title: Intrapulmonary pharmacokinetics of GSK2251052 in healthy volunteers.
abstract: The plasma and intrapulmonary pharmacokinetics (PK) of intravenous (i.v.) GSK2251052, a novel boron-containing antimicrobial, were evaluated in healthy adult subjects. Thirty subjects underwent bronchoscopy and timed bronchoalveolar lavage (BAL) either following a single dose (cohort 1) or after 5 twice-daily doses (cohort 2) of 1,500 mg GSK2251052 i.v. Serial PK and safety assessments were obtained throughout the study. Bronchoscopy was performed on a single occasion in each subject at 2, 6, or 12 h after start of infusion. Noncompartmental analysis was performed to calculate PK parameters. Thirty subjects completed the study. The mean clearance (CL), volume of distribution at steady state (Vss), and half-life (t1/2) values were 22 liters/h, 231 liters, and 10.7 h, respectively. Approximately 30% of the dose was excreted unchanged in urine. The GSK2251052 concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) were approximately 50% and 500 to 600%, respectively, compared to the concentration in plasma. the GSK2251052 exposures in ELF and AM were comparable following single- and repeat-dose administration. The most frequently reported drug-related adverse event (AE) was mild to moderate infusion site reactions (7 subjects) that occurred primarily in the repeat-dose cohort. No serious drug-related AEs or clinically significant trends in laboratory values, vital signs, or electrocardiograms were observed. GSK2251052 given as a 1,500-mg infusion was generally tolerated following single- or repeat-dose administration. GSK2251052 distributes into both the ELF and AM of healthy volunteers, which supports further study in patients with pneumonia.
authors: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors: David
authors: D
authors: Tenero
authors: Gary
authors: G
authors: Bowers
authors: Keith A
authors: KA
authors: Rodvold
authors: Apurva
authors: A
authors: Patel
authors: Milena
authors: M
authors: Kurtinecz
authors: Etienne
authors: E
authors: Dumont
authors: John
authors: J
authors: Tomayko
authors: Parul
authors: P
authors: Patel
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001896:Boron Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018893:Bronchoalveolar Lavage; D001999:Bronchoscopy; D005260:Female; D006207:Half-Life; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000188:drug therapy; D011446:Prospective Studies; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: C583949:3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole; D000900:Anti-Bacterial Agents; D001896:Boron Compounds
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