Anti-drug antibodies, low serum albumin and high C-reactive protein increase infliximab clearance in patients with inflammatory bowel disease: a population pharmacokinetic study of the TAXIT trial
Erwin Dreesen (1), Niels Vande Casteele (1), Sophie Tops (1), SÚverine Vermeire (2), Ann Gils (1)
(1) Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Belgium (2) Department of Gastroenterology, University Hospitals Leuven, Belgium
Objectives: Infliximab (IFX, Remicade®) is an intravenously administered chimeric anti-tumor necrosis factor-alpha monoclonal antibody and is effective for treating patients with Crohn’s disease (CD) and ulcerative colitis (UC). The Trough concentration Adapted infliXImab Treatment (TAXIT) trial was the first prospective study to show that targeting IFX trough concentrations between 3 and 7 µg/mL in responder patients on maintenance therapy leads to better outcome and a lower risk for loss of response. Insight in the factors accounting for inter-individual variability (IIV) in pharmacokinetics (PK) in the dataset is lacking. Our aim was to identify key covariates that explain the IIV in IFX PK.
Methods: PK data originated from 263 patients with CD and UC included in the 1-year TAXIT trial. IFX trough concentrations before each administration and unbound anti-drug antibody (ADAb) titers were assessed using in-house developed ELISAs. Relevant patient demographic, serological, genetic and clinical data were collected prospectively. Data were evaluated using population PK modeling (NONMEM® 7.3).
Results: IFX concentrations (n=2,429) from 263 patients were evaluated. Eighteen patients were identified with unbound ADAbs at one or more time points. IFX PK was best described using a one-compartment model with time-varying immunogenicity effect on linear clearance and an additive error model. Typical clearance was 0.581 L/day and typical volume of distribution was 14.2 L based on the final covariate model. Covariate analysis showed that IFX clearance was higher for male subjects, when serum albumin was low and when C-reactive protein (CRP) was high (p<.001). IFX clearance was typically 27.8 times higher when ADAbs were detected. The estimated effective half-life of IFX was approximately 17 days and less than 1 day when ADAbs were present. The identified covariates explained 21% of the IIV in IFX clearance. Remaining IIV in clearance was 35% and eta shrinkage was 3%.
Conclusions: A population PK model was developed, taking into account time-varying immunogenicity and patient factors. IFX clearance increases in the presence of ADAbs and in an active inflammatory state, represented by a decrease in serum albumin and an increase in CRP. Adapting the dosage regimen based on these covariates may allow more precise individualized dosing and improve outcome for patients with CD and UC.
 Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology (2015) 148(7):1320-9.
 Vande Casteele N, Buurman D, Sturkenboom M, et al. Detection of infliximab levels and anti-infliximab antibodies: A comparison of three different assays. Aliment Pharmacol Ther (2012) 36(8):765-71.