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

Abstract

The steady-state concentrations of meropenem and the ␤-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 g/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 g/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.

Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing

“…60 In the ceftolozane study of healthy volunteers, it is important to note the considerably lower degree of tazobactam penetration versus that observed in critically ill patients, 55-57 which could be ascribed to an increase in paracellular permeability that accompanies inflammation; 14 indeed, this study reported a demonstrably lower value for piperacillin as well (0.26). Counterintuitively, the opposite is found when considering meropenem, with lower ELF:plasma ratios reported for severely ill patients (~0.25) 61,62 versus healthy volunteers (0.65), 63 further indicating a critical need for antibiotic penetration studies in the target population. A singular study for ertapenem 64 in critically ill patients suggests an ELF:plasma ratio of 0.30, whereas studies of doripenem 65 and imipenem 66 in healthy individuals report values of ~0.34, and 0.44, respectively.…”

Resistance Trends and Treatment Options in Gram-Negative Ventilator-Associated Pneumonia

“…Mortality rates were also lower in patients treated with meropenem-varbobactam. Both meropenem and vaborbactam achieve ≥65% ELF:serum AUC ratios in healthy adults, suggestive of activity in HAP and VAP [72]. However, pharmacokinetic data from patients with VAP indicate that meropenem ELF:serum AUC ratios may be lower (median < 30%) and highly variable [132].…”

Recent advances in the rational design and optimization of antibacterial agents

“…Vaborbactam is currently undergoing phase 3 clinical trials in Europe for use in combination with meropenem (Carbavance™, Rempex Pharmaceuticals) for treatment of cUTI, HAP, VAP, & bacteremia caused by carbapenem-resistant Enterobacteriaceae. 64, 65 Vaborbactam has been extensively studied in combination with the investigational carbapenem RPX2003 (biapenem). 66, 67 The combination showed excellent activity against class A carbapenemase-producing Enterobacteriaceae , including KPC-producing strains of K. pneumoniae .…”