Population pharmacokinetic analysis of etrolizumab in patients with moderately‐to‐severely active ulcerative colitis

Etrolizumab is an IgG1‐humanized monoclonal antibody that specifically targets the β7 subunit of α4β7 and α4Eβ7 integrins, and it has been evaluated for the treatment of moderately‐to‐severely active ulcerative colitis (UC). Population pharmacokinetic (PK) analysis was performed to characterize etrolizumab PK properties in patients with moderately‐to‐severely active UC and evaluate covariate impacts on exposure. The population PK model was developed based on etrolizumab serum concentrations from patients with moderately‐to‐severely active UC enrolled in six studies (one phase I, one phase II, and four phase III) and validated using another phase III clinical trial. Stepwise covariate modeling was used to evaluate the impact of 23 prespecified covariates. Etrolizumab PK was best described by a two‐compartment model with first‐order absorption, with clearance decreasing over time. Population typical values were 0.260 L/day for clearance (CL) during the first dosing internal, 2.61 L for central volume, 71.2% for bioavailability, and 0.193/day for absorption rate. CL reduced over the study duration, the typical maximum reduction was 26% with an onset half‐life of 4.8 weeks. Consequently, the predicted mean terminal half‐life was shorter after a single dose (13.0 days) compared to that at steady‐state (17.1 days). Baseline body weight and albumin were the most impactful covariates for etrolizumab exposure. Final population PK model well characterized the PK properties of etrolizumab in patients with moderately‐to‐severely active UC and identified influential covariate effects.