Abstract：
OBJECTIVE: (S)-oxiracetam is the major active enantiomer of oxiracetam, which is being developed for dementia. This trial was designed to evaluate the safety, tolerability, and pharmacokinetics of oral (S)-oxiracetam in healthy Chinese volunteers.
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.
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.
摘要：
目的:(S)-奥拉西坦是奥拉西坦的主要活性对映体,正在为痴呆症开发。这项试验旨在评估安全性，耐受性,口服（S）-奥拉西坦在中国健康志愿者中的药代动力学。
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。
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。
