A Target-Mediated Drug Disposition model for infliximab in patients with Ulcerative Colitis
S.E. Berends(1,2), T.J. van Steeg(3), M.J. Ahsman(3), G.R.A.M. D’Haens(2), R.A.A. Mathôt(1)
(1) Department of Hospital Pharmacy, Academic Medical Center, The Netherlands, (2) Department of Hepatology & Gastroenterology, Academic Medical Center, The Netherlands, (3) LAP&P Consultants BV, The Netherlands
Objectives: Ulcerative Colitis (UC) is an inflammatory bowel disease (IBD) affecting the colon and rectum of the gastrointestinal tract. Infliximab (IFX) is an intravenously administered monoclonal antibody (mAb) directed against the pro-inflammatory cytokine tumor necrosis factor (TNF). The mechanism of clearance of mAbs is not exactly known, but the primary route is via proteolytic catabolism after receptor-mediated endocytosis in the cells of the reticuloendothelial system[1–3]. Target-mediated drug disposition (TMDD) is reported for mAbs meaning that the pharmacokinetics of mAbs are affected because of their high target affinity[4,5]. The objective of this study is to characterize the pharmacokinetics of IFX in patients with UC.
Methods: Twenty anti-TNF naive patients with UC were included in this prospective cohort study and received IFX at a dose of 5 mg/kg at week 0, followed by infusions (5 mg/kg) at week 2 and 6, according to standard guidelines. IFX, antibodies-to-IFX (ATIs) and TNF serum concentrations were measured at day 0 (1hr after the end of the first infusion), 1, 4, 7, 11,14, 18, 21, 28 and 42. Data were analysed with the use of NONMEM using First-Order Conditional Estimation with Interaction (FOCE+I). Concentration-time profiles of TNF were first described using a binding model. Next, a TMDD was developed to describe the target-dependent pharmacokinetics of IFX.
Results: A two-compartment model best described the concentration-time profiles of IFX in this study population. Mean values (plus interindividual variability) for CL, Q and Vc, Vp were 0.396 L/day (29.6%), 0.344 L/day and 3.2 L (21.4%) and 1.81 L (59.7%), respectively. As a binary covariate the formation of ATIs increased clearance 2.3-fold. Patients with low albumin serum concentrations exhibited higher clearance. The binding model described the concentration-time profiles of TNF. Estimates for BMAX and KD were 3.89 pg/ml and 18.2, respectively. Estimated TMDD parameters of the preliminary TMDD model were within the expected range.
Conclusions: The formation of ATIs and low serum albumin levels increased clearance. With the binding model, the concentration-time profile of TNF could be described. A preliminary TMDD model was developed to describe the target-dependent pharmacokinetics of IFX.
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