title: Penetration of GSK1322322 into epithelial lining fluid and alveolar macrophages as determined by bronchoalveolar lavage.
abstract: GSK1322322 is a potent peptide deformylase inhibitor with in vitro and in vivo activity against multidrug-resistant skin and respiratory pathogens. This report provides plasma and intrapulmonary pharmacokinetics, safety, and tolerability of GSK1322322 after repeat (twice daily intravenous dosing for 4 days) dosing at 1,500 mg. Plasma samples were collected over the last 12-hour dosing interval of repeat dosing following the day 4 morning dose (the last dose). Bronchoalveolar lavage samples were collected once in each subject, either before or at 2 or 6 h after the last intravenous dose. Plasma area under the concentration-time curve (AUC0-τ) was 66.7 μg · h/ml, and maximum concentration of drug in serum (Cmax) was 25.4 μg/ml following repeat doses of intravenous GSK1322322. The time course of epithelial lining fluid (ELF) and alveolar macrophages (AM) mirrored the plasma concentration-time profile. The AUC0-τ for ELF and AM were 78.9 μg · h/ml and 169 μg · h/ml, respectively. The AUC0-τ ratios of ELF and AM to total plasma were 1.2 and 2.5, respectively. These ratios increased to 3.5 and 7.4, respectively, when unbound plasma was considered. These results are supportive of GSK1322322 as a potential antimicrobial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under registration number NCT01610388.).
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Odin J
authors.initials: OJ
authors.lastname: Naderer
authors.forename: Keith A
authors.initials: KA
authors.lastname: Rodvold
authors.forename: Lori S
authors.initials: LS
authors.lastname: Jones
authors.forename: John Z
authors.initials: JZ
authors.lastname: Zhu
authors.forename: Chester L
authors.initials: CL
authors.lastname: Bowen
authors.forename: Liangfu
authors.initials: L
authors.lastname: Chen
authors.forename: Etienne
authors.initials: E
authors.lastname: Dumont
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018893:Bronchoalveolar Lavage; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012141:Respiratory Tract Infections; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C583947:GSK1322322; D006877:Hydroxamic Acids