Premium
Randomized, placebo‐controlled study to assess the impact on QT/QTc interval of supratherapeutic doses of ceftazidime–avibactam or ceftaroline fosamil–avibactam
Author(s) -
Das Shampa,
Armstrong Jon,
Mathews David,
Li Jianguo,
Edeki Timi
Publication year - 2014
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.199
Subject(s) - medicine , placebo , qt interval , crossover study , anesthesia , randomized controlled trial , population , pharmacokinetics , avibactam , ceftazidime , alternative medicine , environmental health , pathology , biology , bacteria , pseudomonas aeruginosa , genetics
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.