This was a Phase 1, open-label, single-center Pharmacokinetic (PK) study to evaluate plasma and intrapulmonary pharmacokinetics (PK) of ceftibuten and ledaborbactam in healthy adult participants. Approximately 31 participants were planned to be enrolled in two groups, with approximately 25 in Group 1 and approximately six in Group 2.
In Group 1, participants were to receive a total of five oral doses of ceftibuten ledaborbactam etzadroxil (600 mg ceftibuten/600 mg ledaborbactam etzadroxil) every 12 hours. Following the fifth dose, each participant was to undergo one standardized bronchoscopy with bronchoalveolar lavage (BAL) at one of five designated timepoints (2, 4, 6, 8, and 12 hours), with five participants assigned to each timepoint. In Group 2, participants were to receive a total of five doses of 600 mg oral ceftibuten alone every 12 hours. After the last dose, each participant was to undergo one standardized bronchoscopy with BAL at one of two designated timepoints (4 and 12 hours), with three participants assigned to each timepoint. Blood samples to determine plasma concentrations of ceftibuten, ledaborbactam etzadroxil (Group 1 only), and urea were to be collected at the designated timepoints.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
34
Five doses of ledaborbactam etzadroxil administered orally every 12 hours
Five doses of ceftibuten administered orally every 12 hours
Pulmonary Associates
Phoenix, Arizona, United States
Intrapulmonary PK - AUC0-12 at Steady State in Group 1: Ceftibuten and Ledaborbactam Etzadroxil
The PK parameter AUC0-12 for ceftibuten and ledaborbactam etzadroxil was assessed by standardized bronchoscopy with bronchoalveolar lavage (BAL). BAL samples were collected from each participant at one of five designated time points (2, 4, 6, 8, and 12 hours). The first aspirate was collected separately (BAL 1), while the second through the fourth aspirates were pooled (BAL 2). Mean concentration values at each BAL sampling time point were determined, and data from all sampling times were combined into a single dataset to calculate the AUC0-12 value for each matrix. AUC 0-12 was estimated using Phoenix WinNonlin Non-compartmental analysis. Each participant only contributed one ELF concentration at one time point, so the pharmacokinetic parameters for ELF were calculated using the arithmetic mean concentration at each BAL sampling time point, resulting in a single parameter estimate of ELF across all participants.
Time frame: Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose
Plasma Maximum Concentration (Cmax) of Ceftibuten
The pharmacokinetic parameter (PK) Cmax of ceftibuten assessed at at steady-state.
Time frame: Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose
Plasma Area Under the Curve From Time Zero to 12 Hours (AUC0-12) for Ceftibuten
The PK parameter AUC0-12 for ceftibuten assessed at at steady-state.
Time frame: Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose
Plasma Maximum Concentration (Cmax) of Ledaborbactam Etzadroxil
The pharmacokinetic parameter (PK) Cmax of ledaborbactam etzadroxil assessed at at steady-state.
Time frame: Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose
Plasma AUC0-12h for Ledaborbactam Etzadroxil
The pharmacokinetic parameter (PK) AUC0-12h of ledaborbactam etzadroxil assessed at at steady-state.
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Time frame: Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose
Ratios of Drug Exposure for Ledaborbactam Etzadroxil and Ceftibuten
Drug penetration ratio of epithelial lining fluid (ELF) to unbound plasma were assessed using the AUC values for each matrix for BAL 1 and BAL 2. BAL samples were collected from each participant at one of five designated time points (2, 4, 6, 8, and 12 hours). The first aspirate was collected separately (BAL 1), while the second through the fourth aspirates were pooled (BAL 2). All pharmacokinetic parameters (PK) were estimated using Phoenix WinNonlin Non-compartmental analysis. Each participant only contributed one ELF concentration at one time point, so the PK parameters for ELF were calculated using the arithmetic mean concentration at each BAL sampling time point, resulting in a single parameter estimate of ELF across all participants.
Time frame: Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose
Ratios of Drug Exposure for Ceftibuten
Drug penetration ratio of epithelial lining fluid (ELF) to unbound plasma were assessed using the AUC values for each matrix for BAL 1 and BAL 2. BAL samples were collected from each participant at one of five designated time points (2, 4, 6, 8, and 12 hours). The first aspirate was collected separately (BAL 1), while the second through the fourth aspirates were pooled (BAL 2). All pharmacokinetic parameters (PK) were estimated using Phoenix WinNonlin Non-compartmental analysis. Each participant only contributed one ELF concentration at one time point, so the PK parameters for ELF were calculated using the arithmetic mean concentration at each BAL sampling time point, resulting in a single parameter estimate of ELF across all participants.
Time frame: Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose
Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) After Administration of Ceftibuten and Ledaborbactam Etzadroxil
A TEAE was defined as any event not present prior to the first administration of the study drug, or any event already present that worsens in either severity or frequency following exposure to the study drug.
Time frame: Up to Day 8