Randomized, placebo‐controlled study to assess the impact on QT/QTc interval of supratherapeutic doses of ceftazidime–avibactam or ceftaroline fosamil–avibactam. (22nd October 2013)

• Record Type: Journal Article
• Authors: Das, Shampa; Armstrong, Jon; Mathews, David; Li, Jianguo; Edeki, Timi
• Is Part Of: Journal of clinical pharmacology. Volume 54:Number 3(2014:Mar.)
• Page Start: 331
• Page End: 340
• Publication Date: 2013-10-22
• Subjects: Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.199
• Languages: English
• ISSNs: 0091-2700

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jcph199-sec-0001" sec-type="section"> <p>Potential effects of supratherapeutic doses of intravenous (IV) ceftazidime–avibactam and ceftaroline fosamil–avibactam on cardiac repolarization were assessed in a thorough QT/QTc study. This was a double‐blind, randomized, placebo‐controlled, four‐period crossover Phase I study (NCT01290900) in healthy males (n = 51). Subjects received, in randomized order and separated by ≥3 days washout: single doses of IV ceftaroline fosamil 1, 500 mg with avibactam 2, 000 mg; IV ceftazidime 3, 000 mg with avibactam 2, 000 mg; oral moxifloxacin 400 mg (open‐label positive control); and IV placebo (saline). Least square mean and two‐sided 90% confidence intervals (CI) for change from baseline in Fridericia‐corrected QT interval (ΔQTcF) for active treatments versus placebo were estimated at 10 time points over 24 hours. The upper bound of the two‐sided 90% CI for placebo‐corrected ΔQTcF did not exceed 10 milliseconds at any time point over 24 hours for ceftaroline fosamil–avibactam or ceftazidime–avibactam. The lower bound of the two‐sided 90% CI for the difference between moxifloxacin and placebo in ΔQTcF over 1–4 hours was >5 milliseconds, confirming assay sensitivity. Pharmacokinetics results confirmed achievement of supratherapeutic plasma concentrations. No safety concerns were raised. In conclusion, supratherapeutic doses of ceftaroline fosamil–avibactam or ceftazidime–avibactam were not associated with QT/QTc prolongation in this study population.</p> </sec> </abstract>