No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies
Borje Darpo, Hongqi Xue, Kamal A Hamed, Karine Litherland, Marc Engelhardt, Kathryn Lowe, Paul C McGovernAbstract
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.