Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
Int J Nanomedicine. 2013;8:129-36. doi: 10.2147/IJN.S38271. Epub 2013 Jan 4.
Ursolic acid is a promising anticancer agent. The current study aims to evaluate the single- and multiple-dose pharmacokinetics (PK) as well as the safety of ursolic acid nanoliposomes (UANL) in healthy volunteers and in patients with advanced solid tumors.
Twenty-four healthy volunteers in the single-dose PK study were divided into three different groups, which received 37, 74, and 98 mg/m(2) of UANL. Eight patients in the multiple-dose PK study were administered with 74 mg/m(2) of UANL daily for 14 days. The UA plasma concentrations were determined using ultra-performance liquid chromatograph-tandem mass spectrometry.
The plasma concentration profiles of all subjects were characterized by a biexponential decline after infusion. The mean peak plasma concentration (C(max)) increased linearly as a function of the dose (r = 0.999). The mean area under the plasma concentration-time curve (AUC) from 0 to 16 hours also increased proportionally with dose escalation (r = 0.998). However, the clearance was constant over the specific dose interval. In the multiple-dose PK study, the trough and average concentrations remained low. The mean AUC, half-life, C(max), time to C(max), and the volume of distribution on the first day were similar to those on the last day. All subjects tolerated the treatments well. Most UANL-associated adverse events varied from mild to moderate.
UANL exhibits relatively linear PK behavior with dose levels from 37 mg/m(2) to 98 mg/m(2). No drug accumulation was observed with repeated doses of UANL. The intravenous infusion of UANL was well tolerated by healthy volunteers and patients with advanced tumors.
熊果酸是一种很有前途的抗癌药物。本研究旨在评估熊果酸纳米脂质体（UANL）在健康志愿者和晚期实体瘤患者中的单剂量和多剂量药代动力学（PK）以及安全性。
单剂量 PK 研究中，24 名健康志愿者分为三组，分别接受 37、74 和 98 mg/m2的 UANL。8 名多剂量 PK 研究患者每天接受 74 mg/m2的 UANL 治疗 14 天。采用超高效液相色谱-串联质谱法测定 UA 血浆浓度。
所有受试者的血浆浓度曲线特征均为输注后双指数下降。平均峰血浆浓度（Cmax）随剂量呈线性增加（r=0.999）。AUC0-16h 也随剂量增加呈比例增加（r=0.998）。然而，清除率在特定剂量间隔内保持不变。在多剂量 PK 研究中，谷值和平均值浓度保持较低水平。平均 AUC、半衰期、Cmax、达峰时间和第一天的分布容积与最后一天相似。所有受试者均能耐受治疗。大多数 UANL 相关不良事件从轻度到中度不等。
UANL 表现出与剂量水平从 37mg/m2 到 98mg/m2 相对线性的 PK 行为。重复给予 UANL 未观察到药物蓄积。UANL 静脉输注在健康志愿者和晚期肿瘤患者中耐受性良好。
