Τίτλος:
Fluconazole pharmacokinetics in Galleria mellonella larvae and performance evaluation of a bioassay compared to liquid chromatography-tandem mass spectrometry for hemolymph specimens
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The invertebrate model organism Galleria mellonella can be used to assess the efficacy of treatment of fungal infection. The fluconazole dose best mimicking human exposure during licensed dosing is unknown. We validated a bioassay for fluconazole detection in hemolymph and determined the fluconazole pharmacokinetics and pharmacodynamics in larval hemolymph in order to estimate a humanized dose for future experiments. A bioassay using 4-mm agar wells, 20 l hemolymph, and the hypersusceptible Candida albicans DSY2621 was established and compared to a validated liquid chromatography-tandem mass spectrometry (LC–MS-MS) method. G. mellonella larvae were injected with fluconazole (5, 10, and 20 mg/kg of larval weight), and hemolymph was harvested for 24 h for pharmacokinetics calculations. The exposure was compared to the human exposure during standard licensed dosing. The bioassay had a linear standard curve between 1 and 20 mg/liter. Accuracy and coefficients of variation (percent) values were below 10%. The Spearman coefficient between assays was 0.94. Fluconazole larval pharmacokinetics followed one-compartment linear kinetics, with the 24-h area under the hemolymph concentration-time curve (AUC24 h) being 93, 173, and 406 mg · h/liter for the three doses compared to 400 mg · h/liter in humans under licensed treatment. In conclusion, a bioassay was validated for fluconazole determination in hemolymph. The pharmacokinetics was linear. An exposure comparable to the human exposure during standard licensed dosing was obtained with 20 mg/kg. © 2017 American Society for Microbiology. All Rights Reserved.
Συγγραφείς:
Astvad, K.M.T.
Meletiadis, J.
Whalley, S.
Arendrup, M.C.
Περιοδικό:
Antimicrobial Agents and Chemotherapy
Εκδότης:
American Society for Microbiology
Λέξεις-κλειδιά:
agar; fluconazole; antifungal agent; fluconazole, accuracy; area under the curve; Article; bioassay; Candida albicans; Galleria mellonella; hemolymph; human; kinetics; larva; liquid chromatography-mass spectrometry; maximum plasma concentration; nonhuman; pharmacodynamics; priority journal; weight; animal; animal model; drug effect; larva; liquid chromatography; microbial sensitivity test; microbiology; moth; tandem mass spectrometry, Animals; Antifungal Agents; Candida albicans; Chromatography, Liquid; Fluconazole; Larva; Microbial Sensitivity Tests; Models, Animal; Moths; Tandem Mass Spectrometry
DOI:
10.1128/aac.00895-17
