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

Patrick Lyden, Howard Levy, Sara Weymer, Kent Pryor, William Kramer, John H. Griffin, Thomas P Davis, Berislav Zlokovic

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 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. 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 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. Conclusions. 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.

Original languageEnglish (US)
Pages (from-to)7479-7485
Number of pages7
JournalCurrent Pharmaceutical Design
Volume19
Issue number42
DOIs
StatePublished - 2013

Fingerprint

Protein C
Healthy Volunteers
Pharmacokinetics
Safety
PAR-1 Receptor
Placebos
Blood Pressure
Nausea
Vomiting
Headache
Half-Life
Stroke
Clinical Trials
Morbidity
Pharmaceutical Preparations

Keywords

  • Activated protein C
  • Clinical trials
  • Coagulation
  • Humans
  • PAR1
  • Pharmaco-kinetics
  • Protein C

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

Lyden, P., Levy, H., Weymer, S., Pryor, K., Kramer, W., Griffin, J. H., ... Zlokovic, B. (2013). Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Current Pharmaceutical Design, 19(42), 7479-7485. https://doi.org/10.2174/1381612819666131230131454

Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. / Lyden, Patrick; Levy, Howard; Weymer, Sara; Pryor, Kent; Kramer, William; Griffin, John H.; Davis, Thomas P; Zlokovic, Berislav.

In: Current Pharmaceutical Design, Vol. 19, No. 42, 2013, p. 7479-7485.

Research output: Contribution to journalArticle

Lyden, P, Levy, H, Weymer, S, Pryor, K, Kramer, W, Griffin, JH, Davis, TP & Zlokovic, B 2013, 'Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers', Current Pharmaceutical Design, vol. 19, no. 42, pp. 7479-7485. https://doi.org/10.2174/1381612819666131230131454
Lyden, Patrick ; Levy, Howard ; Weymer, Sara ; Pryor, Kent ; Kramer, William ; Griffin, John H. ; Davis, Thomas P ; Zlokovic, Berislav. / Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. In: Current Pharmaceutical Design. 2013 ; Vol. 19, No. 42. pp. 7479-7485.
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AU - Griffin, John H.

AU - Davis, Thomas P

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AB - 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 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. 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 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. Conclusions. 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.

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