Pharmacodynamics of a New Triazole, Posaconazole, in a Murine Model of Disseminated Candidiasis

Abstract

Previous in vivo studies have characterized the pharmacodynamic characteristics of two triazole compounds, fluconazole and ravuconazole. These investigations demonstrated that the 24-h area under the concentrationtime curve (AUC)/MIC ratio is the critical pharmacokinetic-pharmacodynamic (PK-PD) parameter associated with treatment efficacy. Further analysis demonstrated that a free-drug triazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole, posaconazole. The PK-PD parameters (percent time above MIC, AUC/MIC ratio, and peak serum drug level/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 48 h of therapy. Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice. Peak levels and AUC from 0 h to ؕ values were nonlinear over the 16-fold dose range studied. Serum drug elimination half-life ranged from 12.0 to 17.7 h. Protein binding was 99%. Single dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum posaconazole levels had fallen below the MIC. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio R 2 ‫؍‬ 83%; peak serum drug/MIC ratio R 2 ‫؍‬ 85%; time that serum levels of posaconazole remained above the MIC R 2 ‫؍‬ 65%). Similar studies were conducted with 11 additional C. albicans isolates with various posaconazole susceptibilities (MIC, 0.015 to 0.12 g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The posaconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (6.12 to 26.7, mean ؎ SD ‫؍‬ 16.9 ؎ 7.8, P value, 0.42). These free-drug AUC/MIC ratios are similar to those observed for other triazoles in this model. Antimicrobial pharmacodynamic characterizations have provided an understanding of the relationship between drug exposure and treatment efficacy. Therapeutic outcome predictions based upon these pharmacodynamic studies have correlated well in treatment against both susceptible and resistant pathogens (3). In addition, the strength of these in vivo predictions has been shown to be independent of animal species, infection site, and duration of treatment studied. These pharmacodynamic analyses in animal infection models have proven useful for the design of optimal dosing regimens and the validation of susceptibility breakpoint guidelines (8, 9, 18).Prior in vivo studies have demonstrated that the pharmacokinetic-pharmacodynamic (PK-PD) parameter predictive of triazole efficacy against Candida albicans is the 24-h area under the concentration-time curve (AUC)/MIC rati...

Current Concepts in Antifungal Pharmacology

“…[76][77][78] Although less data are available for other triazoles and mold infections, studies in animal models of aspergillosis also suggest that the AUC:MIC ratio is the best predictor of treatment response to posaconazole, with 50% survival at total-drug AUC:MIC ratios of 100 to 150 and maximal responses at a ratio greater than 440 (free-drug AUC:MIC ratio of approximately 8-25). 79,80 Clinical trial data for candidal infections have suggested that this pharmacokinetic-pharmacodynamic relationship may be helpful for predicting treatment efficacy in For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings a .…”

Understanding antifungal prophylaxis with posaconazole in hematology patients: an evolving bedside to bench story

“…In a mouse model of invasive candidiasis, treatment with a single dose of posaconazole resulted in prolonged inhibition of fungal growth for at least 20 h after the free drug concentration decreased below the MIC of the infecting strain. 12 Prolonged suppression of C. albicans growth was also observed even with a dose of posaconazole that did not result in serum free drug concentrations above the MIC at any point during therapy. 12 Similarly, in a study of A. fumigatus infection in mice, the authors noted that the drug exposure required to achieve stasis and killing of A. fumigatus was lower than that observed in similar studies of other triazoles.…”

“…12 Prolonged suppression of C. albicans growth was also observed even with a dose of posaconazole that did not result in serum free drug concentrations above the MIC at any point during therapy. 12 Similarly, in a study of A. fumigatus infection in mice, the authors noted that the drug exposure required to achieve stasis and killing of A. fumigatus was lower than that observed in similar studies of other triazoles. 13 How can we resolve this apparent discrepancy between relatively low serum posaconazole levels yet documented antifungal efficacy?…”

“…18 Measurement of posaconazole kinetics in epithelial cells demonstrated that this prolonged post-antifungal effect was due to the persistence of high levels of drug within the epithelial cells, 18 thus providing an explanation for the prolonged post-antifungal effect reported in animal studies of posaconazole. 12 In addition, cellular fractionation experiments and localization studies using fluorophore-conjugated posaconazole have demonstrated that this hydrophobic antifungal accumulates only within membrane compartments of host cells, rather than throughout the whole cell. 18,19 Because membranes represent only a small fraction (<10%) of the volume of eukaryotic cells, the actual membrane concentration of posaconazole is at least 10-fold higher than prior estimates of total cellular concentration.…”

Farmacología de los azoles

“…En el caso de los azoles no se dispone de información clínica relevante, aunque en los modelos de animales vivos, es la relación AUC con la CMI (AUIC), el parámetro que mejor predice la eficacia de estos antifúngicos. Los estudios realizados parecen señalar que el valor óptimo del AUIC se sitúa en 20 [1,2]. La comparación de las AUC (Tabla1) permite comprobar las diferencias en el valor AUC/CMI de los diferentes azoles si se utiliza en el cálculo el mismo valor para la CMI.…”