Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat

BACKGROUND & AIMS Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus. METHODS Data from Phase 1/2 trials were used to develop a population kinetic-pharmacodynamic model to characterize the linerixibat dose-TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC$_{0-24}$). Time-matched post hoc estimates of AUC$_{0-24}$ were correlated with pruritus reported on a 0-10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model-estimated TSBA AUC$_{0-24}$ was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS. RESULTS Linerixibat dose dependently reduced TSBA AUC$_{0-24}$, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC$_{0-24}$ correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC$_{0-24}$, 60% were pruritus responders (≥2-point improvement in WIS from baseline). CONCLUSIONS Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC$_{0-24}$ correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.