Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients

Abstract

Ulcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standard infliximab induction therapy (5 mg kg^-1) at week 0, followed by infusions at week 2 and 6. IFX, anti-drug antibodies and TNF serum concentrations were measured at day 0 (1 h after infusion), 1, 4, 7, 11, 14, 18, 21, 28 and 42. A binding model, TMDD model, and a quasi-steady state (QSS) approximation were evaluated using nonlinear mixed effects modeling (NONMEM). A two-compartment model best described the concentration-time profiles of infliximab. Typical clearance of infliximab was 0.404 L day^-1 and increased with the presence of anti-drug antibodies and with lower albumin concentrations. The TMDD-QSS model best described the pharmacokinetic and pharmacodynamics data. Estimate for TNF baseline (B_max was 19.8 pg mL^-1 and the dissociation constant (K_ss) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy.

Keywords: Infliximab; Monoclonal antibody; Target-mediated drug disposition; Ulcerative colitis.

Fig. 1

Schematic overview target-mediated drug disposition model (adapted from Mager and Jusko [26]). Symbols are defined in Table 2. A_C amount drug central compartment, A_P amount drug peripheral compartment, k₁₂ first-order rate constant from the central to the peripheral compartment, k₂₁ first-order rate constant from the peripheral to the central compartment, k_e internalization rate drug, k_off dissociation rate constant, k_on binding rate constant, P complex compartment, R receptor compartment

Fig. 2

Predicted total TNF concentrations over time. Open circles represent the predicted values for total TNF concentrations. The solid line represents the median of the predicted total TNF concentrations and the dashed lines represent the lower and upper limit of the predicted total TNF concentrations

Fig. 3

Infliximab clearance in relation to albumin concentration (a) and anti-drug antibodies (b)

Fig. 4

Time after dose course of model-predicted and observed infliximab and TNF concentrations. Simulations were performed (n = 1000) on the entire dataset based on the final TMDD model with QSS approximation, described by Eq. 8–13 and final parameters estimates in Table 2. Individual observations are depicted by the black dots. The solid red line represents the median of the observed data and the dashed blue lines represent the observed 5th and 95th percentiles. The red shaded area represents the 90% confidence interval of the median of the simulated data, with the red dashed lines representing the median of the simulated data per bin. The blue shaded areas represent the 90% confidence intervals of the 5th and 95th percentiles of the simulated data