Tolerability and pharmacokinetics of TB-402 in healthy male volunteers

Abstract Background: TB-402, a human monoclonal antibody that partially inhibits Factor VIII activity (FVIII:C), is being developed as a long-acting antithrombotic agent. Objectives: The primary goal of this study was to investigate the tolerability of TB-402 in healthy male volunteers. Secondary ob...

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Bibliographic Details
Published in:Clinical therapeutics 2010-06, Vol.32 (6), p.1205-1220
Main Authors: Verhamme, Peter, MD, PhD, Pakola, Steve, MD, Jensen, Thomas J., MD, PhD, Berggren, Kristina, PhD, Sonesson, Elisabeth, PhD, Saint-Remy, Jean-Marie, MD, PhD, Balchen, Torben, MSc, Belmans, Ann, MSc, Cahillane, Geraldine, BA, Stassen, Jean-Marie, PhD, Peerlinck, Kathelijne, MD, PhD, Glazer, Steven, MD, Jacquemin, Marc, MD, PhD
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Antibodies, Monoclonal - adverse effects
Antibodies, Monoclonal - pharmacokinetics
Antibodies, Monoclonal - pharmacology
Anticoagulants - adverse effects
Anticoagulants - pharmacokinetics
Anticoagulants - pharmacology
antithrombotic
Area Under Curve
Biological and medical sciences
Dose-Response Relationship, Drug
Double-Blind Method
Factor VIII
Factor VIII - antagonists & inhibitors
Half-Life
Hemorrhage - chemically induced
Humans
Internal Medicine
long-acting anticoagulant
Male
Medical Education
Medical sciences
Metabolic Clearance Rate
Middle Aged
Pharmacology. Drug treatments
TB-402
Young Adult
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Summary:Abstract Background: TB-402, a human monoclonal antibody that partially inhibits Factor VIII activity (FVIII:C), is being developed as a long-acting antithrombotic agent. Objectives: The primary goal of this study was to investigate the tolerability of TB-402 in healthy male volunteers. Secondary objectives were to determine the pharmacokinetics and pharmacodynamics of TB-402. Methods: In this ascending-dose study, healthy subjects aged 18 to 45 years were randomly assigned in a 2:1 ratio to receive TB-402 administered as a single intravenous bolus at 0.015, 0.1, 0.5, 2.5, 12.5, 37.5, 188, 620, or 1860 μg/kg or matching inactive vehicle (placebo). An older group (55–75 years) was also administered the highest dose that was well tolerated in the younger group (1860 μg/kg). Adverse events (AEs) were obtained from spontaneous reporting and from answers to nonleading questions asked by the principal investigator and study staff during follow-up visits on days 4, 7 (±1 day), 14 (±1 day), 21 (±2 days), 28 (±3 days), 42 (±3 days), and 56 (±3 days) after TB-402 administration. AEs were monitored up to the last study visit on day 56 after the administration of TB-402 or placebo, with special attention to bleeding events. The pharma-codynamic assessment of TB-402 included changes in FVIII:C, activated partial thromboplastin time (APTT), and prothrombin time (PT). Results: The study enrolled 56 subjects (mean ages: younger group, 28 years [range, 20–45 years]; older group, 65 years [range, 58–76 years]; weight, 79 kg [range, 60–104 kg] and 81 kg [range, 64–94 kg], re-spectively). Thirty-one of the 38 subjects who received TB-402 (82%) experienced a total of 85 treatmentemergent AEs (TEAEs), and 14 of 18 subjects who received placebo (78%) experienced 35 TEAEs. A total of 34 bleeding events were reported in 13 of 38 subjects (34%) who received TB-402 and 7 of 18 subjects (39%) who received placebo. Most common AEs reported in subjects who received TB-402 were headache (11 [29%]), vessel puncture-site hematoma (7 [18%]), and traumatic hematoma (5 [13%]); with placebo, these AEs were vessel puncture-site hematoma (4 [22%]), headache (3 [17%]), vasovagal reaction (3 [17%]), and hematuria (3 [17%]). No serious AEs considered to be related to TB-402 were reported, and no dose-dependent increases in bleeding events were observed. On pharmacokinetic analysis of TB-402, the t1/2 values across doses were 22.9 days (age 18–45 years) and 19.5 days (age 55–75 years). TB-402 was a
ISSN:0149-2918
1879-114X
DOI:10.1016/j.clinthera.2010.06.012