No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies

Q: What are the key findings of this study?

Ceftibuten and ledaborbactam etzadroxil excluded a ΔΔQTcF effect ≥10 ms at plasma concentrations up to 44 µg/mL for cis-ceftibuten and 30.3 µg/mL for ledaborbactam.

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Healthy adults (drug under development for complicated urinary tract infections) (n=84). Intervention: Ceftibuten or ledaborbactam etzadroxil vs. Placebo. Primary outcome: Placebo-corrected change from baseline in Fridericia-corrected QT interval (ΔΔQTcF) evaluated via concentration-QTc modelling (Upper bound of 90% CI for model-predicted ΔΔQTcF <10 ms across full observed plasma concentration ranges).

Q: What does this research mean for the field?

Ceftibuten and ledaborbactam etzadroxil do not cause clinically meaningful QTc prolongation, excluding a placebo-corrected change from baseline in QTcF of 10 ms or greater at and above therapeutic plasma concentrations. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate the effects of ceftibuten and ledaborbactam etzadroxil on cardiac repolarization using concentration-QTc analyses.

Börje Darpö; Hongqi Xue; Kamal A. Hamed; Karine Litherland; Marc Frederick Engelhardt; Kathryn R. Lowe; Paul C. McGovern

doi:10.1093/jac/dkag365

October 6, 2026Journal of Antimicrobial ChemotherapyOpen Access

No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies

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Key result

Ceftibuten and ledaborbactam etzadroxil show no clinically meaningful QTcF prolongation across therapeutic plasma concentrations.

Upper bound of 90% CI for model-predicted ΔΔQTcF <10 ms across full observed plasma concentration ranges
n=84

Figures

Why the study?

Ceftibuten and ledaborbactam etzadroxil are being developed as an oral fixed-dose combination for complicated urinary tract infections caused by multidrug-resistant Enterobacterales, and their effects on cardiac repolarization required evaluation.

Does a single oral dose of ceftibuten or ledaborbactam etzadroxil cause clinically relevant QTc interval prolongation (ΔΔQTcF ≥10 ms) in healthy adults?

Key Points

To evaluate the effects of ceftibuten and ledaborbactam etzadroxil on cardiac repolarization using concentration-QTc analyses.
Analyzed ECG and pharmacokinetic data from two randomized, single-centre, double-blind, placebo-controlled, phase I dose-escalation studies (NCT04314206 and NCT04243863) in healthy adults.
Applied linear mixed-effects models to evaluate the relationship between plasma drug concentrations and placebo-corrected change from baseline in Fridericia-corrected QT interval (ΔΔQTcF).
Concentration-QTc analyses excluded an effect on ΔΔQTcF exceeding the 10 ms regulatory threshold up to plasma concentrations of 44 µg/mL for cis-ceftibuten, 2.2 µg/mL for trans-ceftibuten, 30.3 µg/mL for ledaborbactam, and 2.6 µg/mL for ledaborbactam etzadroxil.
Ceftibuten caused a transient increase in heart rate with mean ΔΔHR under 10 bpm across dose groups except for 10.5 bpm at 3 hours with 1200 mg, whereas ledaborbactam etzadroxil showed no clinically meaningful heart rate effect.
Upper bounds of the two-sided 90% CIs for model-predicted ΔΔQTcF remained below 10 ms for all analytes, and no participant had a QTcF >450 ms with ceftibuten or >480 ms with ledaborbactam etzadroxil.

Study Design

Type

RCT (n=84)

Blinding

Double-blind

Randomization

3:1 ratio

Multicenter

No

Structured PICO

Does a single oral dose of ceftibuten or ledaborbactam etzadroxil cause clinically relevant QTc interval prolongation (ΔΔQTcF ≥10 ms) in healthy adults?

P

Population

84 healthy adult volunteers (83 evaluable) across two single-centre Phase I dose-escalation trials in the Netherlands and the United States, monitored with continuous Holter ECG for 24 hours post-dose.

I

Intervention

Single oral ascending dose of ceftibuten (400, 800, or 1200 mg; n=9 per dose level) or single oral ascending dose of ledaborbactam etzadroxil (100, 200, 300, 500, 800, or 1000 mg; n=6 per dose level).

C

Comparator

Oral placebo (n=3 per dose level, pooled n=9 in the ceftibuten study; n=2 per dose level, pooled n=12 in the ledaborbactam etzadroxil study).

O

Outcome

Change from baseline in Fridericia-corrected QT interval (ΔQTcF) and placebo-corrected change from baseline in QTcF (ΔΔQTcF) over 24 hours post-dose, evaluated via linear mixed-effects concentration-QTc modelling to exclude a ΔΔQTcF effect of ≥10 ms at clinically relevant plasma concentrations.safety

Main Result

Effect estimate: Upper bound of 90% CI for model-predicted ΔΔQTcF <10 ms across full observed plasma concentration ranges

Limitations

Concentration-QTc evaluations were performed separately for ceftibuten and ledaborbactam etzadroxil rather than as a co-administered combination, so a potential additive effect on QT prolongation cannot be fully excluded.
The QT evaluation was conducted in healthy participants rather than the target patient population, who may be more susceptible to QTc prolongation due to cardiovascular disease, electrolyte disturbances, or concomitant medications.
Statistical power for the ceftibuten study was relatively low (72%) due to the small sample size.
Concentration-QTc evaluations were performed separately for ceftibuten and ledaborbactam etzadroxil rather than as a combination, so a potential additive effect on QT prolongation cannot be fully excluded
Conducted in healthy participants rather than the targeted patient population, who may be more susceptible to QTc prolongation due to cardiovascular disease, electrolyte disturbances (e.g., hypokalaemia), or concomitant medications
Lower statistical power for the ceftibuten study (retrospectively estimated at 72%)

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Implication

Concentration-QTc modelling from two phase I studies excludes clinically meaningful QTc prolongation (≥10 ms) for both ceftibuten and ledaborbactam etzadroxil at supratherapeutic concentrations, supporting their cardiac safety and obviating the need for a dedicated thorough QT study.

Abstract

Objective Ceftibuten and ledaborbactam etzadroxil are being developed as an oral fixed-dose combination for the treatment of complicated urinary tract infections caused by multidrug-resistant Enterobacterales. This study evaluated their effects on cardiac repolarization using concentration-QTc analyses. Methods ECG and pharmacokinetic data from two randomized, single-centre, double-blind, placebo-controlled, phase I, dose-escalation studies in healthy adults (ClinicalTrials.gov: NCT04314206 and NCT04243863) were analysed using concentration-QTc modelling. Thirty-six participants were randomized to the ceftibuten study (27 active, nine placebo) and 48 to the ledaborbactam etzadroxil study (36 active, 12 placebo). Linear mixed-effects models characterized the relationship between plasma concentrations and placebo-corrected change from baseline in Fridericia-corrected QT interval (ΔΔQTcF). Model-based predictions estimated QTc effects across observed and clinically relevant plasma concentrations. Results Neither agent produced clinically relevant changes in ECG parameters. Concentration-QTc analyses demonstrated no statistically or clinically meaningful relationship between plasma concentrations and ΔΔQTcF. An effect on ΔΔQTcF exceeding the regulatory threshold of 10 ms could be excluded at plasma concentrations up to 44 µg/mL for cis-ceftibuten (the predominant and more potent isomer), 2.2 µg/mL for trans-ceftibuten, 30.3 µg/mL for ledaborbactam (active drug), and 2.6 µg/mL for ledaborbactam etzadroxil (prodrug). A small, transient, not clinically relevant increase in heart rate was observed with ceftibuten, whereas ledaborbactam etzadroxil had no clinically meaningful effect on heart rate. Conclusions Ceftibuten and ledaborbactam etzadroxil demonstrated no clinically relevant effects on cardiac repolarization or ECG parameters. Concentration-QTc analyses excluded clinically meaningful QTc effects at and above anticipated therapeutic plasma concentrations, supporting the cardiac safety profile of this oral fixed-dose combination.

Discussion

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Cite This Study

Darpö et al. (2026) conducted an RCT in Healthy adults (drug under development for complicated urinary tract infections) (n=84). Ceftibuten or ledaborbactam etzadroxil vs. Placebo was evaluated on Placebo-corrected change from baseline in Fridericia-corrected QT interval (ΔΔQTcF) evaluated via concentration-QTc modelling (Upper bound of 90% CI for model-predicted ΔΔQTcF <10 ms across full observed plasma concentration ranges). Ceftibuten and ledaborbactam etzadroxil excluded a ΔΔQTcF effect ≥10 ms at plasma concentrations up to 44 µg/mL for cis-ceftibuten and 30.3 µg/mL for ledaborbactam.

synapsesocial.com/papers/6adc966ca704d151585a5e31 https://doi.org/10.1093/jac/dkag365

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No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies

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Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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