Meropenem-RPX7009 Concentrations in Plasma, Epithelial Lining Fluid, and Alveolar Macrophages of Healthy Adult Subjects

• Published in: Antimicrobial agents and chemotherapy Vol. 59; no. 12; pp. 7232 - 7239
• Main Authors: Wenzler, Eric, Gotfried, Mark H., Loutit, Jeffrey S., Durso, Stephanie, Griffith, David C., Dudley, Michael N., Rodvold, Keith A.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.12.2015
• Subjects: Adult; Anti-Bacterial Agents; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Area Under Curve; Boronic Acids; Boronic Acids - blood; Boronic Acids - pharmacokinetics; Bronchoalveolar Lavage Fluid - chemistry; Bronchoscopy; Drug Administration Schedule; Drug Combinations; Female; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds, 1-Ring - blood; Heterocyclic Compounds, 1-Ring - pharmacokinetics; Humans; Lung; Lung - chemistry; Lung - drug effects; Lung - metabolism; Macrophages, Alveolar; Macrophages, Alveolar - chemistry; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - metabolism; Male; Middle Aged; Pharmacology; Respiratory Mucosa; Respiratory Mucosa - chemistry; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Thienamycins; Thienamycins - blood; Thienamycins - pharmacokinetics
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01713-15

The steady-state concentrations of meropenem and the β-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows: C max = 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml, V ss = 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, and t 1/2 = 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC 0–8 ) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 μg/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.