DataSheet_1_Phase I Trial of Pyragrel, a Novel Thromboxane Synthetase Inhibitor, to Evaluate the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers.docx

Background and Objective: Inhibition of thrombosis and platelet aggregation through a thromboxane synthetase inhibitor proved to be an effective and promising treatment for cardiovascular and/or cerebrovascular disease (CCVD) patients. This phase I study evaluated the safety, tolerability, and pharmacokinetics of sodium pyragrel, a novel thromboxane A2 synthetase inhibitor, in healthy volunteers.
Methods: A total of 84 healthy Chinese volunteers were enrolled in the study and randomized into one of five dosing regimens of intravenous pyragrel, which were single ascending dose (30 to 300 mg), multiple doses (pyragrel 180 mg once daily on Day 1 and Day 6, twice daily from Day 2 to Day 5), 3×3 Latin square crossover (60, 120, 240 mg), and a continuous dose (360 mg in 24 h), respectively. Plasma concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis.
Results: The maximum plasma concentrations of pyragrel were essentially reached at the end of the 3 h infusion. The pharmacokinetic process of pyragrel and two main metabolites (BBS and BJS) is linear over the 30–300 mg dose range, with no significant accumulation on multiple doses. The urinary excretion of pyragrel accounted for more than 70% of the total drug amount. Preliminary pharmacodynamic results demonstrated that the production of urinary 11-D-HTXB2 was time- and dose-dependently inhibited by single i.v. dose of pyragrel.
Conclusions: Pyragrel was well tolerated after single ascending doses up to 300 mg, multiple doses of 180 mg, and continuous administration of 360 mg within 24 h. No drug-related, serious adverse drug reactions occurred during the five-part study. The most common pyragrel-related adverse events (AEs) were total bilirubin (TB)/direct bilirubin (DB) elevations with a relatively low incidence rate and seemed to be dose independent. Given the acceptable safety and appropriate pharmacokinetic properties of sodium pyragrel proven in this study, continued clinical development is warranted. The study was registered at http://www.chictr.org.cn (ChiCTR-IID-16010159).

背景与目的：通过血栓烷合成酶抑制剂抑制血栓形成与血小板聚集，已被证明是治疗心血管和/或脑血管疾病（CCVD）患者的有效且具有前景的手段。本项I期临床试验旨在评估新型血栓烷A2合成酶抑制剂吡格雷钠（sodium pyragrel）在健康志愿者中的安全性、耐受性及药代动力学特征。
方法：本研究共纳入84名健康中国志愿者，随机分为五种静脉给予吡格雷的给药方案，分别为单次递增剂量组（30 mg至300 mg）、多次给药组（第1天和第6天每日一次给予180 mg吡格雷，第2天至第5天每日两次给药）、3×3拉丁方交叉试验组（60 mg、120 mg、240 mg）以及持续给药组（24小时内给予360 mg）。采用高效液相色谱-串联质谱（HPLC-MS/MS）测定血浆药物浓度，通过非房室模型分析计算药代动力学参数。
结果：吡格雷的血浆峰浓度基本在3小时输注结束时达到。吡格雷及其两种主要代谢产物（BBS与BJS）的药代动力学过程在30 mg至300 mg的剂量范围内呈线性特征，多次给药未出现明显蓄积现象。吡格雷的尿排泄量占总给药量的70%以上。初步药效学结果显示，单次静脉给予吡格雷可呈时间和剂量依赖性抑制尿液11-脱氢血栓烷B2（11-D-HTXB2）的生成。
结论：单次递增剂量最高至300 mg、多次给予180 mg以及24小时内持续给药360 mg时，吡格雷均具有良好的耐受性。在本项分为五个部分的研究中，未发生与药物相关的严重不良药物反应。最常见的与吡格雷相关的不良事件（AEs）为总胆红素（TB）/直接胆红素（DB）升高，该不良反应发生率相对较低且似乎与给药剂量无关。鉴于本研究证实吡格雷钠具有可接受的安全性与良好的药代动力学特性，有必要继续推进其临床开发。本研究已在http://www.chictr.org.cn注册（ChiCTR-IID-16010159）。