DOP063 Hospitalised severe ulcerative colitis patients treated with rescue infliximab risk treatment failure due to underexposure caused by high drug clearance
Authors: Démaris A , Ovesen P D , Ilvemark J F , Seidelin J B , Huisinga W , Michelet R , Steenholdt C , Kloft C 
Published: January 2025

Abstract

Background
Acute severe ulcerative colitis (ASUC) occurs in 25% of patients with ulcerative colitis (UC) resulting in hospital admission and treatment with corticosteroids followed by rescue therapy with infliximab, if needed. High baseline infliximab clearance at admission has been associated with risk of colectomy supporting an intensified infliximab regimen in case of insufficient effect.1 However, a recent randomized controlled trial did not find superior outcomes of different intensified infliximab regimens.2 We investigated if admitted patients with severe UC have increased clearance of infliximab.

Methods
Infliximab concentrations from 154 UC patients were retrieved from our biobank resulting in 248 (81%) induction phase and 58 (19%) maintenance phase samples. These data were used to build a non-linear mixed effect model describing infliximab pharmacokinetics (PK) in UC. Variables tested for potentially influencing clearance comprised clinical disease activity (Mayo/SCCAI, 86% of assessments; physician’s global assessment, 14%), endoscopic activity (Mayo) (56%), CRP, albumin, patient demographics, and whether patients were treated as outpatients or hospitalised, including formal fulfilment of Truelove Witt’s criteria.

Results
A 2-compartment model with a linear clearance described infliximab PK, in line with previous reports.3 Hence, central and peripheral volumes of distribution were 6.52 L and 2.56 L, respectively, clearance 0.339 L/day and intercompartmental clearance 0.146 L/day. Hospitalisation status was the most impactful variable significantly influencing infliximab clearance in the model. Hence, hospitalised patients with severe UC (32% of study population) had a 35% [90%CI 14-56%] increased infliximab clearance compared to outpatients (median clearance of 0.463 L/day vs. 0.339 L/day, p&lt;0.0001). This resulted in a substantial decreased IFX exposure from week 2 onwards. Thus, 74% of hospitalised patients had sub-therapeutic infliximab concentration at week 2 (&lt;20 ug/mL4), 69% at week 6 (&lt;15 ug/mL4), and 56% at week 14 (&lt;7 ug/mL4). Formal fulfilment of Truelove Witt’s criteria did not result in additional increase in infliximab clearance among hospitalized patients (ASUC median clearance 0.442 L/day vs non-ASUC 0.516 L/day, p=0.08). Addition of albumin did not significantly improve the model.

Conclusion
Infliximab clearance is substantially increased among hospitalised patients with severe UC, resulting in underexposure in the majority of patients treated with a standard dosing regimen. An intensified regimen should be considered preferably supported by therapeutic drug monitoring and PK modelling.

References
1. Battat R et al. Clin Gastroenterol Hepatol. 2020; 19:511-518.
2. Choy MC et al. Lancet Gastroenterol Hepatol. 2024;9: 981-996.
3. Démaris A al. Pharmaceutics. 2022;14: 2095.
4. Cheifetz AS al. Am J Gastroenterol. 2021;116:2014-2025.