PMID- 34954052 OWN - NLM STAT- MEDLINE DCOM- 20220125 LR - 20220125 IS - 1879-0720 (Electronic) IS - 0928-0987 (Linking) VI - 170 DP - 2022 Mar 1 TI - First-in-human safety, tolerability, and pharmacokinetics of SY-007, a prolonged action neuroprotective drug for ischemic stroke, in healthy Chinese subjects. PG - 106104 LID - S0928-0987(21)00405-X [pii] LID - 10.1016/j.ejps.2021.106104 [doi] AB - BACKGROUND AND PURPOSE: SY-007 is an interfering peptide designed to disrupt the cell death signaling of phosphatase and tensin homolog deleted on chromosome ten (PTEN) nuclear translocation during ischemic stroke. Preclinical studies indicated that rats treated with 1.5 mg/kg SY-007 in the middle cerebral artery occlusion (MACO) model had significantly reduced stroke lesion size even when administered 6 h after the stroke onset. The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of ascending doses of SY-007 administered intravenously in healthy Chinese subjects. METHODS: A total of 78 healthy Chinese subjects were enrolled in the single ascending dose study (1-60 mg) and received a 15-min intravenous infusion SY-007 or placebo. Plasma concentrations of SY-007 were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were determined using non-compartmental and compartment analyses. A model based on target-mediated drug disposition was applied. Model evaluation was performed through visual predictive checks and bootstrap analysis. RESULTS: Across doses of 1-60 mg, SY-007 was well tolerated. All adverse events (AEs) were mild or moderate in intensity, and all resolved without intervention. After infusion, SY-007 plasma concentrations decreased quickly with the mean terminal half-life was shorter than 0.78 h. The area under the concentration-time curve increased with a greater than dose-dependent manner from 1 to 30 mg and resulted in a dose-dependent increased from 30 to 60 mg. The nonlinear phenomenon was well described by a simplified target-mediated drug disposition (TMDD) model. CONCLUSIONS: Intravenous dosing of SY-007 appears to be safe up to a dose of 60 mg. Nonlinear pharmacokinetics was observed across the evaluated doses and TMDD might be the primary reason. The effective dose of SY-007 for neuroprotective effect in patients with ischemic stroke is expected to be 10-30 mg and was recommended for the later multiple ascending dose study of SY-007. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT04111523. CI - Copyright (c) 2021 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Wang, Zhenlei AU - Wang Z AD - Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China. FAU - Jin, Ying AU - Jin Y AD - Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China. FAU - Shen, Qi AU - Shen Q AD - Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China. FAU - Zhuo, Lang AU - Zhuo L AD - Suzhou Yabao Pharmaceutical R&D Co., Ltd., Suzhou, China. FAU - Liu, Runhan AU - Liu R AD - Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China. FAU - Di, Xiangjie AU - Di X AD - Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China. FAU - Xiang, Lisha AU - Xiang L AD - Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China. FAU - Zhang, Guanyu AU - Zhang G AD - Suzhou Yabao Pharmaceutical R&D Co., Ltd., Suzhou, China. FAU - Wang, Ying AU - Wang Y AD - Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China. FAU - Wang, Yongsheng AU - Wang Y AD - Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China. FAU - Zheng, Li AU - Zheng L AD - Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China. Electronic address: zhengli@wchscu.cn. LA - eng PT - Journal Article DEP - 20211223 PL - Netherlands TA - Eur J Pharm Sci JT - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JID - 9317982 RN - 0 (Neuroprotective Agents) SB - IM MH - Animals MH - Area Under Curve MH - *Brain Ischemia/drug therapy MH - China MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Half-Life MH - Humans MH - *Ischemic Stroke MH - *Neuroprotective Agents MH - Rats MH - *Stroke/drug therapy OTO - NOTNLM OT - First-in-human OT - Ischemic stroke OT - Pharmacokinetics OT - SY-007 OT - Safety EDAT- 2021/12/27 06:00 MHDA- 2022/01/27 06:00 CRDT- 2021/12/26 20:36 PHST- 2021/08/29 00:00 [received] PHST- 2021/11/08 00:00 [revised] PHST- 2021/12/17 00:00 [accepted] PHST- 2021/12/27 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/12/26 20:36 [entrez] AID - S0928-0987(21)00405-X [pii] AID - 10.1016/j.ejps.2021.106104 [doi] PST - ppublish SO - Eur J Pharm Sci. 2022 Mar 1;170:106104. doi: 10.1016/j.ejps.2021.106104. Epub 2021 Dec 23.