Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers.
Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers.
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DOI：
10.2174/1381612819666131230131454
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发表时间：
2013
影响因子：
3.1
通讯作者：
Zlokovic B
中科院分区：
文献类型：
--
作者：
Lyden P;Levy H;Weymer S;Pryor K;Kramer W;Griffin JH;Davis TP;Zlokovic B
活化蛋白C （Activated Protein C， APC）通过蛋白酶活化受体-1 （PAR-1）刺激多种细胞保护途径，促进抗凝。3K3A-APC设计用于保留PAR-1的活性，降低抗凝作用。该1期试验表征了3K3A-APC的药代动力学和抗凝作用。受试者（n=64）随机分配接受6、30、90、180、360、540或720 g/kg剂量的3K3A-APC （n=4）或安慰剂（n=6），观察24小时。在安全性审查后，额外的受试者每12小时接受5次剂量的药物治疗（n=6 /组），剂量分别为90、180、360或540 g/kg或安慰剂（n=8），并观察24小时。所有受试者在72小时和15天内返回进行安全性评估。我们发现所有组的不良事件都很少。活跃组和安慰剂组的收缩压都有所升高。在接受720 g/kg剂量治疗的两名受试者中，有一人报告出现中度严重头痛、恶心和呕吐，因此540 g/kg被认为是最高耐受剂量。平均血浆浓度随剂量成比例增加。清除率为11,693±807 ~ 18,701±4,797 mL/hr，分布体积为4,873±828 ~ 6,971±1,169 mL，消除半衰期为0.211±0.097 ~ 0.294±0.054小时。aPTT的升高很小。3K3A-APC在高达540 g/kg的多次剂量下耐受性良好。这些结果应该在卒中患者的相关合并症中得到证实。临床试验注册- url: http://www.clinicaltrials.gov.Unique标识符：NCT01660230
Activated Protein C (APC) stimulates multiple cytoprotective pathways via the protease activated receptor-1 (PAR-1) and promotes anticoagulation. 3K3A-APC was designed for preserved activity at PAR-1 with reduced anticoagulation. This Phase 1 trial characterized pharmacokinetics and anticoagulation effects of 3K3A-APC. Subjects (n=64) were ran- domly assigned to receive 3K3A-APC (n=4) at 6, 30, 90, 180, 360, 540 or 720 g/kg or placebo (n=6) and were observed for 24 hr. After safety review additional subjects received drug every 12 hr for 5 doses (n=6 per group) at 90, 180, 360, or 540 g/kg or placebo (n=8) and were observed for 24 hr. All subjects returned for safety assessments at 72 hours and 15 days. We found few adverse events in all groups. Systolic blood pressure increased in both active and placebo groups. Moderately severe headache, nausea and vomiting were reported in one of two subjects treated with 720 g/kg so 540 g/kg was considered the highest tolerated dose. Mean plasma concentrations increased in proportion to dose. Clearance ranged from 11,693 ± 807 to 18,701 ± 4,797 mL/hr, volume of distribution ranged from 4,873±828 to 6,971 ± 1,169 mL, and elimination half-life ranged from 0.211 ± 0.097 to 0.294 ± 0.054 hours. Elevations in aPTT were minimal. 3K3A-APC was well tolerated at multiple doses as high as 540 g/kg. These results should be confirmed in stroke patients with relevant co-morbidities. Clinical Trial Registration-Url: http://www.clinicaltrials.gov.Unique identifier: NCT01660230