P530 Comparison between liposomial iron and ferrous sulfate in patients with iron deficiency anemia and inflammatory bowel disease. A pilot controlled study

Abstract

Background: Vedolizumab (VDZ), currently in development for treating ulcerative colitis (UC) and Crohn's disease (CD), exhibits target-mediated drug disposition. Described here are a VDZ population pharmacokinetic (PK) model, an estimation of typical VDZ parameter values, and effects of covariates that may be predictors of VDZ PK variability. Methods: The population PK data set included data from 5 VDZ clinical studies (1 phase 1 study in healthy subjects and 1 phase 2 study and 3 phase 3 studies [GEMINI 1, 2, and 3] in UC or CD patients). Analysis of repeatedmeasures was conducted via nonlinear mixed-effects modeling, using NONMEM (Version 7.2). The population PK base model was developed using firstorder conditional estimation with an η-e interaction method and extensively sampled phase 1 and 2 data. Results from the base model were used to develop the full covariate model, which was fit to sparse phase 3 data using the full Bayesian Markov Chain Monte Carlo method. Model selection was based on standard goodness-of-fit criteria. A full covariate modeling approach, emphasizing parameter estimation rather than stepwise hypothesis testing, was implemented for the population PK analysis. Results: The data set comprised 2554 individuals with 18,427 evaluable VDZ serum concentrations. VDZ PK was best described by a 2-compartmentmodel with parallel linear and nonlinear elimination. Reference covariates for the final PK model included baseline age, weight, albumin, disease activity scores (Crohn's Disease Activity Index score [CD]; partial Mayo Clinic score [UC]), prior anti-tumor necrosis factor α treatment, and inflammatory bowel disease diagnosis (CD or UC). Presence of anti-VDZ antibodies and use of adjuvant therapy (immunomodulator or aminosalicylate) were also evaluated. Overall, PK parameter estimates for patients with UC and CD were similar using reference values for individual covariates. At steady state, VDZ half-life estimate was 25 days for the linear elimination phase. Linear clearance of VDZ (CLL) was 0.159 L/day for UC and 0.155 L/day for CD. Volume of distribution for the central compartment (Vc) was 3.19 L and 1.66 L for the peripheral compartment. Interindividual variabilities (coefficients of variation) in CLL and Vc were 35% and 19%, respectively; proportional residual variance estimate was 24%. While baseline albumin had the potential to have a clinically relevant effect on VDZ CLL, defined as an effect size of more than ±25% from the reference value, effects of other covariates tested were not considered clinically meaningful. Conclusions: Population PK parameters were similar in patients with UC and CD. No change in dosing recommendations is needed based on baseline covariates (eg, age, gender, weight, presence of anti-VDZ antibodies, and albumin).