Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution.
Invasive fungal infections in immunocompromised patients have high mortality rates despite current treatment modalities. This study was designed to evaluate the suitability of an aqueous solution of voriconazole solubilized with sulfobutyl ether-beta-cyclodextrin for targeted drug delivery to the lungs via nebulization. A solution was prepared such that the inspired aerosol dose was isotonic with an acceptable mass median aerodynamic diameter of 2.98 microm and a fine particle fraction of 71.7%. Following single and multiple inhaled doses, high voriconazole concentrations were observed within 30 min in the lung tissue and plasma. Drug solubilization with sulfobutyl ether-beta-cyclodextrin contributed to the rapid and high drug concentrations in plasma following inhalation. Maximal concentrations in the lung and plasma were 11.0 +/- 1.6 microg/g wet lung weight and 7.9 +/- 0.68 microg/mL, respectively, following a single inhaled dose with a corresponding tissue/plasma concentration ratio of 1.4 to 1. Following multiple inhaled doses, peak concentrations in lung tissue and plasma were 6.73 +/- 3.64 microg/g wet lung weight and 2.32 +/- 1.52 microg/mL, respectively. AUC values in lung tissue and plasma were also high. The clinically relevant observed pharmacokinetic parameters of inhaled aqueous solutions of voriconazole suggest that therapeutic outcomes could be benefitted through the use of inhaled voriconazole.
Tolman
Justin A
JA
College of Pharmacy, The University of Texas at Austin, TX 78712, USA.
Nelson
Nicole A
NA
Son
Yoen Ju
YJ
Bosselmann
Stephanie
S
Wiederhold
Nathan P
NP
Peters
Jay I
JI
McConville
Jason T
JT
Williams
Robert O
RO
D000336:Aerosols; D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016503:Drug Delivery Systems; D055666:Lipopeptides; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D010316:Particle Size; D019999:Pharmaceutical Solutions / Q000493:pharmacokinetics; D010949:Plasma / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics*; D012996:Solutions / Q000493:pharmacokinetics; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics*; D065819:Voriconazole; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000493:pharmacokinetics
D000336:Aerosols; D055666:Lipopeptides; D019999:Pharmaceutical Solutions; D011743:Pyrimidines; D012996:Solutions; D014230:Triazoles; D047392:beta-Cyclodextrins; D065819:Voriconazole