Pharmacokinetics-Pharmacodynamics of a Sordarin Derivative (GM 237354) in a Murine Model of Lethal Candidiasis

Abstract

Relationships between simulated PK and PK-PD parameters and efficacy were explored. A good correlation independent of the dosing interval was observed with AUC (but not C max or t > MIC) and both AUSTC and kidney burden. Following repeated dosing every 8 h, AUC 50 (AUC at which 50% of the maximum therapeutic efficacy is obtained) was estimated as 21.7 and 37.1 g ⅐ h/ml (total concentrations) for AUSTC and kidney burden using a sigmoid E max and an inhibitory sigmoid E max PK-PD model, respectively. For an efficacy target of 90% survival, AUC was predicted as 67 g ⅐ h/ml. We conclude that the PK-PD approach is useful for evaluating relationships between PK parameters and efficacy in antifungal research. Moreover, the results obtained with this approach could be successfully applied to clinical studies.

Direct Comparison of the Pharmacodynamics of Four Antifungal Drugs in a Mouse Model of Disseminated Candidiasis Using Microbiological Assays of Serum Drug Concentrations

“…Raising the drug concentration to the saturation level which corresponded to serum mMIC for azoles and serum MIC for amphotericin B and maintaining this saturation level appears to be necessary for maximal efficacy. Previous dose fractionation studies have missed this single dose-independent efficacy (2,3,4,7,14). Although saturation levels were comparable to the serum mMIC or MIC in the present study, they should be validated further in models with different infection sites, inoculum sizes, dosing protocols, and additional strains of C. albicans, as in the present study, only one strain of C. albicans was examined.…”

Antifungal Activities of Two New Azasordarins, GW471552 and GW471558, in Experimental Models of Oral and Vulvovaginal Candidiasis in Immunosuppressed Rats

“…Furthermore, oral and vaginal candidiasis models have been shown to afford a simple, reliable, and highly reproducible method for studying the efficacies of new antifungal agents (17,20). On the other hand, strain-related differences in C. albicans pathogenicity in the rat mucosa have been described; consequently, we have used a well-characterized C. albicans strain that has been widely used in previous therapeutic and pharmacodynamic studies in rodents, where its pathogenic properties have been well demonstrated (1,13,14). In the present study, immunosuppression in the VVC model ensured homogeneous and chronic infection in the rats.…”

“…Therapeutic efficacy studies were performed against C. albicans 4711E, a clinical isolate used in previous in vivo studies (1,13,14). C. albicans 4711E was stored at Ϫ80°C in Sabouraud dextrose broth containing 15% glycerol in our laboratory until used.…”

“…Sordarin derivatives have demonstrated potent and relatively broadspectrum antifungal activity in several in vitro (10) and in vivo (1,13,14) studies. A further evolution of this class of compounds has led to a new family of substances called azasordarins.…”

Azasordarins: Susceptibility of Fluconazole-Susceptible and Fluconazole-Resistant Clinical Isolates of Candida spp. to GW 471558

“…J-12, p. 454). In vivo, these compounds have shown efficacy in murine models of candidosis, and a recent report has pointed out activities of sordarins in murine histoplasmosis (1,4). In addition, sordarins display good bioavailability and low toxicity in murine models (1).…”