title: Evaluation of the safety, tolerability, and pharmacokinetics of a single bolus injection of daptomycin in healthy Japanese subjects.
abstract: This was a phase I double-blind, randomized, placebo-controlled, 2-period, single-dose, crossover study in healthy Japanese subjects to evaluate the safety, tolerability, and pharmacokinetics of a single bolus injection of daptomycin. Twenty healthy subjects were randomized; 16 received a single intravenous (IV) administration of 6 mg/kg of daptomycin and 4 received a single intravenous administration of placebo (0.9% sodium chloride) by either bolus injection (10 s) or infusion (30 min) following an overnight fast in Periods 1 or 2. There was a minimum 5-day washout period from the administration in Period 1 to the administration in Period 2. Administration of a single bolus injection of daptomycin 6 mg/kg was generally well tolerated. The geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for AUC0-∞, AUC0-24 h, Cmax, and C24 h of daptomycin in plasma following bolus injection over 10 s relative to IV infusion over 30 min were 1.01 (1.00, 1.03), 1.02 (1.00, 1.03), 1.50 (1.41, 1.60) and 1.05 (1.02, 1.08), respectively. Because no existing studies of this nature were available, Cmax following daptomycin 6 mg/kg/10 s multiple-dose bolus injections was simulated. It was estimated at 178 μg/mL (upper limit) and was expected to be equal to or less than the confirmed Cmax in Japanese or non-Japanese healthy subjects following single- or multiple-dose IV infusion over 30 min. From the results of this study, daptomycin multiple-dose bolus injections over 10 s are expected well tolerated and to have similar Cmax values as IV infusion over 30 min, thus offering potential clinical benefit.
  
  
  BACKGROUND
  Because this was a phase I trial in healthy subjects, the trial was not registered.
authors.affiliation: Japan Development, MSD K.K., Kitanomaru Square, 1-13-12, Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan. Electronic address: ikuo.aoki@merck.com.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Aoki
authors.affiliation: Japan Development, MSD K.K., Urban Ace Kitahama Bldg, 2-7-3, Hiranomachi, Chuo-ku, Osaka 541-0046, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Japan Development, MSD K.K., Kitanomaru Square, 1-13-12, Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Wakana
authors.affiliation: Kitasato University Kitasato Institute Hospital (Former Name: Bio-Iatric Center, Kitasato Institute Research Center for Clinical Pharmacology), 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Aso
authors.affiliation: Japan Development, MSD K.K., Kitanomaru Square, 1-13-12, Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoshinari
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D017576:Daptomycin / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D007564:Japan; D008297:Male; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin
keywords: 10 s; Bolus injection; Daptomycin; Japanese; Pharmacokinetics; Safety