title: Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers.
abstract: OBJECTIVE
  Avibactam is a novel non-β-lactam β-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 Cmax, Tmax, AUC0-∞, plasma clearance, and t½.
  
  
  RESULTS
  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 Cmax was similar in young male, young female, and elderly female subjects (33.8, 36.9, and 38.4 µg/mL) but lower in elderly male subjects (26.5 µg/mL). Point estimates comparing the ratio of Cmax in male and female subjects over all age groups suggested that Cmax values were 18% lower (90% CI, 30%-5% lower) in male subjects compared with female subjects. Mean AUC0-∞ data were similar between the young male, young female, and elderly male cohorts (49.86, 49.75, and 52.40 µg·h/mL) but higher in elderly women (66.23 µg·h/mL). Point estimates comparing the ratio of AUC0-∞ in elderly and young subjects across both sexes suggested that AUC0-∞ values were 17% higher (90% CI, 5%-31%) in elderly subjects compared with young subjects. The t½ 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.
  
  
  CONCLUSIONS
  No notable differences in pharmacokinetics were observed between the male and female cohorts. The generalizability of the study is limited due to its small sample size. However, the small differences observed between the young and elderly cohorts are not sufficient to warrant dosing adjustments based on age.
authors.affiliation: Formerly of Novexel SA, Romainville, France. Electronic address: atarral@dndi.org.
authors.forename: Antoine
authors.initials: A
authors.lastname: Tarral
authors.affiliation: Formerly of Novexel SA, Romainville, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Merdjan
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D019540:Area Under Curve; D053961:Azabicyclo Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012737:Sex Factors; D055815:Young Adult; D065093:beta-Lactamase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; C543519:avibactam
keywords: age; avibactam; pharmacokinetics; sex