM reactively for secondary loss of response (87.1%) and primary nonresponse (66%), whereas only 36.6% used TDM proactively. Even still, these numbers are likely inflated due to selection bias of respondents that chose to fill out the survey.
The greatest barriers to proactive TDM implementation were uncertainty about insurance coverage (77.9%) and high out-of-pocket costs for patients (76.4%), followed by time-lag from serum sample to result (38.5%).
Perhaps most notably, findings indicated that if all barriers were removed, an additional one-third of physicians would apply proactive TDM in the treatment of IBD.
In a Q&A with Consultant360, Dr Cheifetz discussed these findings further and gave insight on potential solutions to the barriers to proactive TDM use. He also shared highlights from his presentation at IAS 2018, “Optimizing the Treatment of IBD through Use of Therapeutic Drug Monitoring.”3
Consultant360: Your study found that cost and insurance coverage are among the top barriers to TDM for IBD. How have these barriers affected treatment accessibility and outcomes in patients with IBD?
Adam Cheifetz: In our recent survey study of American College of Gastroenterology and Crohn & Colitis Foundation members, the uncertainty regarding insurance coverage of testing (77.9%) and high out-of-pocket costs for patients (76.4%) were felt to be the 2 greatest barriers to TDM. This almost certainly stems from one particular company whose recent test comes with a $2500 price tag, which is billed to a patient's insurance company.
Though patients typically pay $0 to $250, there is a possibility that they could be held accountable for more. For example, a patient whose insurance covers the test and they have a high deductible. This uncertainty has scared many physicians away from routine TDM.
There are several more companies that now perform drug concentration testing, which should help move the field forward. However, this had led to other issues, as physicians can be confused by some of the results – particularly the antibodies. It is important to remember that the drug concentration is the most important value and that the antibodies are secondary. Assays that are drug tolerant can report antibodies in the presence of drug. If there is adequate drug, these antibodies are likely to be clinically meaningless, no matter the number.
C360: In your presentation, you mentioned that clarifying the trough concentration window for TDM is another potential barrier that does not have a simple solution. What do you think are the next steps in solving this issue?
AC: This is a difficult question to answer, and more prospective studies on this topic would help. I still think that we should consider a threshold concentration depending on the outcome. These thresholds tend to be higher when the endpoint is more difficult to attain (i.e., mucosal or fistula healing). The data we currently have is population-based. Moreover, the therapeutic drug window to target is also drug-specific.
For example, it seems that higher adalimumab concentrations are needed to achieve similar therapeutic outcomes compared to infliximab. Besides outcome- and drug-dependent, clinically relevant thresholds may also be assay-dependent. Although current data suggest that most of the assays are comparable when measuring drug concentrations, several ongoing prospective studies will certainly shed more light on this.
What we really need to be concerned with is each individual patient and what their concentration should be. If I have a patient in clinical and endoscopic remission with an infliximab or adalimumab concentration of 5μg/mL, I am happy. However, if his or her concentration is 5μg/mL and he or he is in clinical remission but not endoscopic remission, I will push the trough higher and aim for 10μg/mL.
Also, the timing of the testing is important. Most data on the benefits of proactive TDM are for during maintenance. TDM and dose optimization during the induction phase, when patients are sickest and clearing the drug more quickly, is likely to be even more important.
C360: In your presentation, you also said that timing of testing, accessibility to an accurate and inexpensive test, and the need for prospective data on TDM implementation are also issues that can arise with TDM. Are there any potential solutions to these issues?
AC: The hope for the future is for point-of care-testing, where a blood sample (even from finger stick) can be used to run a trough concentration, and that value can be acted upon right away—before the drug is given. Currently the lag-time can be up to a week. Thus, the physician can only change the next dose, typically giving it earlier if needed.
Researchers are also currently working on predictive modeling that will better optimize dosing. Certain variables—such as body mass index, sex, albumin, and C-reactive protein—can be used to predict how much of a drug is needed to attain a particular trough concentration. Once a trough concentration is known, it is used in the model to determine what and when the next dose should be (for the desired trough concentration).
Further prospective studies are needed to confirm the results of our study, which indicate that proactive TDM is better than reactive TDM, or empiric dose escalation.
For our coverage of Dr Cheifetz’s presentation at IAS 2018, click here.4
—Christina Vogt
References:
1. Papamichael K, Chachu KA, Vajravelu RK, et al. Improved long-term outcomes of patients with inflammatory bowel disease receiving proactive compared with reactive monitoring of serum concentrations of infliximab. Clin Gastroenterol Hepatol 2017;15:1580-1588. doi:10.1016/j.cgh.2017.03.031
2. Grossberg LB, Papamichael K, Feuerstein JD, et al. A survey study of gastroenterologists’ attitudes and barriers toward therapeutic drug monitoring of anti-TNF therapy in inflammatory bowel disease. Inflammatory Bowel Dis. 2018;24(1):191-197. https://doi.org/10.1093/ibd/izx023
3. Cheifetz A. Optimizing the treatment of IBD through use of therapeutic drug monitoring. Presented at IAS 2018; April 27-29, 2018; Boston, MA.
4. Vogt C. IBD: therapeutic drug monitoring optimizes outcomes. Consultant360. May 2, 2018. https://www.consultant360.com/exclusives/ibd-therapeutic-drug-monitoring-optimizes-outcomes