DOP068 Insufficient infliximab exposure predisposes to immunogenicity and enhanced clearance of infliximab in IBD
J. F. Brandse*1, D. R. Mould2, Y. K. Ashruf1, O. Smeekes1, S. Kuin1, A. Strik1, G.R. van den Brink1, G. R. D’Haens1
1Academic Medical Centre, Inflammatory Bowel Disease Centre, Amsterdam, Netherlands, 2Projections Research Inc, Projections Research Inc, Phoenixville, Pennsylvania, United States
Factors influencing the pharmacokinetics (PK) of infliximab (IFX) in inflammatory bowel disease (IBD) have mainly been studied in clinical trials. We studied a real-world IBD patient cohort to identify patient, disease, and treatment characteristics influencing IFX PK.
Levels of IFX and antibodies to IFX (ATI) were measured in IBD patients at a single academic IBD centre using an ELISA and antigen-binding test (Sanquin Laboratories, Amsterdam, The Netherlands). Gender, age, weight, disease location and behaviour, IFX dose, immunomodulators, albumin, and serum CRP were collected. PK and ATI were analysed simultaneously by nonlinear mixed-effects modelling.
In the study, 997 IFX concentrations and 756 ATI measurements from 332 IBD patients (253 Crohn’s disease; 79 ulcerative colitis) were included. Of patients, 83% received IFX as the first anti-TNF agent; 43% received concomitant immunomodulation. Mean (SD) IFX dose was 5.47 ± 1.33 mg/kg. ATIs were detected in 75/332 (23%) patients; ATI titres > 30 AU/mL were consistently associated with undetectable IFX concentrations. IFX clearance was affected by body weight (40–149 kg) ranging from 0.27 to 0.53 L/Day, serum albumin (2–5.4 g/dL) from 0.93 to 0.24 L/Day, and titres of ATIs (0–53 000 AU/ml) from 0.36 L/Day to 15.93 L/Day (p < 0.001). Insufficient exposure below an IFX trough level of 3 μg/ml resulted in a 4-fold increased risk of ATI development.
Figure 1. Relationship between IFX concentrations falling below target concentration and probability of ATI for different albumin concentrations.
Our pharmacokinetic model, based on the factors that were identified in this study, was able to predict accurately serum IFX concentrations and ATI development.
ATI, high body weight and low albumin increase IFX clearance. IFX exposure below 3 μg/ml increases risk of ATI significantly. Identification of influential PK and ATI factors improves prediction of infliximab levels, potentially allowing individualised dosing and cost reduction.