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

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Rizk ML, Rhee EG, Jumes PA, Gotfried MH, Zhao T, Mangin E, Bi S, Chavez-Eng CM, Zhang Z, Butterton JR

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

Antimicrob Agents Chemother. 2018 Feb 23;62(3). pii: AAC.01411-17. doi: 10.1128/AAC.01411-17. Print 2018 Mar.

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29311084 [ View in PubMed
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Abstract

This phase I study assessed the intrapulmonary pharmacokinetic profiles of relebactam (MK-7655), a novel beta-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.

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