Bronchopulmonary disposition of IV cefepime/taniborbactam (2–0.5 g) administered over 2 h in healthy adult subjects

Abstract Introduction Taniborbactam (formerly VNRX-5133) is an investigational β-lactamase inhibitor in clinical development in combination with cefepime for the treatment of MDR Gram-negative pathogens. Objectives To assess the safety profile and pulmonary disposition of 2–0.5 g cefepime/taniborbac...

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Published in:Journal of antimicrobial chemotherapy 2023-03, Vol.78 (3), p.703-709
Main Authors: Asempa, Tomefa E, Kuti, Joseph L, Nascimento, Jeffrey C, Pope, Samuel J, Salerno, Edward L, Troy, Patrick J, Nicolau, David P
Format: Article
Language:English
Subjects:
Adult
Anti-Bacterial Agents - pharmacology
Bronchoalveolar Lavage Fluid
Cefepime - pharmacology
Chromatography, Liquid
Humans
Original Research
Tandem Mass Spectrometry
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Summary:Abstract Introduction Taniborbactam (formerly VNRX-5133) is an investigational β-lactamase inhibitor in clinical development in combination with cefepime for the treatment of MDR Gram-negative pathogens. Objectives To assess the safety profile and pulmonary disposition of 2–0.5 g cefepime/taniborbactam administered as a 2 h IV infusion every 8 h following three doses in healthy adult subjects. Methods In this Phase 1 trial, open-label study, plasma samples were collected over the last dosing interval, and subjects (n = 20) were randomized to undergo bronchoalveolar lavage (BAL) at four timepoints after the last dose. Drug concentrations in plasma (total and free as determined by protein binding), BAL fluid and alveolar macrophages (AM) were determined by LC-MS/MS, and the urea correction method was used to calculate epithelial lining fluid (ELF) drug concentrations. Pharmacokinetic parameters were estimated by non-compartmental analysis. Results Mean (±SD) taniborbactam Cmax and AUC0–8 in plasma were 24.1 ± 4.1 mg/L and 81.9 ± 13.9 mg·h/L, respectively. Corresponding values for cefepime were 118.4 ± 29.7 mg/L and 346.7 ± 71.3 mg·h/L. Protein binding was 0% for taniborbactam and 22.4% for cefepime. Mean taniborbactam concentrations (mg/L) at 2, 4, 6 and 8 h were 3.9, 1.9, 1.0 and 0.3 in ELF and 12.4, 11.5, 14.3 and 14.9 in AM, with corresponding AUC0–8 ELF of 13.8 and AUC0–8 AM of 106.0 mg·h/L. Cefepime AUC0–8 ELF was 77.9 mg·h/L. No serious adverse events were observed. Conclusion The observed bronchopulmonary exposures of taniborbactam and cefepime can be employed to design optimal dosing regimens for clinical trials in patients with pneumonia.
ISSN:0305-7453
1460-2091
DOI:10.1093/jac/dkac447