Liver international : official journal of the International Association for the Study of the Liver · 2024
Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat.
СтатьяКлиническое исследование II фазыРандомизированное исследованиеКлиническое исследование I фазыПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Karatza Eleni, Swift Brandon, Carreño Fernando, Mukherjee Sumanta, Casillas Linda, Lennie Janelle, Fettiplace James, McLaughlin Megan M, Kremer Andreas E
Аннотация
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 (AUC0-24). Time-matched post hoc estimates of AUC0-24 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 AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS.
RESULTS: Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 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 AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.
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 (AUC0-24). Time-matched post hoc estimates of AUC0-24 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 AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS.
RESULTS: Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 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 AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.