A single dose, three-arm, placebo-controlled, phase I study of the bradykinin B2 receptor antagonist Anatibant (LF16-0687Ms) in patients with severe traumatic brain injury.

Abstract

Traumatic brain injury (TBI) mortality and morbidity remains a public health challenge. Because experimental studies support an important role of bradykinin (BK) in the neurological deterioration that follows TBI, a double-blind, randomized, placebo-controlled study of Anatibant (LF16- 0687Ms), a selective and potent antagonist of the BK B(2) receptor, was conducted in severe (Glasgow Coma Scale [GCS] < 8) TBI patients (n = 25) at six sites in the United States. At 8-12 h after injury (9.9 +/- 2.8 h), patients received a single subcutaneous injection of Anatibant (3.75 mg or 22.5 mg, n = 10 each) or placebo (n = 5). The primary objective was to investigate the pharmacokinetics of Anatibant; general safety, local tolerability, levels of the bradykinin metabolite BK1-5 in plasma and cerebrospinal fluid (CSF), intracranial pressure (ICP), and cerebral perfusion pressure were also assessed. We observed a dose-proportionality of the pharmacokinetics, Cmax, and AUC of Anatibant. V(d)/F, Cl/F, and t(1/2) were independent on the dose and protein binding was >97.7%. Anatibant, administered as single subcutaneous injections of 3.75 g and 22.5 mg, was well tolerated in severe TBI patients with no unexpected clinical adverse events or biological abnormalities observed. Interestingly, plasma and CSF levels of BK1-5 were significantly and markedly increased after trauma (e.g., 34,700 +/- 35,300 fmol/mL in plasma vs. 34.9 +/- 5.6 fmol/mL previously reported for normal volunteers), supporting the use of Anatibant as a treatment of secondary brain damage. To address this issue, a dose-response trial that would investigate the effects of Anatibant on the incidence of raised ICP and on functional outcome in severe TBI patients is needed.

• Authors: Anthony Marmarou, Martine Guy, Laine Murphey, Francis Roy, Laure Layani, Jean-Philippe Combal, Claude Marquer, American Brain Injury Consortium
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 22 Issue 12 Pg. 1444-55 (Dec 2005) ISSN: 0897-7151 [Print] United States
• PMID: 16379582 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Bradykinin B2 Receptor Antagonists
• LF 16-0687
• Peptide Fragments
• Quinolines
• bradykinin (1-5)
• Bradykinin

Topics

• Adolescent
• Adult
• Aged
• Area Under Curve
• Bradykinin (blood, cerebrospinal fluid, drug effects)
• Bradykinin B2 Receptor Antagonists
• Brain Injuries (drug therapy)
• Double-Blind Method
• Female
• Glasgow Outcome Scale
• Half-Life
• Humans
• Male
• Middle Aged
• Peptide Fragments (blood, cerebrospinal fluid, drug effects)
• Pilot Projects
• Quinolines (adverse effects, pharmacokinetics)