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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.

SUBMITTER: Fasanmade AA

PROVIDER: S-EPMC2778780 | biostudies-other | 2009 Dec

REPOSITORIES: biostudies-other

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Project description:Background: Infliximab (IFX) is a potent therapeutic agent used for the treatment of conventional refractory ulcerative colitis (UC). However, the high non-response rate of IFX brings difficulties to clinical applications. In the context of proteomics research, our study of differentially expressed proteins (DEPs) is essential for non-response to IFX in UC patients and provides powerful insights into underlying drug resistance mechanisms. Methods: A total of 12 UC patients were divided into responders to IFX (UCinfG), non-responders to IFX (UCinfL), severe UC (UCsevere) without an IFX treatment history, and mild UC (UCmild) without an IFX treatment history. Subsequently, DEPs were identified from intestinal biopsy tissue between responders and non-responders to IFX by a label-free proteomic quantitative approach, and the general principle of functional protein screening was followed to deduce the potential drug targets and predictors for non-response to IFX in UC patients. Meanwhile, these targets excluded DEPs caused by the severity of inflammation for the first time. The differential expressions of candidate protein targets were validated at the gene sequence level using GEO2R analysis of the GEO database and qRT-PCR in some independent cohorts. Results: A total of 257 DEPs were screened out by mass spectrometry between UCinfG and UCinfL groups, excluding 22 DEPs caused by the severity of inflammation, and compared and verified at the gene sequence level in the Gene Expression Omnibus (GEO) database. Finally, five DEPs, including ACTBL2 (Q562R1), MBL2 (P11226), BPI (P17213), EIF3D (O15371), and CR1 (P17927), were identified as novel drug targets and predictive biomarkers for non-response to IFX. The drug targets were confirmed in the GEO database of the microarray results from three independent cohorts of 70 human intestinal biopsies and validated in qPCR data from 17 colonic mucosal biopsies. Among them, CR1 might affect the activation of the lectin pathway via complement-coated bacteria to play an opsonizing role in inflammation-related pathways closely associated with non-responders to IFX. Conclusion: This is the first report of proteomics analysis for the identification of novel drug targets based on intestinal biopsy tissue, which is significant for hypotheses for mechanistic investigation that are responsible for non-response to IFX and the development of clinical new pharmaceutical drugs.

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Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis.

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