Ceftibuten + Ledaborbactam Pharmacokinetics in Healthy Subjects

Overseen By Venatorx Clinical Science

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Venatorx Pharmaceuticals, Inc.

Must not be taking: Penicillin, Cephalosporin, β-lactam

Disqualifiers: Drug allergy, Significant diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 5

Duration: 1 week

34 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, since the study is for healthy adults and excludes those with certain health conditions, it's possible that you may need to pause some medications. Please consult with the trial coordinators for specific guidance.

What data supports the effectiveness of the drug ceftibuten-ledaborbactam?

The drug ceftibuten-ledaborbactam has shown effectiveness against multidrug-resistant bacteria, particularly those causing complicated urinary tract infections. It was able to inhibit a high percentage of resistant bacteria in laboratory tests, suggesting it could be a promising option for treating infections that are difficult to manage with other antibiotics. ^{1 2 3 4 5}

Is the combination of ceftibuten and ledaborbactam safe for humans?

The available research does not provide specific safety data for humans regarding the combination of ceftibuten and ledaborbactam. The studies focus on the effectiveness of the combination against drug-resistant bacteria, but do not mention safety outcomes in human trials. ^{1 3 6 7 8}

What makes the drug ceftibuten + ledaborbactam unique compared to other treatments for multidrug-resistant Enterobacterales infections?

Ceftibuten + ledaborbactam is unique because it combines an oral antibiotic (ceftibuten) with a novel β-lactamase inhibitor (ledaborbactam) that restores the antibiotic's effectiveness against resistant bacteria, offering a new oral treatment option for complicated urinary tract infections caused by multidrug-resistant Enterobacterales. ^{1 3 6 8 9}

What is the purpose of this trial?

This is a Phase 1, open-label, single-center PK study in healthy adult male and female participants between 18 and 55 years of age (both inclusive). Thirty-one participants will each undergo one standard bronchoscopy with bronchoalveolar lavage (BAL) following the fifth dose of ceftibuten-ledaborbactam etzadroxil or ceftibuten alone. BAL fluid samples and plasma samples will be collected at designated timepoints to determine the concentrations of ceftibuten, ledaborbactam, and urea.

Research Team

Chief Medical Officer

Principal Investigator

Venatorx Pharmaceuticals, Inc.

Eligibility Criteria

This clinical trial is open to healthy adult men and women aged between 18 and 55. Participants must be willing to undergo a bronchoscopy with bronchoalveolar lavage after receiving doses of the study drugs. Specific eligibility criteria details are not provided.

Inclusion Criteria

Laboratory values meeting defined entry criteria

Body Mass Index: ≥18 and ≤32 kg/m2

Forced expiratory volume in 1 second of at least 80% of predicted value

Exclusion Criteria

History of drug allergy or hypersensitivity to penicillin, cephalosporin, or β-lactam antibacterial drug or to medications used during a bronchoscopy

Positive alcohol, drug, or tobacco use/test

I have a condition that affects how my body absorbs or gets rid of medications taken by mouth.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ceftibuten-ledaborbactam etzadroxil or ceftibuten alone, with bronchoscopy and bronchoalveolar lavage after the fifth dose

1 week

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ceftibuten
• ledaborbactam

Trial Overview The study is testing how two drugs, ceftibuten and ledaborbactam etzadroxil, are processed in the body (pharmacokinetics) when given to healthy individuals. It involves taking samples from lung fluid and blood after drug administration.

Participant Groups

Group I: Group 2 Experimental Treatment 1 Intervention

Participants in Group 2 will undergo one standardized bronchoscopy with bronchoalveolar lavage after the fifth of dose of ceftibuten alone.

Group II: Group 1 Experimental Treatment 2 Interventions

Participants in Group 1 will undergo one standardized bronchoscopy with bronchoalveolar lavage after the fifth dose of ceftibuten-ledaborbactam etzadroxil.

ceftibuten is already approved in United States, European Union for the following indications:

Approved in United States as Cedax for:

• Acute bacterial exacerbations of chronic bronchitis
• Acute bacterial otitis media
• Pharyngitis and tonsillitis

Approved in European Union as Ceftibuten for:

• Lower respiratory tract infections
• Upper respiratory tract infections
• Urinary tract infections

Who Is Running the Clinical Trial?

Venatorx Pharmaceuticals, Inc.

Lead Sponsor

Trials

15

Recruited

1,200+

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator

Trials

3,361

Recruited

5,516,000+

Findings from Research

Ledaborbactam, a novel β-lactamase inhibitor, effectively restores the activity of ceftibuten against ceftibuten-resistant Enterobacterales, as demonstrated in a murine thigh infection model using 12 clinical isolates.

The study quantified the necessary ledaborbactam exposure levels for achieving bacteriostasis, indicating promising potential for the oral combination of ceftibuten and ledaborbactam in treating infections caused by multidrug-resistant bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo pharmacokinetics and pharmacodynamics of ceftibuten/ledaborbactam, a novel oral β-lactam/β-lactamase inhibitor combination. Fratoni, AJ., Avery, LM., Nicolau, DP., et al.[2023]

Ceftibuten is an effective oral cephalosporin antibiotic with broad activity against key respiratory pathogens, including Streptococcus pneumoniae and Haemophilus influenzae, even those producing beta-lactamases.

A single daily dose of 400 mg for adults or 9 mg/kg for children achieves sufficient blood levels to maintain its antibacterial effects throughout most of the dosing period, indicating its potential for convenient treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceftibuten: minimal inhibitory concentrations, postantibiotic effect and beta-lactamase stability--a rationale for dosing programs. Neu, HC.[2018]

Ceftibuten-ledaborbactam etzadroxil is an oral treatment that effectively inhibits 89.7% of multidrug-resistant Enterobacterales at a low concentration (MIC90 of 0.25 μg/mL), showing promise against various resistant strains.

The combination demonstrated high efficacy against specific resistant genotypes, inhibiting 96.3% of CTX-M-9 group isolates and 85.9% of KPC-positive isolates, indicating its potential as a valuable option for treating complicated urinary tract infections caused by resistant bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018-2020 Global Surveillance Collection. Karlowsky, JA., Wise, MG., Hackel, MA., et al.[2022]

Ceftibuten is an effective oral antibiotic for treating upper and lower respiratory tract infections, as well as urinary tract infections, and is stable against certain resistant bacteria, making it a reliable option for various infections.

The drug has a favorable safety profile similar to other cephalosporins, is well-absorbed (75-90%), and can be dosed once a day, which simplifies treatment regimens for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceftibuten: an overview. Owens, RC., Nightingale, CH., Nicolau, DP.[2018]

In a study of 8 patients with difficult-to-treat resistant Gram-negative infections undergoing continuous venovenous haemodiafiltration (CVVHDF), continuous infusion of ceftazidime-avibactam achieved optimal pharmacokinetic/pharmacodynamic (PK/PD) targets, leading to microbiological eradication in all cases assessed.

The total clearance of both ceftazidime and avibactam was positively correlated with the intensity of CVVHDF, suggesting that higher CVVHDF doses may enhance the effectiveness of this antibiotic combination in critically ill patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam for treating DTR gram-negative infections in a case series of critically ill patients undergoing continuous veno-venous haemodiafiltration (CVVHDF). Gatti, M., Rinaldi, M., Gaibani, P., et al.[2023]

Ceftibuten combined with the β-lactamase inhibitor VNRX-5236 showed significantly improved effectiveness against resistant Gram-negative bacteria, with MIC values 256-fold lower than ceftibuten alone, indicating a strong potential for treating infections caused by resistant Enterobacterales.

VNRX-5236 effectively restored the activity of ceftibuten against various β-lactamase producing strains, including ESBL, AmpC, and KPC, suggesting that this combination could serve as a promising oral treatment option while preserving the use of carbapenems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro activity of the orally bioavailable ceftibuten/VNRX-7145 (VNRX-5236 etzadroxil) combination against a challenge set of Enterobacterales pathogens carrying molecularly characterized β-lactamase genes. Mendes, RE., Rhomberg, PR., Watters, AA., et al.[2022]

Ceftibuten/VNRX-7145 is highly effective against multidrug-resistant Enterobacterales, inhibiting 90% of tested urinary isolates at a low concentration of 2 μg/ml, making it a promising oral treatment for complicated urinary tract infections.

The combination shows comparable potency to some intravenous-only antibiotics, indicating its potential as an effective alternative for treating infections caused by resistant bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vitro Activity of Ceftibuten/VNRX-5236 against Urinary Tract Infection Isolates of Antimicrobial-Resistant Enterobacterales. Karlowsky, JA., Hackel, MA., Sahm, DF.[2022]

Ceftibuten, when combined with avibactam at a concentration of 4 mg/L, effectively distinguishes between Enterobacterales strains that are susceptible to avibactam and those that are resistant due to different mechanisms, based on a study of 71 molecularly characterized isolates.

This combination shows promise in overcoming resistance mechanisms, including various β-lactamases, suggesting a potential new treatment strategy for infections caused by resistant Enterobacterales.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selection of the appropriate avibactam concentration for use with ceftibuten in broth microdilution susceptibility testing. Sader, HS., Lindley, J., Deshpande, LM., et al.[2022]

Ceftibuten, a cephalosporin antibiotic, is safe and well tolerated in both healthy and geriatric volunteers, with steady-state pharmacokinetics achieved by days 3 and 4 of treatment.

While there is some accumulation of ceftibuten in elderly patients, the study suggests that no dosage adjustments based on age are necessary, indicating its efficacy across different age groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple-Dose Pharmacokinetics of Ceftibuten in Healthy Adults and Geriatric Volunteers. Radwanski, E., Teal, M., Affrime, M., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

In vivo pharmacokinetics and pharmacodynamics of ceftibuten/ledaborbactam, a novel oral β-lactam/β-lactamase inhibitor combination. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Ceftibuten: minimal inhibitory concentrations, postantibiotic effect and beta-lactamase stability--a rationale for dosing programs. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018-2020 Global Surveillance Collection. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Ceftibuten: an overview. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam for treating DTR gram-negative infections in a case series of critically ill patients undergoing continuous veno-venous haemodiafiltration (CVVHDF). [2023]

6. England pubmed.ncbi.nlm.nih.gov

In vitro activity of the orally bioavailable ceftibuten/VNRX-7145 (VNRX-5236 etzadroxil) combination against a challenge set of Enterobacterales pathogens carrying molecularly characterized β-lactamase genes. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

In Vitro Activity of Ceftibuten/VNRX-5236 against Urinary Tract Infection Isolates of Antimicrobial-Resistant Enterobacterales. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Selection of the appropriate avibactam concentration for use with ceftibuten in broth microdilution susceptibility testing. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Multiple-Dose Pharmacokinetics of Ceftibuten in Healthy Adults and Geriatric Volunteers. [2019]