Penetration of GSK1322322 into epithelial lining fluid and alveolar macrophages as determined by bronchoalveolar lavage

Odin J Naderer, Keith A Rodvold, Lori S Jones, John Z Zhu, Chester L Bowen, Liangfu Chen, Etienne Dumont, Odin J Naderer, Keith A Rodvold, Lori S Jones, John Z Zhu, Chester L Bowen, Liangfu Chen, Etienne Dumont

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.).

Figures

FIG 1
FIG 1
Individual measured concentrations of GSK1322322 in plasma (total), epithelial lining fluid (ELF), and alveolar macrophages (AM) at 2, 6, and 12 h. The y axis is in log scale.
FIG 2
FIG 2
Mean (± SD) concentration-versus-time profiles of GSK1322322 in plasma (unbound), epithelial lining fluid (ELF), and alveolar macrophages (AM) after repeat intravenous dosing of 1,500 mg twice daily. Closed circles represent unbound plasma, open triangles represent ELF, and gray squares represent AM. The y axis is in log scale.

Source: PubMed

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