Early Infliximab Levels and Clearance Predict Outcomes After Infliximab Rescue in Acute Severe Ulcerative Colitis: Results From PREDICT-UC

Abstract

Background & aims: The role of infliximab therapeutic drug monitoring in acute severe ulcerative colitis (ASUC) management is unknown. We aimed to identify whether infliximab therapeutic drug monitoring is associated with ASUC outcomes.

Methods: Serum and stool samples were collected from patients enrolled in the PREDICT-UC randomized controlled trial (NCT02770040), which compared intensified and standard infliximab rescue in steroid-refractory ASUC. Infliximab levels measured after trial conclusion and clearance derived using pharmacokinetic modelling were correlated with outcomes.

Results: Infliximab levels were measured in 681 serum and 198 fecal samples from 135 patients. Lower day 3 serum infliximab levels predicted infliximab failure on day 14 (area under the receiver operator characteristic curve = 0.63; P = .043) and colectomy by 3 months (area under the receiver operator characteristic curve = 0.77; P = .0027); a threshold of ≤57.9 μg/mL had 83% sensitivity, 67% specificity, 24% positive predictive value, and 97% negative predictive value for colectomy. Patients with high clearance between day 1 and 7 (≥0.62 L/d) were more likely to respond to an initial 10 mg/kg vs 5 mg/kg infliximab dose (risk ratio, 1.50; 95% confidence interval [CI], 1.01-2.23), and had a higher risk of colectomy if they received an initial 5 mg/kg vs 10 mg/kg dose (HR, 4.81; 95% CI, 1.09-21.37). In patients with high clearance who did not respond to the first infliximab dose, day 14 response rate was higher with a second 10 mg/kg vs 5 mg/kg dose (38% vs 11%; risk ratio, 3.43; 95% CI, 1.05-11.19). Day 3 fecal infliximab levels correlated with endoscopic severity and was associated with day 7 nonresponse (P = .016).

Conclusions: Early infliximab levels and clearance calculation can predict outcomes in ASUC. This is the first study to demonstrate that high infliximab clearance may be overcome by intensified infliximab dosing. (NCT02770040; Optimizing Infliximab Induction Therapy for Acute Severe Ulcerative Colitis).

Keywords: Biologic; Colectomy; Dose-Response Relationship; Drug; Therapeutic Drug Monitoring.