Early Serum Infliximab Levels Predict Outcomes in Acute Severe Ulcerative Colitis: Results from PREDICT-UC

Abstract Background The utility of infliximab (IFX) therapeutic drug monitoring (TDM) in acute severe ulcerative colitis (ASUC) is unclear. We aimed to assess whether IFX levels are associated with outcomes in ASUC. Methods PREDICT-UC (NCT02770040) was a randomised controlled trial that compared dosing strategies in 138 steroid-refractory ASUC patients.1 Serum and faecal IFX levels were quantified by ELISA (MabTrack level infliximab, Essange Reagents, Netherlands) after conclusion of the trial and correlated with outcomes: IFX response by day 7 (Lichtiger score [LS]<10, with ≥3-point reduction and decrease in rectal bleeding and stool frequency ≤4/day); eventual response by day 14 (LS<10); and colectomy by month 3. Individual IFX clearance was estimated using a two-compartment pharmacokinetic model with fixed V1, V2 and Q. Results 681 serum IFX levels were available across 135 patients; 91 received an initial 5mg/kg and 44 an initial 10mg/kg IFX dose. 85 responded by day 7 and 17 required colectomy by month 3. Post-IFX serum levels were higher on days 1 and 3 (median ug/mL, IQR) in the 10mg/kg group (175.4, 137.2-202.7 and 116.3, 83.4-132.9) compared to the 5mg/kg group (91.8, 77.2-109.4 and 56.0, 46.0-67.0; each P<0.001). Day 1 and day 3 serum IFX levels were not significantly different in responders and non-responders. A higher day 3:day 1 serum IFX ratio predicted response (63.1%, IQR 56.0-72.1 vs 58.1%, IQR 51.6-62.8, P=0.006; AUC 0.67). A lower day 3 serum IFX level predicted colectomy (51.0, IQR 39.2-57.4 vs 69.0, IQR 51.1-101.7, P=0.003; AUC 0.23). IFX clearance using serum levels between days 1-7 was higher in non-responders compared to responders (0.72L/day, IQR 0.55-0.89 vs 0.56L/day, IQR 0.39-0.72, P<0.001) and in patients who had colectomy (P=0.011). Patients with high clearance (≥0.62L/day) were more likely to respond to an initial 10mg/kg vs 5mg/kg IFX dose (RR 1.50, 95%CI 1.01-2.23, P=0.046), and more likely to require colectomy if they received an initial 5mg/kg vs 10mg/kg dose (HR 4.81, 95%CI 1.09-21.37, P=0.039). In patients with high clearance who did not respond initially, response by day 14 was higher in those receiving a second 10mg/kg dose compared to 5mg/kg (10/26 [38%] vs 1/9 [11%]; RR 3.43, 95%CI 1.05-11.19, P=0.041). Day 1 and 3 faecal IFX correlated with IFX clearance (both rho=0.36, both P<0.001), CRP and the UCEIS (including bleeding and erosion/ulcer sub-scores). Conclusion Elevated day 3:day 1 serum IFX ratio was associated with IFX response by day 7. Early IFX clearance predicted IFX response and month 3 colectomy. High IFX clearance may be overcome by higher IFX dosing, resulting in improved response and reduced colectomy rates. Early IFX level quantification can help predict outcomes in ASUC. References 1.Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024; 9(11): 981-96.