Optimizing Treatment Regimens in Immune-Mediated Diseases

Reactive therapeutic drug monitoring (TDM) has been demonstrated to improve the management of inflammatory bowel disease (IBD) in patients with primary nonresponse or loss of response to biologics, as well as  more cost-effective than empiric dose optimization, according to Adam Cheifetz, MD, and David Hudesman, MD, who presented on this topic at the virtual Interdisciplinary Autoimmune Summit 2020.

Dr Cheifetz is the director of the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center in Boston, Massachusetts. Dr Hudesman is codirector of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City, New York.

Reactive TDM is the most cost-effective option when assessing patients who have a secondary loss of response to a biologic, Dr Cheifetz noted. He discussed a study that included 102 patients with IBD being treated with infliximab who underwent initial reactive testing. The participants were then separated into two groups. The group that received reactive TDM had a much higher rate of treatment failure, defined as infliximab discontinuation due to loss of response or a serious adverse event, compared with the proactive TDM group. The proactive TDM group also had a lower rate of hospitalization.

Dr Hudesman discussed the importance of not abandoning a biologic without first increasing the dose and monitoring the concentration. “If the drug concentration level is really low, then you give more drug, but if the patient has developed antibodies, then you need to switch drugs,” he stressed. Agreeing with Dr Hudesman, Dr Cheifetz added that the BRIDGe group, a collaboration of gastroenterologists with expertise in IBD, urges physicians not to give up on a drug unless the level is 10 or even 15.

Many patients with IBD are treated with combination therapy consisting of a biologic and another immunomodulator. “But what it a patient wants to stop the immunomodulator,” Dr Cheifetz asked. “What do you say?” He discussed a post hoc analysis performed by Stephen Hanauer, MD, on the benefit of combination therapy in the first year, which tends to increase drug concentration of anti-tumor necrosis factor (TNF) therapies. Conversely, Dr Hudesman said he would consider removing the secondary drug, “but first, we have to check the drug level.”

In addition, Dr Cheifetz prefers to use proactive TDM and push the concentration of the TNF inhibitor. He reported the effects of this method among patients who wanted to change their dose. “Even after stopping the immunomodulators, the trough concentration of infliximab remained where it needed to be,” stated Dr Cheifetz. Data suggests that stopping immunomodulators does not appear to affect the 1- to 2-year remission rates. “You want adequate trough concentrations on anti-TNFs before and after stopping the immunomodulators,” he added.

Dr Hudesman noted that guidelines of gastroenterology associations recommend reactive testing. “There still a bit of debate about doing proactive early, or with patients who are doing well on their therapy,” he said. However, he noted he had a patient who experienced a severe flare and was found to have undetectable concentrations of infliximab but high antibodies. “Could we have prevented this with earlier testing of his drug concentration?” he wondered.

One of the key issues with drug concentration, Drs Cheifetz and Hudesman agreed, is the rate of drug clearing. “Men clear drugs faster than women,” Dr Hudesman noted. Patients with more inflammation, higher CRP, and lower albumin also clear drugs faster.

In a 2014 study, patients who received proactive TDB had lower rates of drug discontinuation, fewer hospitalizations, serious infection reactions, and IBD-related surgeries compared with those who received reactive testing. Dr Hudesman reviewed his study on the effects of proactive monitoring on clinical and biological remission after 1 year. The primary endpoint showed no difference, but “the secondary endpoints clearly favored dosing to the appropriate infliximab concentration,” he said. According to Dr Hudesman, this study shows that optimization can be done early and does not have to be performed more than once or twice a year.

However, there are still issues about proactive TDM that need clarification such as when should proactive TDM begin; what is the optimal trough concentration to achieve the desired outcome; and how often proactive TDM should be performed. Dr Hudesman stated, “We need accurate, accessible, inexpensive testing that health insurance will cover” to fully implement proactive TDM.

For more coverage of IAS 2020, visit the newsroom.

--Rebecca Mashaw

Reference

Cheifetz A, Hudesman, D. Optimizing treatment regimens: therapeutic dose monitoring vs empiric dosing. Presented virtually at: Interdisciplinary Autoimmune Summit 2020; July 11, 2020.