The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
GSK, Durham, North Carolina, USA.
Liver Int. 2024 Sep;44(9):2293-2302. doi: 10.1111/liv.15982. Epub 2024 May 23.
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.
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). Time-matched post hoc estimates of AUC 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 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS.
Linerixibat dose dependently reduced TSBA AUC, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC, 60% were pruritus responders (≥2-point improvement in WIS from baseline).
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 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.
原发性胆汁性胆管炎（PBC）患者的总血清胆汁酸（TSBA）水平升高，可能介导胆汁淤积性瘙痒。伊立替康，一种回肠胆汁酸转运蛋白抑制剂，可改善 PBC 患者的瘙痒。我们探讨了 linerixibat 剂量、TSBA 浓度与瘙痒之间的关系。
使用 1/2 期试验的数据，建立了一个群体药代动力学-药效学模型，以描述 linerixibat 剂量-TSBA 关系。使用 GLIMMER 研究中参与者的个体贝叶斯参数估计值，得出 24 小时内 TSBA 浓度曲线下面积（AUC）。将时间匹配的事后 AUC 估计值与 0-10 数字评分量表上报告的瘙痒进行相关性分析。将基线 TSBA 浓度与每月瘙痒评分（MIS）的基线变化（ΔBL）进行相关性分析。模型估计的 TSBA AUC 的 ΔBL 与时间匹配的每周瘙痒评分（WIS）或 MIS 的 ΔBL 进行相关性分析。
Linerixibat 剂量依赖性地降低了 TSBA AUC，在 5 天后达到稳态。GLIMMER 中的基线 TSBA 水平与 MIS 的 ΔBL 不相关。TSBA AUC 的 ΔBL 与治疗 12 周时 WIS 的改善相关（r=0.52，p<0.0001）。在 TSBA AUC 下降≥30%的参与者中，60%为瘙痒应答者（WIS 从基线改善≥2 分）。
Linerixibat 治疗导致快速、剂量依赖性的 TSBA 降低。基线 TSBA 水平与治疗期间的瘙痒变化不相关，表明它们不能预测 linerixibat 的反应。TSBA AUC 的变化与 PBC 患者瘙痒的改善显著相关，并且可以预测其改善。
