Pharmacovigilence, Takeda Development Center Americas Inc., 1 Takeda Parkway, Deerfield, IL, 60015, USA.
Quantitative Clinical Pharmacology, Takeda Development Center Americas Inc., Deerfield, IL, USA.
Drugs R D. 2018 Jun;18(2):109-118. doi: 10.1007/s40268-018-0229-9.
Fasiglifam, a potent, selective novel agonist of G protein-coupled receptor 40, stimulates insulin secretion at elevated blood glucose levels in a glucose-dependent manner. This study evaluated the potential effect of hepatic impairment on the pharmacokinetics and safety of a single dose of fasiglifam and its metabolite M-I. Fasiglifam's clinical development was halted due to liver safety concerns.
In this phase I, open-label study, subjects with mild or moderate hepatic impairment, along with matched controls (gender, weight, age, and smoking status), received a single, 25-mg oral dose of fasiglifam. Blood samples were collected through 336 h post-dose for pharmacokinetic evaluation.
Overall, 73% of subjects were male with a mean age of 54 years. Compared with normal hepatic function subjects (n = 14), mean systemic fasiglifam exposure (C and AUC) was reduced in mild (n = 8) and moderate (n = 8) hepatic impairment subjects by approximately 20-40%. However, the observed percent unbound drug plasma concentration appeared comparable across all groups. Mean oral clearance was higher and terminal half-life lower in subjects with mild or moderate hepatic impairment compared with normal hepatic function subjects. Fasiglifam M-I systemic exposure increased by approximately twofold in subjects with mild or moderate hepatic impairment compared with those with normal hepatic function. Fasiglifam was well tolerated, and there were no reports of hypoglycemia.
Hepatic status did not significantly impact systemic exposure of fasiglifam in this study, in fact, a decrease was observed, suggesting no dose reduction would be required for patients with hepatic impairment.
法昔列汀是一种新型 G 蛋白偶联受体 40 高选择性激动剂，可在血糖升高的情况下葡萄糖依赖性刺激胰岛素分泌。本研究评估了肝损伤对单次给予法昔列汀及其代谢产物 M-I 的药代动力学和安全性的潜在影响。由于肝安全性问题，法昔列汀的临床开发已停止。
在这项 I 期、开放标签研究中，轻度或中度肝损伤患者（性别、体重、年龄和吸烟状况匹配）接受了单次 25mg 口服法昔列汀。通过 336 小时后采集血样进行药代动力学评估。
总体而言，73%的受试者为男性，平均年龄为 54 岁。与肝功能正常受试者（n=14）相比，轻度（n=8）和中度（n=8）肝损伤受试者的全身法昔列汀暴露（C 和 AUC）平均减少约 20-40%。然而，观察到的未结合药物血浆浓度在所有组中似乎相当。与肝功能正常受试者相比，轻度或中度肝损伤受试者的口服清除率较高，终末半衰期较短。与肝功能正常受试者相比，轻度或中度肝损伤受试者的法昔列汀 M-I 全身暴露增加约两倍。法昔列汀耐受性良好，无低血糖报告。
在这项研究中，肝状况并未显著影响法昔列汀的系统暴露，实际上观察到下降，表明肝损伤患者无需减少剂量。
