Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis

Abstract

Purpose: Infliximab, a monoclonal antibody, is approved for the treatment of inflammatory diseases at doses that depend on the patient disease population. It was the aim of this study to evaluate its population pharmacokinetics in patients with moderately to severely active ulcerative colitis and characterize patient covariates that affect its disposition in this population.

Methods: Information collected from 482 patients in two randomized, double-blind, placebo-controlled international studies were analyzed using NONMEM.

Results: A two-compartment, population pharmacokinetic model described the serum infliximab concentration-time data. Population pharmacokinetic estimates (typical value +/- standard error), based on the final covariate model, were clearance (CL: 0.407 +/- 0.0103 L/day), apparent volumes of distribution in the central (V(1): 3.29 +/- 0.0679 L) and peripheral (V(2): 4.13 +/- 0.16 L) compartments, and intercompartment clearance (Q: 7.14 +/- 0.489 L/day). Infliximab exhibited interindividual variability for CL and V(1) of 37.7% and 22.1%, respectively. Infliximab t(1/2) is approximately 14 days. Covariate analysis showed that V(1) increased as body weight increased, and CL was higher in patients who developed antibodies to infliximab. An additional novel covariate, serum albumin concentration, was found to be inversely and strongly related to infliximab clearance in this population.

Conclusions: The disposition of infliximab in patients with moderately to severely active ulcerative colitis, unlike in rheumatoid arthritis, was not affected by coadministration of immunomodulators and corticosteroids but was related to formation of antibodies to infliximab and, notably, to serum albumin levels.

Figures

Fig. 1

Goodness-of-fit plots for the base model. Dashed lines represent the locally weighted smoothing (LOESS) of the data

Fig. 2

Goodness-of-fit plots for the final model. Dashed lines represent the locally weighted smoothing (LOESS) of the data

Fig. 3

Empirical Bayesian Estimates (EBEs) of V1 (panel A), clearance (CL) (panel B), and ETA2(V1) (panels C and D) versus body weight. V1 volume of distribution in the central compartment, CL clearance, ETA2(V1) random effect of V1

Fig. 4

Empirical Bayesian estimates (EBEs) of CL (panel A), ETA1(CL) (panels B and C) versus baseline albumin. CL learance, ETA1(CL) random effect of clearance

Fig. 5

Empirical Bayesian stimates (EBEs) of CL (panel A), ETA1(CL) (panels B and C) versus antibody to infliximab status. CL clearance, ETA1(CL) random effect of clearance

Fig. 6

Empirical Bayesian stimates (EBEs) of CL (panel A), V1 (panel B), ETA1(CL) for base model (panel C) and ETA1(CL) for final model (panel D); ETA2(V1) for base model (panel E), and ETA2(V1) for final model (panel F) versus Sex. V1 volume of distribution in the central compartment, CL clearance, ETA2(V1) random effect of V1, ETA1(CL) random effect of clearance

Fig. 7

Visual predictive check for representative patients shown by an overlay of individual Bayesian-estimated pharmacokinetic (PK) parameter predicted curve on the raw data: representative patients in the 5 mg/kg group in the ACT 1 (panel A);representative patients in the 10 mg/kg group in ACT 1 (panel B); representative patients in the 5 mg/kg group in the ACT 2 (panel C); representative patients in the 10 mg/kg group in the ACT 2 (panel D). Note that the dosing frequency at the beginning and early part of the study (0, 2, 6 weeks) is higher than in the later period in the study when dosing was every 8 weeks. This is reflected in the higher concentrations at early time points in the graphs