P473 Antibodies to infliximab, body weight and low serum albumin levels increase clearance of infliximab, a population pharmacokinetic study in 324 IBD patients
J.F. Brandse*1, D.R. Mould2, Y.K. Ashruf1, O.S. Smeekes1, M. Löwenberg1, C.Y. Ponsioen1, G.R. van den Brink1, G.R. D'Haens1
1Academic Medical Center, Inflammatory Bowel Disease Center, Amsterdam, Netherlands, 2Projections Research Inc, Projections Research Inc, Phoenixville, United States
Factors suggested to influence the pharmacokinetics (PK) of infliximab (IFX) in patients with inflammatory bowel disease (IBD) have mainly been derived from clinical trials or computer modelling, clinical data are scarce. Therefore we aimed to study the real-life PK of IFX in a large historical cohort of IBD patients and to identify patient, disease and treatment characteristics that influence serum concentrations and clearance of IFX.
In this cross-sectional study all measurements (November 2004 - August 2014) of IFX serum concentrations in IBD patients collected in a tertiary referral center were identified. Medical charts of these patients were reviewed for patient, disease and treatment characteristics. IFX serum concentrations and antibodies to IFX (ATI) had been measured using an ELISA and antigen binding test (radioimmunoassay, Sanquin Laboratories). PK was analysed by nonlinear mixed-effects modelling and described using a 2-compartiment PK model. All influential covariates were combined into a full model.
A total of 734 distinct IFX concentrations measurements were included, comprising data from 324 IBD patients (mean 2.27 measurements). Disease extent was scored based on the Montreal classification for 252 Crohn's disease patients (L1:53/252, L2:79/252, L3: 120/252) and 72 ulcerative colitis patients (E1: 6/72, E2: 26/72, E3:40/72). 318/324(98%) of patients were anti-TNF naïve at start of IFX. Mean dose of IFX was 5.49 mg/kg (SD 1.39). ATI were detected in 100/324 (31%) patients. Mean (inter individual variability) values for clearance, central and peripheral volume of distribution were 0.34 L/day (74%), 12.8 L (98%) and 15.1 L (153%). Disease extent did not affect PK. Body weight and anti-IFX antibodies were identified as independent covariates (P<0.001) increasing clearance (mean (SE)) by 2.76 (14.1) fold and 6.04 (10.3) fold respectively, whereas serum albumin had a -0.69 (22.2) fold inverse impact on clearance. Because serum CRP values tended to change rapidly after initiation of treatment, and use of concomitant immunomodulators was often intermittent, these factors could not be evaluated as independent covariates although the administration of continuous concomitant immunomodulators was associated with a decrease in clearance.
Antibodies to infliximab, body weight and low serum albumin levels increase clearance of infliximab.