title: Randomized pharmacokinetic and drug-drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects.
abstract: We assessed pharmacokinetic and safety profiles of ceftazidime-avibactam administered ± metronidazole, and whether drug-drug interactions exist between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. The first study (NCT01430910) involved two cohorts of healthy subjects. Cohort 1 received ceftazidime-avibactam (2000-500 mg) as a single infusion or as multiple intravenous infusions over 11 days to evaluate ceftazidime-avibactam pharmacokinetics. Cohort 2 received ceftazidime, avibactam, or ceftazidime-avibactam over 4 days to assess drug-drug interaction between ceftazidime and avibactam. The second study (NCT01534247) assessed interaction between ceftazidime-avibactam and metronidazole in subjects receiving ceftazidime-avibactam (2000-500 mg), metronidazole (500 mg), or metronidazole followed by ceftazidime-avibactam over 4 days. In all studies, subjects received a single-dose on the first and final days, and multiple-doses every 8 h on intervening days. Concentration-time profiles for ceftazidime and avibactam administered as single- or multiple-doses separately or together with/without metronidazole were similar. There was no evidence of time-dependent pharmacokinetics or accumulation. In both interaction studies, 90% confidence intervals for geometric least squares mean ratios of area under the curve and maximum plasma concentrations for each drug were within the predefined interval (80-125%) indicating no drug-drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. There were no safety concerns. In conclusion, pharmacokinetic parameters and safety of ceftazidime, avibactam, and metronidazole were similar after single and multiple doses with no observed drug-drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole.
authors.affiliation: AstraZeneca Macclesfield, United Kingdom.
authors.forename: Shampa
authors.initials: S
authors.lastname: Das
authors.affiliation: AstraZeneca Waltham, Massachusetts.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.affiliation: AstraZeneca Macclesfield, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: AstraZeneca Macclesfield, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Learoyd
authors.affiliation: AstraZeneca Wilmington, Delaware.
authors.forename: Timi
authors.initials: T
authors.lastname: Edeki
keywords: Avibactam; ceftazidime; drug–drug interaction; infectious disease; pharmacokinetics