Research published in The Journal of Infectious Diseases suggests the novel antifungal agent F901318, an orotomide, is a potential new treatment for infections caused by Aspergillus flavus, a common cause of invasive aspergillosis. F901318 inhibits pyrimidine synthesis as a reversible dihydroorotate dehydrogenase inhibitor.
The pharmacokinetics (PK) and pharmacodynamics (PD) of F901318 were evaluated against 4 strains of A flavus using in vitro and in vivo models of invasive fungal sinusitis. Concentration-dependent reduction in galactomannan was selected as the PD end point.
Minimum inhibitory concentrations (MICs) were estimated according to European Committee on Antimicrobial Susceptibility Testing and Clinical Laboratory Standards Institute methodologies for posaconazole (Sigma-Aldrich, Dorset, UK), voriconazole (Sigma-Aldrich, Dorset, UK), and F901318 (F2G Ltd, Manchester, UK).
Static and dynamic in vitro models used cellular bilayers of human nasal epithelial cells and human pulmonary artery endothelial cells constructed on cell culture inserts inoculated with conidia. Custom-designed stainless steel bioreactors were used to simulate human-like PK.
PD studies in the static model used voriconazole and F901318 in 7 concentrations ranging from 0.03 to 2 mg/L and 0.015 to 1 mg/L, respectively. PD studies in the dynamic model used voriconazole concentrations of 0.6, 0.25, 1, and 2 mg/L, in addition to a drug-free control. F901318 infusions were prepared to achieve final concentrations of 0.015, 0.06, 0.25, and 1 mg/L.
In vivo studies were conducted using mice inoculated with suspensions of conidia in both nares. F901318 regimens of 24 mg/kg/d, 8 mg/kg every 8 hours, and 15 mg/kg every 8 hours were initiated 6 hours after inoculation. A positive control cohort received oral posaconazole 20 mg/kg/d.
Plasma PK of F901318 was determined using liquid chromatography-tandem mass spectrometry and PD was determined by serum galactomannan levels. Survival experiments were also performed in which cohorts of mice (n=10) received intravenous F901318 at 24 mg every 24 hours, 8 mg/kg every 8 hours, or 15 mg/kg every 8 hours for 3 days or posaconazole at 2.5, 5, 10, or 20 mg/kg/d. After treatment mice were followed for 7 days and sacrificed if terminally unwell.
MICs for F901318 against the 4 strains of A flavis ranged from 0.015 to 0.06 mg/L. The static model showed both voriconazole and F901318 induced a concentration-dependent decline in galactomannan. The dynamic model showed an exposure-dependent decline in circulating galactomannan whereby a minimum concentration of approximately 2 mg/L and 0.3 mg/L of voriconazole and F901318, respectively, resulted in complete suppression.
Suppression of galactomannan in the in vitro model was equivalent to or exceeded the effect induced by posaconazole. Histologic clearance of lung tissue consistent with the effects of F901318 on galactomannan was also observed.
These results show F901318 has potent antifungal activity in both in vitro and in vivo models and will inform the selection of regimens for further study of invasive aspergillosis.
Disclosures: This study was funded by a grant provided by F2G Ltd, the manufacturer of F901318.
Negri CE, Johnson A, McEntee L, et al. Pharmacodynamics of the novel antifungal agent F901318 for acute sinopulmonary aspergillosis caused by Aspergillus flavus [published online September 12, 2017]. J Infect Dis. doi: 10.1093/infdis/jix479