Dose-optimization for loss-of-response to vedolizumab - pharmacokinetics and immune mechanisms.

BACKGROUND Real-life-data regarding pharmacokinetics of vedolizumab in patients needing dose-optimization are scarce. We set to examine whether pre-optimization vedolizumab-levels associate with therapy-outcomes and which mechanisms explain the associations. METHODS A multi-center observational study assessed the outcome of dose-increase in association with pre-escalation levels in vedolizumab-treated patients. SubsequentIy, α4β7 occupancy on peripheral blood (PB) and intestinal-lamina-propria (LP) tissues was investigated on various cellular subsets in patients undergoing lower endoscopy on infusion-day. Cellular localization of vedolizumab-bound α4β7 and effects on M1 and M2 macrophages were also explored. RESULTS 161 IBD patients were included. Among 129/161 patients intensified during maintenance (week 14 onward), pre-intensification trough-levels were comparable or higher among those subsequently attaining post-optimization clinical, biomarker and endoscopic remission, compared with non-remitting patients (p=0.09, 0.25, 0.04, respectively). Similar results were demonstrated for those dose-optimized during induction (week 6, n=32). In the immune sub-study (n=43), free α4β7-receptors at trough were similarly low among patients with/without mucosal healing, on PB-T-cells (p=0.15), LP-T-cells (p=0.88) and on PB-eosinophils (p=0.08). Integrin-receptors on M1 and M2-macrophages were also saturated by low levels of vedolizumab and anti-inflammatory cytokine secretion was not increased. Co-localization and dissociation experiments demonstrated membranal α4β7 receptors of two origins: non-internalized and newly-generated α4β7, but re-binding was still complete at very low concentrations. CONCLUSIONS These results do not support pharmacokinetics as the mechanism responsible for loss of response to vedolizumab, nor do they support a need for higher drug concentration to enhance vedolizumab's immune effects. Higher pre-escalation levels may indicate less clearance (less severe disease) & higher likelihood of subsequent re-gained response, regardless of therapy escalation.