A Randomized, Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of Ceftazidime-Avibactam in Healthy Chinese Subjects.

Abstract

Avibactam is a non-β-lactam β-lactamase inhibitor that restores the in vitro activity of β-lactams, such as ceftazidime, against bacterial pathogens harboring Ambler class A, C, and some class D β-lactamases. This randomized, double-blind, placebo-controlled, phase I study (NCT01920399) evaluated the safety, tolerability, and pharmacokinetics of single and repeated doses of avibactam and ceftazidime in healthy Chinese subjects. Sixteen healthy Chinese males aged 18-45 years were randomized 3:1 to receive 2000 mg ceftazidime and 500 mg avibactam (n = 12) or matched placebo (n = 4) as a 120-min intravenous infusion, once on Days 1 and 9, and every 8 h on Days 2-8. Avibactam and ceftazidime showed time-independent pharmacokinetics. Plasma exposure to avibactam and ceftazidime was similar following single and multiple dosing and accumulation of either agent was negligible. The majority of the avibactam and ceftazidime dose was recovered in urine. Adverse events were reported in three subjects (25.0%) in the ceftazidime-avibactam group and one subject (25.0%) in the placebo group. Two subjects in the ceftazidime-avibactam group had elevations in transaminases and one subject in the placebo group had elevated serum bilirubin levels that were considered causally related to study treatment. All adverse events were of mild intensity. Single and multiple doses of 2000 mg ceftazidime and 500 mg avibactam were well tolerated in healthy Chinese subjects, and the observed pharmacokinetics were comparable to previous studies conducted in Western subjects.