Effect of Age and Sex on the Pharmacokinetics and Safety of Avibactam in Healthy Volunteers

Purpose: Avibactam is a novel non-beta-lactam P-lactamase inhibitor currently being assessed in combination with ceftazidime, ceftaroline fosamil, and aztreonam. The objectives of this study were to investigate the pharmacokinetics, safety, and tolerability of avibactam in healthy young (aged 18-45 years) and elderly (aged >= 65 years) volunteers of both sexes. Methods: This was a Phase I, open-label study in which healthy volunteers aged >= 18 years were enrolled into 4 cohorts: young male, young female, elderly male, and elderly female (n = 8 in each group). Subjects were excluded if they had any condition requiring regular medication or any other relevant conditions. All subjects received a single dose of avibactam 500 mg/100 mL given intravenously over 30 minutes. Pharmacokinetic measurements included C-max, T-max, AUC(0-infinity), plasma clearance, and t(1/2). Findings: Within the two age categories the mean age across male and female subjects was well matched. The majority of subjects in the young cohort were black (>= 62.5%), whilst the majority of those in the elderly cohorts were white (>= 75%). Mean avibactam plasma clearance was similar between the young male, young female, and elderly male cohorts (10.16, 10.34, and 9.82 L/h, respectively), and slightly lower in elderly women (7.98 L/h). Mean C-max was similar in young male, young female, and elderly female subjects (33.8, 36.9, and 38.4 mu g/mL) but lower in elderly male subjects (26.5 mu g/mL). Point estimates comparing the ratio of C-max in male and female subjects over all age groups suggested that C-max values were 18% lower (90% CI, 30%-5% lower) in male subjects compared with female subjects. Mean AUC(0-infinity) data were similar between the young male, young female, and elderly male cohorts (49.86, 49.75, and 52.40 mu g.h/mL) but higher in elderly women (66.23 mu g.h/ML). Point estimates comparing the ratio of AUC(0-infinity) in elderly and young subjects across both sexes suggested that AUC(0-infinity) values were 17% higher (90% CI, 5%-31%) in elderly subjects compared with young subjects. The t1/2 was slightly longer for elderly subjects compared with younger subjects. The most common adverse event was administration/venipuncture site bruising (6 events); all adverse events were mild. (C) 2015 Elsevier HS Journals, Inc. All rights reserved.