East Hanover, Novartis Institutes for Biomedical Research, New Jersey, USA.
Novartis Institute for Biomedical Research, Cambridge, Massachusetts, USA.
J Clin Pharmacol. 2022 Apr;62(4):520-531. doi: 10.1002/jcph.1996. Epub 2022 Feb 24.
Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's pharmacokinetics, safety, and tolerability following a 200-μg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percentage free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUC ]) and a 1.3-fold increase in maximal exposure (C ) vs those with normal hepatic function (geometric mean ratio: AUC , 1.64 [90%CI, 1.25-2.16]; C , 1.30 [90%CI, 0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUC (1.61 [90%CI, 1.04-2.49]) and comparable C (1.02 [90%CI, 0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment.
替芬戈诺，一种非胆汁酸法尼醇 X 受体（FXR）激动剂，具有剂量比例的药代动力学特征，且无明显的主要肝胆循环。这项开放标签研究调查了肝损伤（HI）对替芬戈诺药代动力学、安全性和耐受性的影响，采用禁食状态下 200μg 剂量，根据 Child-Pugh 分级进行评估。在给药后 168 小时内采集血样进行定量和血浆蛋白结合测定。在有 HI 的参与者和肝功能正常的参与者中，总替芬戈诺暴露情况相当。在所有组别的参与者中，替芬戈诺在人血浆中高度结合（>99%）。平均未结合分数（游离百分比）在肝功能正常和轻度 HI 的参与者中为 0.14%，在中度和重度 HI 的参与者中分别增加至 0.17%和 0.24%。在轻度 HI 和肝功能正常的参与者中，也观察到类似的未结合药物暴露情况。中度 HI（N=8）的参与者的未结合暴露量（从 0 到无穷大的血浆浓度-时间曲线下面积[AUC ]）增加了 1.6 倍，最大暴露量（C ）增加了 1.3 倍，与肝功能正常的参与者相比（几何均数比：AUC ，1.64[90%CI，1.25-2.16]；C ，1.30[90%CI，0.96-1.76]）。重度 HI（N=8）的参与者的 AUC 增加了 1.6 倍（1.61[90%CI，1.04-2.49]），C 相似（1.02[90%CI，0.60-1.72]），与肝功能正常的参与者相比。替芬戈诺耐受良好。替芬戈诺对 HI 的相对不敏感为治疗严重肝病患者提供了无需调整剂量的潜力。
