No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies.
4 affiliations
- 1Clario, part of Thermo Fisher Scientific, Philadelphia, PA, USA.
- 2Basilea Pharmaceutica International Ltd, Allschwil, Switzerland.
- 3Venatorx Pharmaceuticals, Inc., Malvern, PA, USA.
- 4McGovern ID Consulting LLC, Berwyn, PA, USA.
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.
Related
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- A Conceptual Translational Bench-to-Bedside Cardiac Safety Framework for Predicting Drug-Induced QT Interval Prolongation from Molecular Structure to Clinical Data
- Incidence and Predictors of QTC Prolongation Among Drug-Resistant Tuberculosis Patients Receiving Bedaquiline-Based TB Regimens in Uganda: A Countrywide Retrospective Cohort Study.
BibTeX
@article{darpo2026clinically,
title = {{No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies.}},
author = {Borje Darpo and Hongqi Xue and Kamal A Hamed and Karine Litherland and Marc Engelhardt and Kathryn Lowe and Paul C McGovern},
journal = {The Journal of antimicrobial chemotherapy},
year = {2026},
month = oct,
doi = {10.1093/jac/dkag365},
url = {https://europepmc.org/article/MED/42920101},
note = {CC BY},
}
RIS
TY - JOUR
TI - No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies.
AU - Borje Darpo
AU - Hongqi Xue
AU - Kamal A Hamed
AU - Karine Litherland
AU - Marc Engelhardt
AU - Kathryn Lowe
AU - Paul C McGovern
PY - 2026
DA - 2026/10/01
JO - The Journal of antimicrobial chemotherapy
DO - 10.1093/jac/dkag365
UR - https://europepmc.org/article/MED/42920101
AB - 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.
SN - 0305-7453
SN - 1460-2091
ER -