Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Meropenem-RPX7009 in 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/RPX7009 2 g administered every 8 hours, as a 3-hour intravenous (IV) 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 hours after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. Mean (± standard deviation) pharmacokinetic parameters of meropenem and RPX7009 determined from serial plasma concentrations were: C_max 58.2 ± 10.8 and 59.0 ± 8.4 μg/mL, V_ss 16.3 ± 2.6 and 17.6 ± 2.6 L, CL 11.1 ± 2.1 and 10.1 ± 1.9 L/h, and T_1/2 1.03 ± 0.15 and 1.27 ± 0.21 hours, respectively. The intrapulmonary penetration of meropenem and RPX7009 were approximately 63% and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 hours (AUC_0-8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetration was 65% and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AM were below the quantitative limit of detection whereas median concentrations of RPX7009 in AM ranged 2.35 to 6.94 μg/mL. The results from this study lend support to exploring a fixed combination of meropenem 2 g/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.