Lyden Patrick, Levy Howard, Weymer Sara, Pryor Kent, Kramer William, Griffin John H, Davis Thomas P, Zlokovic Berislav
Department of Neurology, 8700 Beverly Blvd, Los Angeles, CA 90048.
Curr Pharm Des. 2013;19(42):7479-85. doi: 10.2174/1381612819666131230131454.
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 randomly assigned to receive 3K3A-APC (n=4) at 6, 30, 90, 180, 360, 540 or 720 µg/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 µg/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 µg/kg so 540 µg/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 µg/kg. These results should be confirmed in stroke patients with relevant co-morbidities. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660230.
活化蛋白C（APC）通过蛋白酶激活受体-1（PAR-1）刺激多种细胞保护途径并促进抗凝作用。3K3A-APC旨在保留在PAR-1上的活性，同时降低抗凝作用。这项1期试验对3K3A-APC的药代动力学和抗凝效果进行了表征。
受试者（n = 64）被随机分配接受6、30、90、180、360、540或720μg/kg的3K3A-APC（n = 4）或安慰剂（n = 6），并观察24小时。经过安全性评估后，额外的受试者每12小时接受一次药物，共5剂（每组n = 6），剂量为90、180、360或540μg/kg或安慰剂（n = 8），并观察24小时。
所有受试者均在72小时和15天时返回进行安全性评估。我们发现所有组中不良事件较少。活性组和安慰剂组的收缩压均升高。接受720μg/kg治疗的两名受试者中有一名报告了中度严重的头痛、恶心和呕吐，因此540μg/kg被认为是最高耐受剂量。平均血浆浓度与剂量成比例增加。清除率范围为11,693±807至18,701±4,797 mL/小时，分布容积范围为4,873±828至6,971±1,169 mL，消除半衰期范围为0.211±0.097至0.294±0.054小时。活化部分凝血活酶时间（aPTT）的升高最小。
高达540μg/kg的多剂量3K3A-APC耐受性良好。这些结果应在患有相关合并症的中风患者中得到证实。临床试验注册-网址：http://www.clinicaltrials.gov。唯一标识符：NCT01660230。
