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 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
Keywords: Protein C, coagulation, Activated protein C, PAR1, pharmaco-kinetics, clinical trials, humans.
Current Pharmaceutical Design
Title:Phase 1 Safety, Tolerability and Pharmacokinetics of 3K3A-APC in Healthy Adult Volunteers
Volume: 19 Issue: 42
Author(s): Patrick Lyden, Howard Levy, Sara Weymer, Kent Pryor, William Kramer, John H. Griffin, Thomas P. Davis and Berislav Zlokovic
Affiliation:
Keywords: Protein C, coagulation, Activated protein C, PAR1, pharmaco-kinetics, clinical trials, humans.
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 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
Export Options
About this article
Cite this article as:
Lyden Patrick, Levy Howard, Weymer Sara, Pryor Kent, Kramer William, Griffin H. John, Davis P. Thomas and Zlokovic Berislav, Phase 1 Safety, Tolerability and Pharmacokinetics of 3K3A-APC in Healthy Adult Volunteers, Current Pharmaceutical Design 2013; 19 (42) . https://dx.doi.org/10.2174/1381612819666131230131454
DOI https://dx.doi.org/10.2174/1381612819666131230131454 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Sex Steroid Hormone Effects in Normal and Pathologic Conditions in Lung Physiology
Mini-Reviews in Medicinal Chemistry Modeling Oxidative Stress in the Central Nervous System
Current Molecular Medicine Impact of Curcumin on Traumatic Brain Injury and Involved Molecular Signaling Pathways
Recent Patents on Food, Nutrition & Agriculture Therapeutic Targeting of TRPV1 by Resiniferatoxin, from Preclinical Studies to Clinical Trials
Current Topics in Medicinal Chemistry Neuroinflammation as a Common Mechanism Associated with the Modifiable Risk Factors for Alzheimer’s and Parkinson’s Diseases
Current Aging Science Editorial [Hot Topic: Auditory Processing Disorder (Guest Editors: Vasiliki Maria Iliadou)]
Current Pediatric Reviews A Magnetic Resonance Spectroscopy Study of Lovastatin for Treating Bipolar Mood Disorder: A 4-Week Randomized Double-Blind, Placebo- Controlled Clinical Trial
Recent Patents on Inflammation & Allergy Drug Discovery A Therapeutic Target of Cerebral Hemorrhagic Stroke: Matrix Metalloproteinase- 9
Current Drug Targets A Fatal Case of Acute Interstitial Pneumonia (AIP) in a Woman Affected by Glioblastoma
Current Drug Safety Structure-Based Design, Synthesis and Molecular Modeling Studies of Thiazolyl Urea Derivatives as Novel Anti-Parkinsonian Agents
Medicinal Chemistry A Clinician’s Guide to Monoamine Oxidase Inhibitors
Current Psychiatry Reviews Emerging Role of NF-κB in the Pathogenesis of Hepatic Encephalopathy
Current Signal Transduction Therapy Neurodegeneration with Dementia: From Fundamentals of Pathology to Clinical Imaging by MRI and SPECT.
Current Medical Imaging Homology-Based Design for Selective GSK-3 Peptide Inhibitors: Patent Applications and Type 2 Diabetes Mellitus
Current Signal Transduction Therapy Impact of HIV on Regional & Cellular Organisation of the Brain
Current HIV Research The Design of Experiment Approach, Rheology for Optimization of a Topical Anti-inflammatory and Analgesic Cream
Current Drug Delivery The Potential Applications of Stem Cells for Cancer Treatment
Current Stem Cell Research & Therapy Insights Into the Molecular Aspects of Neuroprotective Bacoside A and Bacopaside I
Current Neuropharmacology Synthesis and Biological Activities of Naturally Functionalized Polyamines: An Overview
Current Medicinal Chemistry The Infectious Etiology of Alzheimer’s Disease
Current Neuropharmacology