Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers

P Lyden, H Levy, S Weymer, K Pryor… - Current …, 2013 - ingentaconnect.com
P Lyden, H Levy, S Weymer, K Pryor, W Kramer, JH Griffin, TP Davis, B Zlokovic
Current pharmaceutical design, 2013ingentaconnect.com
Background and Purpose. 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.
Methods. 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 …
Background and Purpose
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.
Methods
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.
Results
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 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.
Conclusions
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
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