Impact of cyp51A Mutations on the Pharmacokinetic and Pharmacodynamic Properties of Voriconazole in a Murine Model of Disseminated Aspergillosis

The in vivo efficacy of voriconazole against 4 clinical Aspergillus fumigatus isolates with MICs ranging from 0.125 to 2 mg/liter (CLSI document M38A) was assessed in a nonneutropenic murine model of disseminated aspergillosis. The study involved TR/L98H, M220I, and G54W mutants and a wild-type control isolate. Oral voriconazole therapy was started 24 h after intravenous infection of mice and was given once daily for 14 consecutive days, with doses ranging from 10 to 80 mg/kg of body weight, using survival as the endpoint. Survival for all isolates was dependent on the voriconazole dose level (R-2 value of 0.5 to 0.6), but a better relationship existed for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) or the AUC for the free, unbound fraction of the drug divided by the MIC (fAUC/MIC ratio) (R-2 value of 0.95 to 0.98). The 24-h fAUC/MIC ratio showed a clear relationship to effect, with an exposure index for amount of free drug required for 50% of maximum effectiveness (fEI(50)) of 11.17 at day 7. Maximum effect was reached at values of around 80 to 100, comparable to that observed for posaconazole and A. fumigatus. Mice infected with an isolate having a MIC of 2 mg/liter required an exposure that was inversely correlated with the increase in MIC compared to that of the wild-type control, but due to nonlinear pharmacokinetics, this required only doubling of the voriconazole dose. The efficacy of voriconazole for isolates with high MICs for other triazoles but voriconazole MICs within the wild-type population range was comparable to that for the wild-type control. Finally, we used a grapefruit juice-free murine model of aspergillosis and concluded that this model is appropriate to study pharmacokinetic/pharmacodynamic relationships of voriconazole.