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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how the drugs ceftibuten and ledaborbactam move through the body. Researchers test these drugs in healthy adults to observe their absorption and processing. Participants are divided into two groups: one receives both drugs, and the other receives only ceftibuten. This trial suits adults who are generally healthy and have no history of drug allergies. Participants will undergo bronchoscopy, a procedure to examine the lungs, to help gather data. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive these new drugs.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ceftibuten is generally easy for people to handle. One study found that some participants experienced mild side effects like nausea and headaches, but these were not serious. The FDA has already approved ceftibuten for other uses, indicating a good safety record.

For the ceftibuten-ledaborbactam combination, studies indicate it is also well-tolerated when taken in multiple doses. Most side effects, if any, were mild and similar to those seen with ceftibuten alone.

Since this trial is in its early phase, it focuses on understanding how the body processes the drugs. While early phases primarily assess safety, the history of these treatments suggests they are likely safe for participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine ceftibuten, an established antibiotic, with ledaborbactam, which has the potential to boost its effectiveness against resistant bacteria. Unlike standard antibiotics that typically target a broad range of bacteria, this combination aims to tackle specific resistant strains more effectively. The unique feature here is ledaborbactam’s ability to inhibit certain enzymes that make bacteria resistant to treatments like ceftibuten. This could lead to more efficient eradication of infections with reduced chances of resistance development, offering a promising alternative to current options.

What evidence suggests that this trial's treatments could be effective?

This trial will compare the pharmacokinetics of ceftibuten alone and in combination with ledaborbactam. Studies have shown that ceftibuten is a strong antibiotic, used safely in multiple doses without major side effects. Research suggests that ledaborbactam can enhance the effectiveness of antibiotics like ceftibuten. Participants in Group 1 of this trial will receive the combination of ceftibuten and ledaborbactam, which is believed to work well against bacteria that resist regular antibiotics. Early findings suggest this combination can help fight infections more effectively by making the bacteria easier to treat. While more research in humans continues, early data shows promise for these drugs working together. ^{1 2 6 7 8}

Who Is on the Research Team?

Kamal Hamed, MD

Principal Investigator

Basilea Pharmaceutica International Ltd, Allschwil

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Basilea Pharmaceutica

Lead Sponsor

Trials

53

Recruited

9,900+

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

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-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, 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]

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 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, 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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10777847/

and multiple-dose study of the pharmacokinetics, safety ... Subjects received single 400, 600, or 800 mg doses of ceftibuten on Days 1 and 4, followed by 7 days of twice-daily dosing from Days 4 to 10.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0022354915495978

Multiple-Dose Pharmacokinetics of Ceftibuten After Oral ... Twelve healthy subjects were treated orally twice daily with 400 mg of the drug for 7 days; on day 8, the subjects received a last dose of 400 mg of ceftibuten.

3. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2009/050685s011,050686s014lbl.pdf

cedax - accessdata.fda.gov Patients with renal insufficiency: Ceftibuten pharmacokinetics have been investigated in adult patients with renal dysfunction. The ceftibuten plasma half-life ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC162542/

Multiple-dose pharmacokinetics of ceftibuten in healthy ... The pharmacokinetics of ceftibuten, a new cephalosporin antibiotic, and its conversion product, ceftibutentrans, were studied in healthy male volunteers.

5. journals.asm.org journals.asm.org/doi/abs/10.1128/aac.01099-23

and multiple-dose study of the pharmacokinetics, safety, and ... Subjects received single 400, 600, or 800 mg doses of ceftibuten on Days 1 and 4, followed by 7 days of twice-daily dosing from Days 4 to 10. Non-compartmental ...

6. journals.asm.org journals.asm.org/doi/10.1128/aac.00087-25

Pharmacokinetics and safety of single and repeat doses of ... Of the 36 participants, 25 (ceftibuten 67%, placebo 78%) reported 65 treatment-emergent adverse events (TEAEs). Nausea (22%), headache (15%), ...

7. venatorx.com venatorx.com/wp-content/uploads/2024/11/Venatorx_IDWeek-2024_P-1240_Ceftibuten_Poster_final.pdf

Dose-Escalation Study to Evaluate the Pharmacokinetics ... All 36 subjects (27 ceftibuten; 9 placebo) were included in the safety analysis set and all ceftibuten subjects were in the PK analysis set. • 39% were males ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06733675

Study Details | NCT06733675 | Safety and PK of Ceftibuten ... It identifies the role of the intervention that participants receive. Types of arms include experimental arm, active comparator arm, placebo comparator arm, ...