Higher serum concentrations of infliximab are associated with clinical response, mucosal healing, and clinical remission in adults with moderate to severe ulcerative colitis, according to post hoc analyses of data from the Active Ulcerative Colitis Trials, ACT-1 and ACT-2.
In the 728 patients from the two randomized, controlled phase III pivotal trials, median serum concentrations of infliximab at week 8 were higher among patients with clinical response or mucosal healing during induction than in those who did not achieve these endpoints. For example, the median concentration among those who received 5-mg/kg doses of infliximab was 35.0 mcg/mL in responders, compared with 25.8 mcg/mL in nonresponders, Omoniyi J. Adedokun of Janssen Research and Development, Spring House, Pa., and colleagues reported in the December issue of Gastroenterology [doi:10.1053/j.gastro.2014.08.035].
“Similar results were observed for clinical response and mucosal healing during maintenance at week 30 and week 54,” the investigators wrote, noting that in the 5-mg/kg group, the median trough serum infliximab concentration was several-fold higher in responders than in nonresponders (3.9 vs. 1.2 mcg/mL at week 30 and 5.0 vs. 0.7 mcg/mL at week 54).
Concentrations did not differ significantly at 8 weeks in remitters and nonremitters in the 5-mg/kg group, but they did in patients who received 10 mg/kg and in patients in both dose groups at weeks 30 and 54, the investigators reported.
When assessed by infliximab concentration quartiles, treatment efficacy – defined by clinical response, mucosal healing, and/or clinical remission – generally improved with increasing concentrations in patients in both the 5- and 10-mg/kg groups; those with concentrations in the lowest quartile consistently were less likely to show clinical response, clinical remission, or mucosal healing, and had rates of success approaching those observed in the placebo groups.
Optimal infliximab concentration target thresholds associated with clinical improvement in ulcerative colitis patients in these analyses were 41 mcg/mL at week 8 (sensitivity, specificity, and positive predictive values of 63%, 62%, and 80%, respectively) and 3.7 mcg/mL at week 30 for maintenance of clinical response (sensitivity, specificity, and positive predictive values of 65%, 71%, and 82%, respectively). The data at week 54 suggested a range for serum infliximab concentrations of similar sensitivity, specificity, and positive predictive value, but those data represented only a subset of patients assessed, the investigators said.
Patients who achieved an efficacy outcome, but who failed to maintain that outcome, had lower serum infliximab concentrations earlier in the course of therapy than did those who maintained the outcome, the investigators said.
“In general, the lower the infliximab concentration at a given time point, the more likely the patients were to fail to maintain remission,” they wrote.
The findings demonstrate a strong association between serum infliximab concentration and efficacy outcomes in patients with ulcerative colitis, and highlight the possibility of infliximab dose optimization – particularly in patients who are likely to lose efficacy while receiving a standard dose of infliximab, the investigators said.
Target threshold concentrations identified by this analysis could help clinicians understand why an individual patient fails to achieve the expected efficacy, but a prospective study designed to confirm the importance of optimizing infliximab concentrations is needed before it can be determined whether these results can be exploited to achieve better outcomes for patients with ulcerative colitis, Mr. Adedokun and coinvestigators said.
The ACT trials were funded by Janssen Research and Development, which also employs Mr. Adedokun.