Author information

¹The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

²GSK, Durham, North Carolina, USA.

³GSK, Collegeville, Pennsylvania, USA.

⁴GSK, London, UK.

⁵Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Abstract

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_0-24correlated 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.