title: Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens.
abstract: OBJECTIVE
  The aim of this Phase 1, open-label study (NCT01395420) was to measure and compare concentrations of ceftazidime and avibactam in bronchial epithelial lining fluid (ELF) and plasma, following administration of two different dosing regimens in healthy subjects.
  
  
  METHODS
  Healthy volunteers received 2000 mg of ceftazidime + 500 mg of avibactam (n = 22) or 3000 mg of ceftazidime + 1000 mg of avibactam (n = 21), administered intravenously every 8 h for 3 days (total of nine doses). Bronchoscopy with bronchoalveolar lavage was performed once per subject, 2, 4, 6 or 8 h after the last infusion. Pharmacokinetic parameters were estimated from individual plasma concentrations and the composite ELF concentration-time profile. Safety was assessed.
  
  
  RESULTS
  Forty-three subjects received treatment (2000 mg of ceftazidime + 500 mg of avibactam, n = 22; 3000 mg of ceftazidime + 1000 mg of avibactam, n = 21). Plasma and ELF concentrations increased dose-proportionally for both drugs, with 1.5- and 2-fold increases in AUCτ, for respective components. Ceftazidime Cmax and AUCτ in ELF were ∼ 23%-26% and 31%-32% of plasma exposure. Avibactam Cmax and AUCτ in ELF were ∼ 28%-35% and 32%-35% of plasma exposure. ELF and plasma elimination were similar for both drugs. No serious adverse events were observed.
  
  
  CONCLUSIONS
  Both ceftazidime and avibactam penetrated dose-proportionally into ELF, with ELF exposure to both drugs ∼ 30% of plasma exposure.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA david.nicolau@hhchealth.org.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.affiliation: Quintiles Phase I Unit, London, UK.
authors.forename: Leonard
authors.initials: L
authors.lastname: Siew
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: AstraZeneca, Wilmington, DE, USA.
authors.forename: James
authors.initials: J
authors.lastname: Li
authors.affiliation: AstraZeneca, Wilmington, DE, USA.
authors.forename: Timi
authors.initials: T
authors.lastname: Edeki
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Learoyd
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Shampa
authors.initials: S
authors.lastname: Das
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D053961:Azabicyclo Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D015992:Body Mass Index; D002442:Ceftazidime / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism*; D010949:Plasma / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; C543519:avibactam; D002442:Ceftazidime