Intrapulmonary penetration of voriconazole in lung transplant patients

Optimal management of infection requires that adequate drug concentrations reach the infection site. Voriconazole (VORI) has become a preferred agent in the treatment of invasive pulmonary aspergillosis; however, the lung penetration of VORI has not been studied in humans. The epithelial lining fluid (ELF) of the lung is well-accepted as a representative medium for extracellular pulmonary drug concentrations. Our objective was to determine the degree of VORI penetration to the lung in comparison to the plasma through simultaneous measurement of plasma and ELF steady-state VORI concentrations in lung transplant recipients. Five lung transplant recipients, 61± 5 years, who were on a VORI prophylactic regimen and who underwent a bronchoscopy as standard post transplant care, participated. Recipients received VORI 200 mg orally either twice (n= 4) or once daily (n= 1) and underwent a bronchoscopy at an average of 26± 10 days post transplant. Blood and bronchoalveolar lavage (BAL) samples were obtained at either 3, 5, 5.3, 6.3 or 7.5 hours (h) after the last VORI dose, respectively, in individual recipients. The plasma and BAL supernatant were assayed for VORI by high pressure liquid chromatography. ELF concentrations were calculated by the urea dilution method. VORI concentrations (mg/L) in the plasma/ELF of each recipient were; 3h: 1.2/10.8, 5h: 2.6/38, 5.3h: 3.1/40, 6.3h: 4.8/66 and 7.5h: 1.4/14. The average ELF: plasma VORI concentration was 12:1± 3:1. ELF concentrations superceded those of the plasma in all recipients studied. These data indicate that extracellular pulmonary concentrations of VORI are adequate to exceed published minimum inhibitory concentrations required to inhibit 90% of various Aspergillus species (MIC90 mg/L); A. fumigatus 2, A. flavus 2, A. niger 4 with the doses studied.