title: 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.
  
  
  OBJECTIVE
  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 microg/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 microg/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 treatment-emergent 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 t(1/2) values across doses were 22.9 days (age 18-45 years) and 19.5 days (age 55-75 years). TB-402 was associated with a reduction in FVIII:C over a period of approximately 48 hours in the d37.5-microg/kg dose groups. TB-402 was associated with a prolonged APTT at doses >or=2.5 microg/kg approximately 1.1-1.2-fold predose APTT). Administration of a higher dose of TB-402 was associated with an extended duration of APTT prolongation. No significant effect on PT was found.
  
  
  CONCLUSIONS
  In this study in healthy male volunteers, TB-402 was well tolerated in the population studied. Based on the findings from this study, the long t(1/2) of TB-402 may allow a pharmacodynamic effect over a prolonged period after single-dose administration. Further trials are needed to address the tolerability and efficacy of this agent in preventing thromboembolism. Clinicaltrials.gov identifier: NCT00612196.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium. peter.verhamme@med.kuleuven.be
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
authors.forename: Steve
authors.initials: S
authors.lastname: Pakola
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jensen
authors.forename: Kristina
authors.initials: K
authors.lastname: Berggren
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sonesson
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saint-Remy
authors.forename: Torben
authors.initials: T
authors.lastname: Balchen
authors.forename: Ann
authors.initials: A
authors.lastname: Belmans
authors.forename: Geraldine
authors.initials: G
authors.lastname: Cahillane
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Stassen
authors.forename: Kathelijne
authors.initials: K
authors.lastname: Peerlinck
authors.forename: Steven
authors.initials: S
authors.lastname: Glazer
authors.forename: Marc
authors.initials: M
authors.lastname: Jacquemin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005169:Factor VIII / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants; C559990:TB 402; D005169:Factor VIII