The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: Results from ATTRACT, a multicenter, randomized, double‐blind, placebo‐controlled trial

Abstract

Objective. To investigate the relationship between serum concentrations of infliximab, a monoclonal antitumor necrosis factor ␣ antibody, and clinical improvement from infliximab therapy for rheumatoid arthritis (RA).Methods. Multiple blood samples were obtained from each of 428 subjects with active RA who were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy]) evaluating the clinical efficacy and safety of infliximab therapy. Serum levels of infliximab were measured by enzyme-linked immunosorbent assay. Dose-response trends were analyzed using generalized logistic regression techniques. Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial.Results. At week 54, 26% of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab, a significantly greater proportion than in the other 3 treatment groups (P < 0.001). Increased magnitude of American College of Rheumatology (ACR) response (measured by the ACR-N, a continuous measure of clinical improvement derived from the ACR 20% response criteria) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab (P < 0.001), as was less progression of radiographic joint damage (P ‫؍‬ 0.004), providing support for a dose-response relationship. Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab than increasing the dose by 100 mg.Conclusion. These results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks.

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

“…Confluent monolayers were cultured for 24 h in the presence of 100 U/ml (equivalent to 1 ng/ml) of TNF-␣, 4 g/ml sCD40L, or 100 U/ml IL-1␤ (R&D Systems) in the presence and absence of therapeutic levels (5 g/ml) of infliximab (34,35). In some experiments, increasing doses of TNF-␣ or infliximab were used, and HIMEC were stained at days 0, 1, 3, 5, and 7.…”

Therapeutic Drug Monitoring in Inflammatory Bowel Disease

“…No consensus regarding the optimal escalation strategy exists. A pharmacokinetic modeling study in patients with rheumatoid arthritis suggested that interval reduction would provide a more eff ective drug level AUC compared to the equivalent dose increase [53]. However, retrospective studies comparing dose augmentation with shortening of the interval did not demonstrate any signifi cant diff erence in the rates of regained response in CD [36,54] or UC [55].…”

Pharmacocinétique des anticorps monoclonaux

“…Cette variabilité PK, observée pour tous les Acm, est pertinente en clinique puisque les concentrations sériques d'anticorps influencent la réponse thérapeutique : c'est le cas pour les Acm suivants : adalimumab [25], alemtuzumab [26], cétuximab [27], infliximab [28], rituximab [29] et trastuzumab [30].…”