title: Safety, pharmacokinetics and pharmacodynamics of four-hour intravenous infusions of eritoran in healthy Japanese and Caucasian men.
abstract: Eritoran, a synthetic analogue of lipid A, has been shown to bind to TLR4/MD-2 complex and thereby block the interaction of endotoxins with TLR4. We report here the results of a study conducted to assess the single-dose safety and tolerability, as well as the pharmacokinetics and pharmacodynamics, of eritoran infusion in Japanese and Caucasian healthy adult men. Sixty-four men (aged 20-45 years; body mass index 18-30 kg/m(2)) were randomized into four groups: 4-mg total dose (six Japanese and six Caucasian men); 12-mg total dose (12 Japanese and 12 Caucasian men); 28-mg total dose (six Japanese and six Caucasian men); and placebo (eight Japanese and eight Caucasian men). Eritoran in single doses up to 28 mg over 4 h was well tolerated, with no apparent ethnic differences noted. Plasma concentrations were slightly higher in Japanese versus Caucasian men; these differences were not significant after adjustment for differences in body mass (clearance: approximately 1.2 ml/h/kg; volume of distribution at steady state: approximately 0.07 l/kg). The ex vivo endotoxin inhibitory activity of eritoran was similar in Japanese and Caucasian men. The data do not indicate any need for clinical dose adjustment for possible ethnic-based differences in drug distribution or metabolism.
authors.affiliation: Emergency and Critical Care Medicine, School of Medicine, Keio University, Tokyo, Japan. aikawa7@rc4.so-net.ne.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Aikawa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okubo
authors.forename: Melvyn
authors.initials: M
authors.lastname: Lynn
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Rossignol
authors.forename: Y Nancy
authors.initials: YN
authors.lastname: Wong
authors.forename: Edgar
authors.initials: E
authors.lastname: Schuck
authors.forename: Yasumi
authors.initials: Y
authors.lastname: Kitahara
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nakano
authors.forename: Olena
authors.initials: O
authors.lastname: Sivak
authors.forename: Kishor M
authors.initials: KM
authors.lastname: Wasan
authors.forename: Christa
authors.initials: C
authors.lastname: Nagy
authors.forename: Mark
authors.initials: M
authors.lastname: Yen
mesh_terms: D000328:Adult; D044466:Asian People; D004187:Disaccharides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004731:Endotoxins / Q000037:antagonists & inhibitors; D006801:Humans; D007262:Infusions, Intravenous; D007564:Japan; D008050:Lipid A / Q000031:analogs & derivatives; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000187:drug effects; D013403:Sugar Phosphates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D044465:White People; D055815:Young Adult
chemical_list: D004187:Disaccharides; D004731:Endotoxins; D008050:Lipid A; D013403:Sugar Phosphates; D051197:Toll-Like Receptor 4; C512420:eritoran