索磷布韦片在中国健康受试者中的药代动力学和安全性研究

目的：研究中国人群中索磷布韦及其代谢产物GS-331007和GS-566500的主要药代动力学特征和安全性。方法：本试验共入组12例健康受试者，分为四个周期；前三周期为单次给药（低剂量400 mg空腹组、高剂量800 mg空腹组和低剂量400 mg高脂餐组）药代动力学试验；第四周期为多次给药（低剂量400 mg空腹组）药代动力学试验。采用HPLC-MS/MS测定给药前后不同时间点人血浆中索磷布韦及其代谢产物GS-331007和GS-566500的浓度。结果：索磷布韦及其代谢产物GS-566500的暴露与剂量有成比例增加趋势。在多次给药试验中，未观察到明显蓄积现象。与空腹相比，餐后状态下索磷布韦的Cmax变化不大，AUC增加约30%；GS-331007的Cmax和AUC分别减少约30%和10%；GS-566500的Cmax和AUC分别增加约15%和25%。饮食对索磷布韦、GS-331007和GS-56650的Tmax无显著影响。未发生严重不良事件和导致退出的不良事件，所有受试者耐受性良好。结论：在中国健康受试者中，开展的索磷布韦片药代动力学研究结果表明，其药动学特征和安全性与国外研究数据无明显差异，安全性和耐受性良好。

Pharmacokinetics and Safety of Sofosbuvir Tablets in Healthy Chinese Subjects

Objective: The present study investigated the pharmacokinetics and safety of sofosbuvir and its metabolites GS-331007 and GS-566500. Methods: The trail enrolled 12 healthy Chinese subjects and included four cycles. The subjects received a single oral dose of generic sofosbuvir, in a three-way crossover design, at 400 mg in fasted state or after a high-fat meal, or 800 mg in fasted state, and then all subjects were administered with 400 mg sofosbuvir in fasted state daily for 8 days. The plasma sofosbuvir, GS-331007 and GS-566500 concentrations at different time points were determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Results: Plasma exposure to sofosbuvir and its metabolite GS-566500 was increased in an approximately proportional manner to the increased dose. Compared with fasting, Cmax of sothibuvir changed little, and AUC increased by about 30% after a high-fat meal; Cmax and AUC of GS-331007 respectively decreased by about 30% and 10%; Cmax and AUC of GS-566500 respectively increased by about 15% and 25%; Tmax of sothibuvir, GS-331007 or GS-56650 had no significant change. Repeated dosing did not result in drug accumulation in the blood. No serious adverse events or withdrawal by adverse events were observed, and all subjects tolerated the doses well. Conclusions: The study of sothibuvir tablets in Chinese healthy subjects indicated that there were no significant differences from foreign pharmacokinetic data, and the safety and tolerability were good.