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

Abstract

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.

FIG 1

Mean (± the SD) concentration-versus-time profile of meropenem and RPX7009 in plasma (A) and epithelial lining fluid (B) before and after the third dose meropenem (2 g) and RPX7009 (2 g) administered as a 3-h i.v. infusion. In plate A, meropenem is illustrated by the filled circles and a solid line, and RPX7009 is illustrated by open circles and a dashed line. In plate B, meropenem is illustrated by the filled triangles and a solid line, and RPX7009 is illustrated by open triangles and a dashed line. Shaded region represents the 3-h infusion period. The y axis is in the log scale.

FIG 2

Individual concentrations of meropenem in plasma (A; ●) and epithelial lining fluid (ELF) (B; ▲) and RPX7009 in plasma (C; ○) and ELF (D; △) at 1.5, 3.25, 4, 6, and 8 h after the third dose of meropenem (2 g) and RPX7009 (2 g) administered as a 3-h i.v. infusion. The shaded region represents the 3-h infusion period. Solid and dashed lines represent the median concentrations in plasma and ELF, respectively. The y axis is in the log scale.

FIG 3

Individual concentrations of RPX7009 in alveolar macrophages (AM) (open squares) at 1.5, 3.25, 4, 6, and 8 h after the third dose of meropenem (2 g) and RPX7009 (2 g) administered as a 3-h i.v. infusion. The shaded region represents the 3-h infusion period. The solid line represents the median concentration in AM. The y axis is in the log scale.

FIG 4

Mean (± the SD) plasma (● and ○; solid line) and epithelial lining fluid (ELF) (▲ and △; dashed lines) concentration-versus-time profiles of meropenem (A) and RPX7009 (B) at 1.5, 3.25, 4, 6, and 8 h after the third dose of meropenem (2 g) and RPX7009 (2 g) administered as a 3-h i.v. infusion. The shaded region represents the 3-h infusion period. The y axis is in the log scale.