Population Pharmacokinetics and Exposure-Response Relationships of Etrolizumab in Patients with Moderately-to-Severely Active Crohn's Disease.

Abstract

This study aimed to characterize the pharmacokinetics (PK) of etrolizumab, an IgG1-humanized monoclonal anti-β7 integrin antibody, and assess its exposure-response (ER) relationship for key clinical outcomes in patients with moderately-to-severely active Crohn's disease. ER analyses were based on data from Phase 3 BERGAMOT trial, which evaluated etrolizumab at 105 or 210 mg during induction phase and 105 mg during maintenance phase. Population pharmacokinetic analysis was performed to characterize etrolizumab PK and identify influential covariates. ER analyses were conducted at end of induction and maintenance for clinical remission, endoscopic improvement, and endoscopic remission. ER modeling was performed using logistic regression, and full covariate model was used to examine the impact of baseline covariates on clinical outcomes. Pharmacokinetics of etrolizumab was best characterized using a two-compartment model with first-order absorption, demonstrating a time-dependent decrease in clearance. Typical maximum reduction of clearance was 22.0% (95% CI: 20.5%-23.5%) with onset half-life of 3.45 (95% CI: 2.84-4.04) weeks. Baseline body weight, albumin, and C-reactive protein were the most impactful covariates for etrolizumab exposure. Based on population PK results, trough concentration at Week 4 of induction was selected as exposure metric. Etrolizumab exposure-response slope was significant (P < .05) for clinical remission, endoscopic improvement, and endoscopic remission final models in maintenance phase, but none of final ER models of induction phase. For all induction ER endpoints, tumor necrosis factor (TNF)-naive patients had significantly higher probability of a favorable outcome at end of induction compared to TNF-experienced patients. In summary, exposure-response was more evident at end of maintenance than at end of induction.