The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Abstract

Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a one-compartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.

Keywords: Ankylosing spondylitis; Crohn's disease; inflammatory bowel disease; infliximab; monoclonal antibodies; pharmacokinetics; psoriatic arthritis; rheumatoid arthritis; therapeutic drug monitoring; ulcerative colitis.

Figure 1.

Observed vs. predicted concentrations of infliximab. Population predicted (PRED, A) and individual predicted values (IPRED, B).

Figure 2.

Population (top) and individual (bottom) residuals vs. time (A, B) and vs. predictions (C, D) and normalized population distribution error vs. Gaussian law (NPDE, E).

Figure 3.

Individual fits of observed and model-predicted infliximab concentrations. A representative patient is figured for each underlying disease: ankylosing spondylitis (AS), rheumatoid arthritis (RA) with (MTX +) and without (MTX -) methotrexate cotreatment, psoriatic arthritis (PsA), Crohn's disease (CD) and ulcerative colitis (UC). The observed concentrations are represented by crosses and the model-predicted concentrations over time is represented by the curve.

Figure 4.

Influence of continuous (A, B) and binary (C, D, E) demographic covariates on pharmacokinetic parameters of infliximab: volume of distribution (A) and clearance (B) vs. body weight, and association of sex with volume of distribution (C) and clearance (D), and association of age with volume of distribution (E). From bottom to top, horizontal lines of boxes represent 5^th, 25^th, 50^th, 75^th and 95^th percentiles (bottom).

Figure 5.

Influence of treated disease on the pharmacokinetic parameters of infliximab. Compared to ankylosing spondylitis (AS), there was an influence of inflammatory bowel disease (IBD) on volume of distribution (A) and on clearance (B), and of rheumatoid arthritis (RA) on clearance (C). From bottom to top, horizontal lines of boxes represent 5^th, 25^th, 50^th, 75^th and 95^th percentiles.

Figure 6.

Boxplots representing 90% prediction intervals of simulated trough concentrations of infliximab at week 22 following 3, 5 and 7.5 mg/kg doses infused at weeks 0, 2, 6 and 14 in ankylosing spondylitis (AS), psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel diseases (IBD). Horizontal dotted or solid lines represent reported concentrations predictive of good clinical response for RA (2.5 mg/kg), Crohn's disease (3.5 mg/L) and ulcerative colitis (3.7 mg/L). Percentages are proportion of patients above the target concentration for the corresponding disease. From bottom to top, horizontal lines of boxes represent 5^th, 25^th, 50^th, 75^th and 95^th percentiles.