Phase I, Open-Label, Safety and Pharmacokinetic Study To Assess Bronchopulmonary Disposition of Intravenous Eravacycline in Healthy Men and Women

• Published in: Antimicrobial agents and chemotherapy Vol. 58; no. 4; pp. 2113 - 2118
• Main Authors: Connors, Kevin P., Housman, Seth T., Pope, J. Samuel, Russomanno, John, Salerno, Edward, Shore, Eric, Redican, Susan, Nicolau, David P.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.04.2014
• Subjects: Adult; Anti-Bacterial Agents; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - urine; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Female; Humans; Macrophages, Alveolar - metabolism; Male; Medical sciences; Pharmacology; Pharmacology. Drug treatments; Tetracyclines - adverse effects; Tetracyclines - blood; Tetracyclines - pharmacokinetics; Tetracyclines - urine; Young Adult; Human; Intravenous administration; Healthy subject; Toxicity; Tetracycline derivatives; Sex; Bronchopulmonary; Eravacycline; Antibiotic; Phase I trial; Protein synthesis inhibitor; Safety; Antibacterial agent; Pharmacokinetics
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.02036-13

This study evaluated the pulmonary disposition of eravacycline in 20 healthy adult volunteers receiving 1.0 mg of eravacycline/kg intravenously every 12 h for a total of seven doses over 4 days. Plasma samples were collected at 0, 1, 2, 4, 6, and 12 h on day 4, with each subject randomized to undergo a single bronchoalveolar lavage (BAL) at 2, 4, 6, or 12 h. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry, and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods. Penetration for ELF and AM was calculated by using a ratio of the area under the concentration time curve (AUC 0–12 ) for each respective parameter against free drug AUC ( f AUC 0–12 ) in plasma. The total AUC 0–12 in plasma was 4.56 ± 0.94 μg·h/ml with a mean f AUC 0–12 of 0.77 ± 0.14 μg·h/ml. The eravacycline concentrations in ELF and AM at 2, 4, 6, and 12 h were means ± the standard deviations (μg/ml) of 0.70 ± 0.30, 0.57 ± 0.20, 0.34 ± 0.16, and 0.25 ± 0.13 with a penetration ratio of 6.44 and 8.25 ± 4.55, 5.15 ± 1.25, 1.77 ± 0.64, and 1.42 ± 1.45 with a penetration ratio of 51.63, respectively. The eravacycline concentrations in the ELF and AM achieved greater levels than plasma by 6- and 50-fold, respectively, supporting further study of eravacycline for patients with respiratory infections.