title: 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.affiliation: American Brain Injury Consortium, ABIC Technical Center, Old City Hall Suite 235, 1001 East Broad Street, Richmond, VA 23298-0449, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Marmarou
authors.forename: Martine
authors.initials: M
authors.lastname: Guy
authors.forename: Laine
authors.initials: L
authors.lastname: Murphey
authors.forename: Francis
authors.initials: F
authors.lastname: Roy
authors.forename: Laure
authors.initials: L
authors.lastname: Layani
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Combal
authors.forename: Claude
authors.initials: C
authors.lastname: Marquer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001920:Bradykinin / Q000097:blood / Q000134:cerebrospinal fluid / Q000187:drug effects; D065094:Bradykinin B2 Receptor Antagonists; D001930:Brain Injuries / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D023261:Glasgow Outcome Scale; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid / Q000187:drug effects; D010865:Pilot Projects; D011804:Quinolines / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; C403051:LF 16-0687; D010446:Peptide Fragments; D011804:Quinolines; C079000:bradykinin (1-5); D001920:Bradykinin