METHODS: A randomized, controlled, double-blind and dose-escalation design was used in this Phase I trial, which consisted of a single-ascending-dose (SAD) study (400-2000 mg) and a multiple-ascending-dose (MAD) study (400-1600 mg). Blood, urine and feces samples were collected for pharmacokinetic analysis. Safety was evaluated by monitoring adverse events (AEs).
RESULTS: AEs in both studies were mild or moderate in severity and dose-independent. In the SAD study, no chiral transformation was observed. 55.03% and 36.16% of (S)-oxiracetam was excreted unchanged in urine and feces, respectively. Exposures exhibited dose-proportional increases over the range of 400 to 1600 mg but almost unchanged from 1600 to 2000 mg. (S)-oxiracetam was absorbed rapidly, reaching a peak at 0.75-1.00 h, and t1/2 was 6.12-6.60 h. Food had no effect on AUC, but prolonged Tmax to 3.00 h. In the MAD study, steady-state was observed on day 5. Mild accumulations were observed after 7 days of repeated dosing.
CONCLUSIONS: (S)-oxiracetam was safe and tolerated with favorable pharmacokinetic profiles at all study doses, providing dosing evidence for further efficacy evaluation.
方法:随机,控制,该I期试验采用双盲和剂量递增设计,其中包括单剂量递增(SAD)研究(400-2000mg)和多剂量递增(MAD)研究(400-1600mg)。血,收集尿液和粪便样本进行药代动力学分析.通过监测不良事件(AE)评估安全性。
结果:两项研究中的不良事件严重程度和剂量依赖性均为轻度或中度。在SAD研究中,没有观察到手性转化。55.03%和36.16%的(S)-奥拉西坦在尿液和粪便中排泄不变,分别。在400至1600mg的范围内,暴露量表现出剂量成比例的增加,但从1600至2000mg几乎没有变化。(S)-奥拉西坦吸收迅速,在0.75-1.00h达到峰值,t1/2为6.12-6.60h。食物对AUC没有影响,但将Tmax延长至3.00h。在MAD研究中,在第5天观察到稳态。在重复给药7天后观察到轻度累积。
结论:(S)-奥拉西坦在所有研究剂量下都是安全和耐受的,具有良好的药代动力学特征,为进一步的疗效评估提供剂量证据。