A Houston Methodist gastroenterologist has established therapeutic drug-monitoring guidelines for patients receiving ustekinumab for inflammatory bowel disease (IBD), a much-needed tool to optimize the biologic treatment's use over time.

In a study that found a clear benefit from such guidelines, Dr. Bincy Abraham analyzed the amount of drug found in a patient's blood just prior to the administration of the next dose — trough levels — against a variety of clinical indicators for IBD.

"There are many physicians who are unsure of what to do with therapeutic monitoring of this drug, whether the levels mean anything or not," says Dr. Abraham. "We see this as a missed opportunity to get the dosing right during that critical induction phase, and during maintenance. That's why we did this study."

Dr. Abraham says she hopes the study results help correct the clinical underutilization of therapeutic drug monitoring for ustekinumab, which was approved for use in Crohn's disease in 2016 and ulcerative colitis in 2019. Until now, drug monitoring levels haven't been defined.

The study, presented this week at the American College of Gastroenterology annual scientific meeting, is the first large review of real-world data outside of clinical trials to evaluate therapeutic drug monitoring of ustekinumab in clinical practice.

In addition to identifying target trough values, Dr. Abraham's research team found that infusion schedule and naïveté to anti-TNF therapy correlated significantly with ustekinumab levels. High levels of erythrocyte sedimentation rate and C-reactive protein, common biomarkers of inflammation, were significantly related to lower trough levels, indicating that treatment efficacy is dependent on retention of the drug.

Individual results may vary

Biologic therapies have revolutionized the treatment of moderate to severe Crohn's disease and ulcerative colitis. However, a third of all IBD patients don't respond to induction therapy, and half of all IBD patients lose response over time.

"Every person responds to these drugs a little differently," says Dr. Abraham. "How much drug remains in a person's blood after an extended period of time is an important predictor of success, but it's dependent on a variety of factors, including clinical history, current level of inflammation, what therapies they've tried before, genetic makeup, strength of immune response and much more."

Since individual responses can't be predicted, therapeutic drug monitoring is commonly used to guide the administration of anti-TNF therapies.

In general, the higher the serum drug concentration, the higher the likelihood of achieving clinical, biochemical, endoscopic, histologic or composite remission.

"If we measure your drug level and see that it is low, we can bump up the dosage or frequency, making the treatment significantly more effective," Dr. Abraham explains. "But first we need to establish what a low level is and what an effective level is, and that's not something that comes printed on the box when a new drug comes out. Clinical teams have to figure it out by monitoring their patients' responses and drug levels, and that takes time."

Instead, clinical teams have to figure it out by monitoring their patients' responses and drug levels, and that takes time.

Key findings on ustekinumab

To help establish the evidence base needed to advance the implementation of therapeutic drug monitoring for ustekinumab, the research team retroactively analyzed their own patients' records across a multitude of variables, including dose schedules, patient characteristics, previous biologic use, concomitant therapies, biomarkers, clinical scores and endoscopic disease activity.

Using endoscopic remission as the primary endpoint, the researchers identified under 4.0 µg/mL as a low titer and over 4.0 µg/mL as an adequate titer.

Trough levels differed significantly by dosing schedule, with 74% of patients on a four-week interval, 77% of patients on a six-week interval and 40.4% of patients on an eight-week interval demonstrating adequate titer levels.

Naïveté to anti-TNF therapy correlated with higher trough levels (67% of naïve patients had adequate titer levels vs. 48% non-naïve). Only 25% of patients receiving prednisone concomitantly with ustekinumab therapy had an adequate titer, versus 45% of patients not currently on prednisone.

"This doesn't necessarily preclude these patients from using ustekinumab; rather, it may mean that prior anti-TNF failure and current prednisone use necessitate higher dosing," Dr. Abraham notes.

Age, gender, ethnicity, BMI, age at diagnosis, disease duration, disease subtype, disease location, biologic combination therapy and total naïveté to biologics were not significantly correlated with trough levels.

Erythrocyte sedimentation rate and C-reactive protein were significantly associated with titer levels; interestingly, albumin and fecal calprotectin levels were not.

Clinical scores for both Crohn's disease and ulcerative colitis were not significantly associated with titers.

Endoscopic scores for ulcerative colitis did not correlate with titer levels, but endoscopic scores for Crohn's disease did.

"There is a strong correlation between adequate drug levels and endoscopic healing among patients with Crohn's disease," Dr. Abraham explains. "A similar trend was observed for patients with ulcerative colitis, but a larger sample would be needed to demonstrate statistical significance."

None of the study's 177 patients developed anti-drug antibodies over the observed period.

"Overall, our findings indicate that ustekinumab is a strong choice for a first-line therapy, or after bio-failures, and there is a clear benefit to therapeutic drug monitoring to ensure adequate response," Dr. Abraham concludes.