Background: F901318 is the leading member of the orotomide class of antifungal agents and acts via inhibition of DHODH, an important enzyme in pyrimidine biosynthesis. F901318 has a mould-only spectrum of activity and is highly potent in vitro against Aspergillus spp. F901318 is currently being developed for the treatment of invasive aspergillosis. As part of the development process, detailed PK studies are required from multiple animal species to help interpret in vivo efficacy and toxicological data.
Methods: PK profiling in the mouse, rat and cynomolgus monkey was carried out to determine total drug concentrations in plasma following both IV and oral dosing. All doses were administered at 10mg/kg. Blood samples were taken at appropriate time intervals for analysis by LC MC/MS. In a separate study mice were dosed IV with F901318, 8mg/kg TID for four days and levels were measured in key tissues after one and four days, to examine distribution of F901318 in tissues.
Results: The PK parameters of F901318 following a single IV or PO 10mg/kg dose in mice, rats and cynomolgus monkeys are shown in the Table.
|Species||Mouse||Mouse||Rat||Rat||Cyno||Cyno (F)||Cyno (M)|
|AUC 0-24 (ng·hr/ml)||21005||13382||13489||6610||18190||8182||14915|
F901318 shows a typical pharmacokinetic profile when dosed by the IV route. When dosed orally, bioavailability in all species was good with values > 45%. A difference in bioavailability between male and female cynomolgus monkey was noted. In mice dosed with 8mg/kg F901318, there was good distribution in tissues after both single and repeat (TID) dosing for four days. Levels in kidney and liver were higher than those in plasma. Levels in lung were similar to those in plasma. Levels in brain and spleen were lower than plasma levels, however, after repeat dosing potentially therapeutic levels of F901318 were seen in the brain.
Conclusion: F901318 shows good pharmacokinetics and oral bioavailability in various animal species. It also distributes well into the tissues of mice.
- ICAAC 55th (2015)