Pharmacokinetics, Healthy Volunteers
Conditions
Brief summary
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.
Detailed description
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.
Interventions
Five doses of ledaborbactam etzadroxil administered orally every 12 hours
DRUGceftibuten
Five doses of ceftibuten administered orally every 12 hours
Sponsors
Basilea Pharmaceutica
Biomedical Advanced Research and Development Authority
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Participants must have met the following key criteria to be eligible for enrollment into the study: Inclusion Criteria: * Healthy adults 18-55 years * Males or non-pregnant, non-lactating females * Body Mass Index: ≥18 and ≤32 kg/m2 * Forced expiratory volume in 1 second of at least 80% of predicted value * Laboratory values meeting defined entry criteria
Exclusion criteria
* History of drug allergy or hypersensitivity to penicillin, cephalosporin, or β-lactam antibacterial drug or to medications used during a bronchoscopy * Conditions that potentially alter absorption and/or excretion of orally administered drugs * History or presence of significant diseases, including any clinically relevant acute illness or surgery within the past 3 months * Positive alcohol, drug, or tobacco use/test
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Maximum Concentration (Cmax) of Ledaborbactam Etzadroxil | Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose | The pharmacokinetic parameter (PK) Cmax of ledaborbactam etzadroxil assessed at at steady-state. |
| Plasma AUC0-12h for Ledaborbactam Etzadroxil | Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose | The pharmacokinetic parameter (PK) AUC0-12h of ledaborbactam etzadroxil assessed at at steady-state. |
| Intrapulmonary PK - AUC0-12 at Steady State in Group 1: Ceftibuten and Ledaborbactam Etzadroxil | Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose | 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. |
| Plasma Maximum Concentration (Cmax) of Ceftibuten | Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose | The pharmacokinetic parameter (PK) Cmax of ceftibuten assessed at at steady-state. |
| Plasma Area Under the Curve From Time Zero to 12 Hours (AUC0-12) for Ceftibuten | Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose | The PK parameter AUC0-12 for ceftibuten assessed at at steady-state. |
| Ratios of Drug Exposure for Ledaborbactam Etzadroxil and Ceftibuten | Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose | 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. |
| Ratios of Drug Exposure for Ceftibuten | Samples were taken at 0, 2, 4, 6, 8, and 12 hours post 5th dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) After Administration of Ceftibuten and Ledaborbactam Etzadroxil | Up to Day 8 | 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. |
Countries
United States
Contacts
STUDY_DIRECTORKamal Hamed, MD, MPH
Basilea Pharmaceutica International Ltd, Allschwil
Participant flow
Recruitment details
Participants were screened and randomized at one site in the USA
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 38.8 years STANDARD_DEVIATION 10.02 |
| BMI | 27.27 kg/m^2 STANDARD_DEVIATION 3.75 |
| Height | 173.2 cm STANDARD_DEVIATION 9.01 |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants |
| Race/Ethnicity, Customized Hispanic Or Latino | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic Or Latino | 25 Participants |
| Race/Ethnicity, Customized Other | 4 Participants |
| Race/Ethnicity, Customized White | 15 Participants |
| Region of Enrollment United States | 34 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 7 Participants |
| Weight | 78.97 kg STANDARD_DEVIATION 12.52 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 6 |
| other Total, other adverse events | 3 / 28 | 0 / 6 |
| serious Total, serious adverse events | 0 / 28 | 0 / 6 |
Outcome results
None listed