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J Antimicrob Chemother. 2015 Oct;70(10):2862-9. doi: 10.1093/jac/dkv170. Epub 2015 Jul 1.

Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens.

Author information

1
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA david.nicolau@hhchealth.org.
2
Quintiles Phase I Unit, London, UK.
3
AstraZeneca, Macclesfield, UK.
4
AstraZeneca, Wilmington, DE, USA.

Abstract

OBJECTIVES:

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.

PATIENTS AND 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.

PMID:
26133566
DOI:
10.1093/jac/dkv170
[Indexed for MEDLINE]

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