Pharmacodynamics of the Novel Antifungal Agent F901318 for Acute Sinopulmonary Aspergillosis Caused by Aspergillus flavus.



Negri, CE, Johnson, A ORCID: 0000-0002-6684-3321, McEntee, L, Box, H, Whalley, S, Schwartz, JA, Ramos-Martín, V, Livermore, J, Kolamunnage-Dona, R ORCID: 0000-0003-3886-6208, Colombo, AL
et al (show 1 more authors) (2018) Pharmacodynamics of the Novel Antifungal Agent F901318 for Acute Sinopulmonary Aspergillosis Caused by Aspergillus flavus. The Journal of infectious diseases, 217 (7). 1118 - 1127.

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Abstract

Aspergillus flavus is one of the most common agents of invasive aspergillosis and is associated with high mortality. The orotomides are a new class of antifungal agents with a novel mechanism of action. An understanding of the pharmacodynamics of the lead compound F901318 is required to plan safe and effective regimens for clinical use.The pharmacokinetics (PK) and pharmacodynamics (PD) of F901318 were evaluated by developing new in vitro and in vivo models of invasive fungal sinusitis. Galactomannan was used as a pharmacodynamic endpoint in all models. Mathematical PK-PD models were used to describe dose-exposure-response relationships.F901318 MICs ranged from 0.015 to 0.06 mg/L. F901318 induced a concentration-dependent decline in galactomannan. In the in vitro model a Cmin:MIC of 10 resulted in suppression of galactomannan; whereas, values of approximately 10 and 9-19 when assessed by survival of mice or the decline in galactomannan, respectively were equivalent or exceeded the effect induced by posaconazole. There was histological clearance of lung tissue that was consistent with the effects of F901318 on galactomannan.F901318 is a potential new agent for the treatment of invasive infections caused by Aspergillus flavus with pharmacodynamics that are comparable to other first-line triazole agents.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 04 Oct 2017 06:23
Last Modified: 22 Nov 2021 21:10
DOI: 10.1093/infdis/jix479
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3009758