Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis

Abstract

Aims: Infliximab, an anti-tumour necrosis factor-α monoclonal antibody, is indicated in rheumatoid arthritis (RA). Our objective was to evaluate the influence of the sources of infliximab pharmacokinetic variability in RA.

Methods: Eighty-four patients treated with infliximab for RA were included in a prospective noncomparative study. They were analysed between two consecutive infliximab infusions. Infliximab concentrations were measured before the infusion, 2 h, 1 and 4 weeks after the infusion and immediately before the next infusion. Infliximab concentrations were described using a two-compartment population pharmacokinetic model.

Results: The mean (interindividual standard deviation) estimated central volume of distribution was 2.3 l (36%) and systemic clearance was 0.019 l h(-1) (37%). The central volume of distribution increased with bodyweight; it was doubled between 50 and 90 kg. Systemic clearance increased with pre-infusion C-reactive protein concentration by 20%, varying from 3 to 14 mg l(-) 1, and was decreased by 30% when methotrexate was coadministered.

Conclusions: The influence of methotrexate and inflammation on infliximab clearance suggests that individual adjustment of infliximab doses according to disease activity may be useful in RA.

Keywords: inflammation; infliximab; monoclonal antibodies; pharmacokinetics; rheumatoid arthritis.

Figure 1

Observed vs. population model-predicted concentrations (PRED; A), individual predicted values (IPRED; B), log-PRED (C) and log-IPRED (D)

Figure 2

Visual predictive check for infliximab pharmacokinetics. Filled circles are infliximab concentrations, continuous line is median prediction and grey shaded area indicates 5–95% confidence interval

Figure 3

Population (left) and individual residuals (middle), and normalized prediction distribution errors (NPDE; right). Plots are vs. time (top), vs. estimated concentrations (middle) and vs. distribution (bottom)

Figure 4

Log values of pharmacokinetic parameters (top) and random effects (ETA; bottom). Central volume of distribution is influenced by bodyweight (WT on V_C), and systemic clearance is influenced by C-reactive protein concentration at inclusion (CRP on CL) and by methotrexate cotreatment (MTX on CL)

Figure 5

Dose–concentration–response relationship for infliximab in rheumatoid arthritis. Observed and latent relationships are represented in bold and dotted arrows or boxes, respectively. The boxes represent dose (AMT), infliximab concentrations (IFX), unobserved (latent) tumour necrosis factor-α (TNF-α) concentrations and C-reactive protein (CRP) concentrations. Arrows represent relationships between compartments, which are as follows: (1) the dose–concentration relationship (pharmacokinetic); (2) the observed concentratio CRP relationship; (3) the latent concentration–TNF-α relationship; (4) the latent TNF-α–CRP relationship; (5) the observed reciprocal influence of CRP on pharmacokinetics; (6) the latent target-antigen influence of TNF-α on infliximab pharmacokinetics; and (7) the inflammatory effect of methotrexate (MTX)