title: Pulmonary disposition of tedizolid following administration of once-daily oral 200-milligram tedizolid phosphate in healthy adult volunteers.
abstract: This study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC(0-24)) for ELF and AM relative to the free AUC(0-24) (fAUC(0-24)) in plasma. The half-life and volume of distribution in plasma were 9.23 ± 2.04 h and 108.25 ± 20.53 liters (means ± standard deviations), respectively. Total AUC(0-24) in plasma was 25.13 ± 5.78 μg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a mean fAUC(0-24) of 2.65 ± 0.72 μg · h/ml in plasma. Mean concentrations (μg/ml) at 2, 6, 12, and 24 h were 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 in ELF and 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Seth T
authors.initials: ST
authors.lastname: Housman
authors.forename: J Samuel
authors.initials: JS
authors.lastname: Pope
authors.forename: John
authors.initials: J
authors.lastname: Russomanno
authors.forename: Edward
authors.initials: E
authors.lastname: Salerno
authors.forename: Eric
authors.initials: E
authors.lastname: Shore
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001798:Blood Proteins / Q000737:chemistry; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D001999:Bronchoscopy; D002853:Chromatography, Liquid; D005260:Female; D006207:Half-Life; D006801:Humans; D016676:Macrophages, Alveolar / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D033281:Nontherapeutic Human Experimentation; D023303:Oxazolidinones / Q000097:blood / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D011650:Pulmonary Alveoli / Q000737:chemistry; D053719:Tandem Mass Spectrometry; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D023303:Oxazolidinones; D011355:Prodrugs; D013777:Tetrazoles; C546016:tedizolid