Intrapulmonary pharmacokinetics and pharmacodynamics of posaconazole at steady state in healthy subjects.

We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole (POS) in a prospective, open-label study. Twenty-five healthy adults received 14 doses of POS oral suspension (400 mg twice daily) with a high-fat meal over 8 days. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage, and blood samples were collected during the 24 h after the last dose. POS concentrations were determined using liquid chromatography with tandem mass spectrometry parameters. The maximum concentrations (C(max)) (mean +/- standard deviation) in plasma, ELF, and ACs were 2.08 +/- 0.93, 1.86 +/- 1.30, and 87.7 +/- 65.0 microg/ml. The POS concentrations in plasma, ELF, and ACs did not decrease significantly, indicating slow elimination after multiple dosing. The mean concentrations of POS in plasma, ELF, and ACs were above the MIC(90) (0.5 microg/ml) for Aspergillus spp. over the 12-h dosing interval and for 24 h following the last dose. Area under the curve from 0 to 12 h (AUC(0-12)) ratios for ELF/plasma and AC/plasma were 0.84 and 33. AUC(0-24)/MIC(90) ratios in plasma, ELF, and AC were 87.6, 73.2, and 2,860. Nine (36%) of 25 subjects had treatment-related adverse events during the course of the study, which were all mild or moderate. We conclude that a dose of 400 mg twice daily resulted in sustained plasma, ELF, and AC concentrations above the MIC(90) for Aspergillus spp. during the dosing interval. The intrapulmonary PK/PD of POS are favorable for treatment or prevention of aspergillosis, and oral POS was well tolerated in healthy adults.

Intrapulmonary pharmacodynamics of high-dose levofloxacin in subjects with chronic bronchitis or chronic obstructive pulmonary disease.

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered levofloxacin in subjects with stable chronic lung disease. Three doses of 1000 mg levofloxacin were administered once daily to 16 adult subjects divided into four groups of 4 subjects each. Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed at 4 h, 8 h, 12 h and 24 h following administration of the last dose. Blood was obtained for drug assay prior to drug administration, at the end of the last infusion (maximum concentration (Cmax)) and at the time of BAL. Levofloxacin was measured using a high-performance liquid chromatographic tandem mass spectrometric (HPLC/MS/MS) technique. Plasma, epithelial lining fluid (ELF) and alveolar cell (AC) pharmacokinetics were derived using non-compartmental methods. Cmax/MIC(90) and area under the concentration-time curve for 0-24 h after the last dose (AUC(0-24 h)/MIC(90) ratios were calculated for respiratory pathogens with minimum inhibitory concentrations for 90% of the organisms (MIC(90)) of 0.03-2 microg/mL. The Cmax (mean+/-standard deviation), AUC(0-24h) and half-life were, respectively, 9.2+/-2.7 microg/mL, 130 microg h/mL and 8.7 h for plasma, 22.8+/-12.9 microg/mL, 260 microg h/mL and 7.0 h for ELF and 76.3+/-28.7 microg/mL, 1492 microg h/mL and 49.5 h for ACs. Levofloxacin concentrations were quantitatively greater in ACs than in ELF or plasma at all time points, however only the differences between AC concentration and ELF or plasma concentrations in the 4-h and 8-h time groups were statistically significant. Cmax/MIC(90) and AUC/MIC(90) ratios in ELF were, respectively, 11.4 and 130 for Mycoplasma pneumoniae, 22.8 and 260 for Streptococcus pneumoniae, 91.2 and 1040 for Chlamydia pneumoniae and 760 and 8667 for Haemophilus influenzae. In ACs the ratios were 38.2 and 746 for M. pneumoniae, 76.3 and 1492 for S. pneumoniae, 305 and 5968 for C. pneumoniae and 2543 and 49 733 for H. influenzae. In conclusion, Cmax/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 respiratory infection in patients with chronic lung disease.

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.

Intrapulmonary pharmacokinetics and pharmacodynamics of itraconazole and 14-hydroxyitraconazole at steady state.

We determined the steady-state intrapulmonary pharmacokinetic and pharmacodynamic parameters of orally administered itraconazole (ITRA), 200 mg every 12 h (twice a day [b.i.d.]), on an empty stomach, for a total of 10 doses, in 26 healthy volunteers. Five subgroups each underwent standardized bronchoscopy and bronchoalveolar lavage (BAL) at 4, 8, 12, 16, and 24 h after administration of the last dose. ITRA and its main metabolite, 14-hydroxyitraconazole (OH-IT), were measured in plasma, BAL fluid, and alveolar cells (AC) using high-pressure liquid chromatography. Half-life and area under the concentration-time curves (AUC) in plasma, epithelial lining fluid (ELF), and AC were derived using noncompartmental analysis. ITRA and OH-IT maximum concentrations of drug (C(max)) (mean +/- standard deviation) in plasma, ELF, and AC were 2.1 +/- 0.8 and 3.3 +/- 1.0, 0.5 +/- 0.7 and 1.0 +/- 0.9, and 5.5 +/- 2.9 and 6.6 +/- 3.1 microg/ml, respectively. The ITRA and OH-IT AUC for plasma, ELF, and AC were 34.4 and 60.2, 7.4 and 18.9, and 101 and 134 microg. hr/ml. The ratio of the C(max) and the MIC at which 90% of the isolates were inhibited (MIC(90)), the AUC/MIC(90) ratio, and the percent dosing interval above MIC(90) for ITRA and OH-IT concentrations in AC were 1.1 and 3.2, 51 and 67, and 100 and 100%, respectively. Plasma, ELF, and AC concentrations of ITRA and OH-IT declined monoexponentially with half-lives of 23.1 and 37.2, 33.2 and 48.3, and 15.7 and 45.6 h, respectively. An oral dosing regimen of ITRA at 200 mg b.i.d. results in concentrations of ITRA and OH-ITRA in AC that are significantly greater than those in plasma or ELF and intrapulmonary pharmacodynamics that are favorable for the treatment of fungal respiratory infection.