Objectives: Recently, Aspergillus fumigatus (Af) strains with reduced azole susceptibility have been discovered. A non-neutropenic murine model of invasive aspergillosis was used to determine the pharmacokinetics and pharmacodynamics (PK-PD) of posaconazole (POS) against various Af strains. Methods: Groups of 11 female CD1 mice were inoculated in the tail vein with Af strains having MICs of 0.031, 0.5, 0.5 and 16 mg/l, reflecting 1 wildtype and 3 mutations in CYP51a, respectively. Antifungal therapy with POS was administered through oral gavages for 14 days as once-daily dosages of 1, 4, 16 and 64 mg/kg or placebo starting 24 hours after inoculation. PK were determined in infected animals by collecting plasma at day 2 of POS treatment through the orbital vein at: 0, 0.5, 1, 2, 4, 8, 12 and 24 h after POS administration, n=3 per time point. The arithmetic mean plasma concentrations were calculated per time point. A non-compartmental analysis (WinNonLin 5.2) was then used to determine PK parameters of POS. Survival (previously determined) was determined daily until day 14. Results were analyzed by survival curve analysis and plotting PD indices against survival and fitting the Hill equation with variable slope (HEVS) using Prism 5.0. Results: PK: 96 mice were assessable. The AUC normalized to a dose of 1 mg/kg was 10.19, 11.27, 9.96 and 4.64 mg/L.h for dosages of 1, 4, 16 and 64 mg/kg, respectively. The AUC was strongly correlated with dose in a linear fashion from 1 to 16 mg/kg (r2=0.99). Higher dosages of 64 mg/kg however resulted in a slightly less linear relation (r2=0.92). The apparent oral clearance (CL/F) was 0.10, 0.09, 0.10 and 0.22 L/h/kg for dosages of 1, 4, 16 and 64 mg/kg respectively. PD: 176 mice were available for PD assessment. Survival curves indicated that exposure responses were obtained for all 4 strains, with increasing exposure needed to obtain the same result if the MIC was higher. Survival best correlated with AUC/MIC ratio; an AUC/MIC survival plot of all four strains indicated a clear sigmoid exposure-response. The HEVS fitted the data well with a R2 of 0.93. The EI50 was 357 (95% CI 222.1 - 573.8). Conclusion: The AUC - dose correlation of POS is linear for dosages up to 16 mg/kg. The higher apparent oral clearance in the 64 mg/kg group is most probably caused by a lower bioavailability possibly related to saturation of uptake. The concentration effect relationships indicate that AUC/MIC of POS best correlates with outcome.
Full conference title:
19th European Congress of Clinical Microbiology and Infectious Diseases
- ECCMID 19th (2009)