麻豆传媒

Maintaining higher trough levels of infliximab (Remicade) of >7 μg/mL provided better control of inflammatory bowel disease (IBD) in hard-to-treat patients with no increase in infection risk, according to researchers in Slovenia.

Median fecal calprotectin and median C-reactive protein (CRP) levels were lower in patients with high trough levels. For calprotectin, the median was 66 mg/kg (interquartile range 30-257) at the high trough level versus 155 mg/kg (IQR 72-474) at the low trough level, reported David Drobne, MD, of the University of Ljubljana Medical Center, and colleagues.

For CRP the medians for the high and low trough levels were 3 mg/L (IQR 3-3) and 3 mg/L (IQR 3-14.5, P<0.001 for both). High trough levels remained superior even after excluding samples with very low trough levels of <3 μg/mL, they stated in the .

The findings departs from the results of a recent suggesting that targeting a lower serum threshold of 3-7 μg/mL may be an adequate goal for most patients.

"Our main finding was that increasing the concentrations of infliximab beyond 7 μg/mL by means of infliximab dose escalations was effective in many patients," Drobne told 麻豆传媒. "Furthermore, this was safe, as it was not linked to more infectious complications."

While low trough levels have been associated with loss of treatment response over time, data on the therapeutic benefit and safety of higher levels have been scarce. To answer this question, Drobne's group conducted a prospective trial in 183 adult and pediatric IBD patients.

The cohort was almost 60% male, and consisted of 109 Crohn's disease (CD) patients, 68 ulcerative colitis (UC) patients, and six IBD-unclassified patients, who were analyzed with the UC group. All were on infliximab maintenance therapy at the University Medical Center during 2010-2015. The median age at diagnosis of CD was 19.5 years and 27.7 for UC.

The investigators correlated fecal calprotectin and C-reactive protein to trough levels in 426 samples at different time points during treatment, and compared infection rates in quadrimesters with high trough levels (median 10 μg/mL) to quadrimesters with lower trough levels of <7 μg/mL over 420 patient-years.

Clinically, an increase above the higher threshold resulted in better or complete disease control in most patients who still had active disease at levels of 3-7 μg/mL.

From a cost perspective, however, maintaining high trough levels resulted in a 32% (IQR 2%-54%) increase in infliximab consumption.

"But as the costs of infliximab decrease with the introduction of biosimilars, this could be an attractive treatment alternative to switching to drugs with different mechanisms of action for patients not responding to standard doses and concentrations of infliximab," Drobne said.

Biosimilars are coming closer to being interchangeable with original biologics.

For the endpoint of infections, no significant difference in frequency emerged between quadrimesters with high trough levels (16/129, 12.4%) versus those with low trough levels of (32/344, 9.3%, P=0.32). In 77 patients with high levels at any time point, 55% had a total of 42 infections compared with 44 infections (42%) in 106 patients with levels always <7 μg/mL (P=0.08). No difference in infection rates was observed between CD and UC patients.

The authors said they believe the findings have important treatment implications for partial responders.

"Many gastroenterologists may decide to switch to drugs such as vedolizumab [Entyvio] or ustekinumab [Stelara] for patients who still have active disease along with increased CRP and fecal calprotectin," Drobne said. "Yet switching out of class in such scenarios is only modestly effective, while the strategy to further optimize dosing of infliximab for attaining higher trough levels was effective in most patients."

Study limitations included the fact that the authors only had data on trough levels from 38% of quadrimesters, which could have limited the infection analysis. Also, the cross-section design may limit the findings, as at some time points trough levels may not have been measured, the authors noted.

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