Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects.

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered levofloxacin in healthy volunteers. Three doses of either 750 mg or 1000 mg levofloxacin were administered intravenously to 4 healthy adult subjects (750 mg) to 20 healthy adult subjects divided into five groups of 4 subjects (1000 mg). Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed following administration of the last dose. Blood was obtained for drug assay prior to drug administration and at the time of BAL. Levofloxacin was measured in plasma, BAL fluid and alveolar cells (ACs) using a sensitive and specific combined high-performance liquid chromatographic tandem mass spectrometric technique (HPLC/MS/MS). Plasma, epithelial lining fluid (ELF) and AC pharmacokinetics were derived using non-compartmental methods. The maximum plasma drug concentration to minimum inhibitory concentration ratio (C(max)/MIC(90)) and the area under the drug concentration curve to minimum inhibitory concentration ratio (AUC/MIC(90)) during the dosing interval were calculated for potential respiratory pathogens with MIC(90) values from 0.03 microg/mL to 2 microg/mL. In the 1000 mg dose group, the C(max) (mean+/-standard deviation (S.D.)), AUC(0-8h) and half-life were: for plasma, 9.2+/-1.9 microg/mL, 103.6 microg h/mL and 7.45 h; for ELF, 25.8+/-7.9 microg/mL, 279.1 microg h/mL and 8.10h; and for ACs, 51.8+/-26.2 microg/mL, 507.5 microg h/mL and 14.32 h. In the 750 mg dose group, the C(max) values in plasma, ELF and ACs were 5.7+/-0.4, 28.0+/-23.6 and 34.2+/-18.7 microg/mL, respectively. Levofloxacin concentrations were significantly higher in ELF and ACs than in plasma at all time points. For pathogens commonly associated with community-acquired pneumonia, C(max)/MIC(90) ratios in ELF ranged from 12.9 for Mycoplasma pneumoniae to 859 for Haemophilus influenzae, and AUC/MIC(90) ratios ranged from 139 to 9303, respectively. The C(max)/MIC(90) ratios in ACs ranged from 25.9 for M. pneumoniae to 1727 for H. influenzae, and AUC/MIC(90) ratios ranged from 254 to 16917, respectively. The C(max)/MIC(90) and AUC/MIC(90) ratios provide a pharmacokinetic rationale for once-daily administration of a 1000 mg dose of levofloxacin and are favourable for the treatment of community-acquired respiratory pathogens.