How Fat Burden May Affect IBD Drug Dosing

Megan Brooks

June 02, 2023

Adults with inflammatory bowel disease (IBD) who have a high visceral adipose tissue (VAT) burden may need a higher dose of infliximab to achieve clinical and endoscopic remission.

In a prospective cross-sectional study of patients with IBD on maintenance infliximab, trough levels of the anti-TNF agent associated with remission varied based on VAT burden, suggesting the potential need to personalize dosing strategies.

The findings also suggest that clinicians may need to reconsider prematurely discontinuing infliximab treatment in "non-responders" with higher VAT burden and instead consider adjusting the dose to achieve a higher drug concentration before declaring nonresponse, the researchers say.

The study, led by Andres Yarur, MD, division of gastroenterology and hepatology, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, was published online May 19 in the American Journal of Gastroenterology.

Explanation for Treatment Failures?

While largely effective in IBD, infliximab fails to achieve remission in a significant proportion of patients. Research has shown that nearly one-third of patients are primary nonresponders, and up to half of patients with initial clinical benefit may have a secondary loss of response.

A substantial proportion of nonresponders have subtherapeutic drug concentrations and may also have antibodies against infliximab. However, the optimal trough levels of infliximab needed for clinical and endoscopic remission are "ambiguous," leading to premature drug discontinuation in some patients, the researchers note.

And recent evidence suggests that infliximab effectiveness may be influenced by body composition, specifically VAT burden.

To investigate further, Yarur and colleagues assessed whether VAT burden may affect target trough levels of infliximab associated with remission in 142 adults receiving maintenance therapy with infliximab for Crohn's disease (87 patients) or ulcerative colitis (55 patients).

They found a clear correlation between VAT burden and infliximab trough levels needed to achieve remission.

To achieve steroid-free, deep remission, patients in the highest two VAT quartiles required higher infliximab levels (optimal cutoff 15.3 μg/mL and 13.6 μg/mL for the third and fourth quartiles, respectively) compared with those in the lowest two quartiles (optimal cutoff 3.9 μg/mL and 4.9 μg/mL for the first and second quartiles, respectively).

In multivariate analysis, the only factors independently associated with steroid-free, deep remission were VAT burden (odds ratio [OR], 0.3 per VAT%; P < .001) and infliximab trough level (OR, 1.11 per μg/mL; P < .001).

Weight-Based Dosing Insufficient

Differences were not seen when examining total body mass. "These results do not prove causation but may suggest that the higher infliximab clearance seen with higher body mass may be driven by visceral fat, not total body mass," the researchers write.

"Thus, weight-based dosing alone may be insufficient for disease control in many individuals, particularly those with disproportionate ratios of total body mass to visceral fat," they add.

The findings are important, given current recommendations to switch therapies for patients on infliximab who are not in remission and have infliximab levels within a specific "therapeutic window," the researchers write.

Based on the data, the therapeutic window may vary substantially depending on the patient's body composition, in that people with higher VAT may need greater drug concentrations, they add.

The study was supported by grants from the National Institutes of Health. Yarur is a consultant for Takeda Pharmaceuticals USA, Procise Inc, Bristol Myers Squibb, Boehringer Ingelheim, and Arena pharmaceuticals, and is on the speaker bureau for Bristol Myers Squibb.

Am J Gastroenterol. Published online May 19, 2023. Abstract

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