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 (Bmax was 19.8 pg mL−1 and the dissociation constant (Kss) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy.
Highlights
Ulcerative colitis (UC) is a chronic auto-immune disease of the colonic mucosa [1]
Supported by the available data and the assumption that degradation of the IFX-tumor necrosis factor (TNF) complex is not negligible, a Target-mediated drug disposition (TMDD) model with quasi-steady state (QSS) approximation best described the interaction between IFX and TNF serum concentrations
The TMDD-QSS approximation allowed the estimation of the steady state equilibrium constant (Kss), the complex internalization constant (ke(P)) and of the degradation constant TNF
Summary
Ulcerative colitis (UC) is a chronic auto-immune disease of the colonic mucosa [1]. Patients with active UC suffer from episodes of bloody diarrhea, often accompanied with abdominal pain. The precise pathophysiology of UC has not been unraveled yet, tumor necrosis factor (TNF) plays an important role in mucosal inflammation. TNF is a pro-inflammatory cytokine and has been found in increased concentrations in blood, stool, and epithelial tissue of UC patients [2–6]. In patients with inflammatory bowel disease (IBD) (i.e. UC or Crohn’s disease), serum TNF concentrations are significantly higher compared to healthy controls [3]. Higher TNF concentrations are present in inflamed tissue samples of IBD patients, compared to uninflamed tissue samples, suggesting a local higher inflammatory TNF load in inflamed epithelial tissue [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
