Steady-State Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole in Lung Transplant Recipients

Abstract

This prospective study evaluated the plasma and intrapulmonary pharmacokinetics and pharmacodynamics (PKPD) of posaconazole (POS) in lung transplant recipients. Twenty adult lung transplant patients were instructed to take a 400-mg POS oral suspension twice daily (BID) with a high-fat meal for a total of 14 doses. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage, and blood samples were collected at the approximate time of bronchoscopy. POS concentrations were assayed using liquid chromatography with tandem mass spectrometry. The maximum concentrations (C(max)) (mean +/- standard deviation [SD]) in plasma, ELF, and AC were 1.3 +/- 0.4, 1.3 +/- 1.7, and 55.4 +/- 44.0 microg/ml. POS concentrations in plasma, ELF, and AC did not decrease significantly, indicating slow elimination after multiple dosing. Mean concentrations of POS in plasma, ELF, and AC were above the MIC(90) (0.5 microg/ml) for Aspergillus species over the 12-h dosing interval and for 24 h following the last dose. Area under the concentration-time curve from 0 to 12 h (AUC(0-12))/MIC(90) ratios in plasma, ELF, and AC were 21.98, 22.42, and 1,060. We concluded that a dose of 400 mg BID resulted in sustained plasma, ELF, and AC concentrations above the MIC(90) for Aspergillus spp. during the dosing interval. Confirmation of the therapeutic value of these observations requires further investigation. The intrapulmonary PKPD of POS may be favorable for treatment or prevention of aspergillosis, although further research on the relevant PKPD parameters and the effect of POS protein binding is required.