Theory Based Analysis of Anti-Inflammatory Effect of Infliximab on Crohn's Disease

Abstract

Tumor necrosis factor (TNF)-alpha, a primary mediator of inflammatory responses, is increased in patients with active Crohn's disease (CD) and considered to play an important role in the regulation of inflammation in CD. Infliximab (IFX) is a chimeric murine-human monoclonal IgG1 antibody that targets TNF-alpha and is used as a therapeutic agent for CD. Although that dosage regimen has been established through clinical trial experience, it has not been analyzed theoretically. We analyzed of sequential changes of the Crohn's disease activity index (CDAI) using a pharmacokinetic-pharmacodynamic model integrating the pharmacokinetics of IFX and turnover rate of TNF-alpha. The time course effects of IFX derived from the present model were matched to reported data regarding CDAI ratios, and we found that the clinical effect of IFX reached a maximum value 2 to 4 weeks after administration and was maintained for the next several weeks. Our results suggested that the standard dosage regimen of IFX is theoretically appropriate. Further, based on the results of various dosage regimens, a second administration of IFX 2 weeks after the first dose was shown to achieve remission in the early stage of active CD, when IFX was given as a repeated treatment.

Theory-based analysis of anti-inflammatory effect of infliximab on Crohn’s disease and rheumatoid arthritis

“…In addition, the clinical responsiveness of CD was evaluated using Crohn's disease activity index (CDAI), which is commonly utilized in clinical studies to determine the severity of CD activity. In another previous study [11], values for sequential changes in CDAI with repeated IFX treatments were used to investigate 2 groups of patients who responded to a single infusion of IFX within 2 weeks, according to the following protocol [14]. Following assessment of response after week 2, all patients were randomly grouped with those who received repeated infusions of 5 mg/kg of IFX at weeks 2 and 6, and then every 8 weeks thereafter until week 46 (group 1), or those who received 5 mg/kg of IFX at weeks 2 and 6, followed by a single administration of 10 mg/kg (group 2).…”

“…The fitted curves were well matched to the observed data. The estimated pharmacokinetic parameters of IFX administered for RA and pharmacokinetic parameters of IFX administered for CD, which were reported previously, [11] are shown in Table 1. The pharmacokinetic parameters of C 0 IFX and k e were not significantly different between RA and CD.…”

“…1 using the nonlinear least squares methods. On the other hand, those of patients with CD were derived from previous study [11]. We used the nonlinear least squares program MLAB (Civilized Software) for analysis.…”

“…In a previous study, we constructed a pharmacokineticpharmacodynamic model to determine the effects of IFX for CD and found it useful to establish a rational dosage regimen of IFX for individual patients [11]. In the present study, we investigated whether the model could be applied to cases of RA and also used it to evaluate the validity of the dosage regimen.…”

Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity

“…Furuya et al 76 developed a PK/PD model for infliximab, a chimeric murine-human monoclonal IgG1 antibody that targets tumor necrosis factor (TNF) and is used as a therapeutic agent for CD. The PK of infliximab was described with a TMDD model.…”