Meropenem-RPX7009 Concentrations in Plasma, Epithelial Lining Fluid, and Alveolar Macrophages of Healthy Adult Subjects.
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: Cmax = 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml, Vss = 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, and t1/2 = 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 (AUC0-8) 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.
College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
Eric
E
Wenzler
Pulmonary Associates, Phoenix, Arizona, USA.
Mark H
MH
Gotfried
The Medicines Company, San Diego, California, USA.
Jeffrey S
JS
Loutit
The Medicines Company, San Diego, California, USA.
Stephanie
S
Durso
The Medicines Company, San Diego, California, USA.
David C
DC
Griffith
The Medicines Company, San Diego, California, USA.
Michael N
MN
Dudley
College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA kar@uic.edu.
Keith A
KA
Rodvold
D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001897:Boronic Acids / Q000097:blood / Q000493:pharmacokinetics*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D001999:Bronchoscopy; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008168:Lung / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D020545:Respiratory Mucosa / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D013845:Thienamycins / Q000097:blood / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D001897:Boronic Acids; D004338:Drug Combinations; D006573:Heterocyclic Compounds, 1-Ring; C000599945:RPX7009; D013845:Thienamycins; D000077731:Meropenem