Comparative Pharmacodynamics of Posaconazole in Neutropenic Murine Models of Invasive Pulmonary Aspergillosis and Mucormycosis.
Antimicrob Agents Chemother. 2014 Sep 2;
Authors: Lewis RE, Albert ND, Kontoyiannis DP
We used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between posaconazole AUC:MIC and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure studied doses reflected human exposures with the oral suspension, delayed-release tablet and IV formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice with Aspergillus fumigatus 293 (AF 293, posaconazole MIC 0.5 mg/L) or R. oryzae 969 (RO 969, posaconazole MIC 2 mg/L), and treated with escalating daily dosages of oral posaconazole designed to achieve AUCs ranging from 1.10- 392 mg⋅h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationship of total drug AUC:MIC (AUC:MIC) and treatment response was similar in both models, with EC90s corresponding to an AUC:MIC threshold of 76 (95% CI 46-102) for AF 293 vs. 87 (95% CI 66-101) for RO 969. Using a provisional AUC:MIC target of > 100, these exposures correlated with serum posaconazole Cmin of 1.25 mg/L for AF 293 and 4.0 mg/L for RO 969. The addition of deferasirox, but not liposomal AMB or caspofungin improved the activity of a suboptimal posaconazole regimen (AUC:MIC 33) in animals with pulmonary mucormycosis. However, no combination was as effective as high-dose monotherapy posaconazole regimen (AUC:MIC 184). Our analysis suggest that posaconazole pharmacodynamics are similar for A. fumigatus and R. oryzae when indexed to pathogen MICs.
PMID: 25182639 [PubMed - as supplied by publisher]