Intrapulmonary Pharmacokinetics of Relebactam, a Novel β-Lactamase Inhibitor, Dosed in Combination with Imipenem-Cilastatin in Healthy Subjects

• Published in: Antimicrobial agents and chemotherapy Vol. 62; no. 3
• Main Authors: Rizk, Matthew L., Rhee, Elizabeth G., Jumes, Patricia A., Gotfried, Mark H., Zhao, Tian, Mangin, Eric, Bi, Sheng, Chavez-Eng, Cynthia M., Zhang, Zufei, Butterton, Joan R.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.03.2018
• Subjects: beta-Lactamase Inhibitors; Cilastatin; Cilastatin, Imipenem Drug Combination; Imipenem; Pharmacology; relebactam; intrapulmonary pharmacokinetics; healthy subjects; imipenem
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.01411-17

This phase I study assessed the intrapulmonary pharmacokinetic profiles of relebactam (MK-7655), a novel β-lactamase inhibitor, and imipenem. Sixteen healthy subjects received 250 mg relebactam with 500 mg imipenem-cilastatin, given intravenously every 6 h for 5 doses, and were randomized to bronchoscopy/bronchoalveolar lavage at 0.5, 1, 1.5, or 3 h after the last dose (4 subjects per time point). Both drugs penetrated the epithelial lining fluid (ELF) to a similar degree, with the profiles being similar in shape to the corresponding plasma profiles and with the apparent terminal half-lives in plasma and ELF being 1.2 and 1.3 h, respectively, for relebactam and 1.0 h in both compartments for imipenem. The exposure (area under the concentration-time curve from time zero to infinity) in ELF relative to that in plasma was 54% for relebactam and 55% for imipenem, after adjusting for protein binding. ELF penetration for relebactam was further analyzed by fitting the data to a two-compartment pharmacokinetic model to capture its behavior in plasma, with a partitioning coefficient capturing its behavior in the lung compartment. In this model, the time-invariant partition coefficient for relebactam was found to be 55%, based on free drug levels. These results support the clinical evaluation of relebactam with imipenem-cilastatin for the treatment of bacterial pneumonia.