Plasma and Intrapulmonary Concentrations of Tebipenem following Oral Administration of Tebipenem Pivoxil Hydrobromide to Healthy Adult Subjects

Abstract

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug being developed for the treatment of serious bacterial infections. The active moiety, tebipenem, has broad-spectrum activity against common Enterobacterales pathogens, including extended-spectrum-β-lactamase (ESBL)-producing multidrug-resistant strains. This study evaluated the intrapulmonary pharmacokinetics (PK) and epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations of tebipenem relative to plasma levels in nonsmoking, healthy adult subjects. Thirty subjects received oral TBP-PI-HBr at 600 mg every 8 h for five doses. Serial blood samples were collected following the last dose. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) 1, 2, 4, 6, or 8 h after the fifth dose of TBP-PI-HBr. The tebipenem area under the concentration-time curve for the 8-h dosing interval (AUC0-8) values in plasma, ELF, and AMs were calculated using the mean concentration at each BAL sampling time. Ratios of AUC0-8 values for total ELF and AMs to those for unbound plasma were determined, using a plasma protein binding value of 42%. Mean values ± standard deviations (SD) of tebipenem maximum (Cmax) and minimum (Cmin) total plasma concentrations were 11.37 ± 3.87 mg/L and 0.043 ± 0.039 mg/L, respectively. Peak tebipenem concentrations in plasma, ELF, and AMs occurred at 1 h and then decreased over 8 h. Ratios of tebipenem AUC0-8 values for ELF and AMs to those for unbound plasma were 0.191 and 0.047, respectively. Four (13.3%) subjects experienced adverse events (diarrhea, fatigue, papule, and coronavirus disease 2019 [COVID-19]); all resolved, and none were severe or serious. Tebipenem is distributed into the lungs of healthy adults, which supports the further evaluation of TBP-PI-HBr for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT04710407.).

Keywords: SPR859; SPR994; alveolar macrophages; epithelial lining fluid; pharmacokinetics; tebipenem.

Conflict of interest statement

The authors declare a conflict of interest. K.A.R. and M.H.G. are consultants to Spero Therapeutics. All other authors are employees of Spero Therapeutics, Cambridge, Massachusetts, USA.

Figures

FIG 1

Mean (±SD) plasma concentration-versus-time profile of tebipenem with the fifth oral dose of tebipenem pivoxil hydrobromide administered at 600 mg every 8 h.

FIG 2

Individual concentrations of tebipenem in plasma (circles), epithelial lining fluid (ELF) (triangles), and alveolar macrophages (AM) (squares) 1, 2, 4, 6, and 8 h after the fifth oral dose of tebipenem pivoxil hydrobromide administered at 600 mg every 8 h. The filled symbols represent male subjects, and the open symbols are female subjects. The lines represent the median concentrations. The y axis is on a semilog scale.

FIG 3

Mean plasma (total), plasma (unbound), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations (±SD) of tebipenem after the fifth oral dose of tebipenem pivoxil hydrobromide administered at 600 mg every 8 h. The y axis is on a semilog scale.