Correlation between in vitro and in vivo activities of GM 237354, a new sordarin derivative, against Candida albicans in an in vitro pharmacokinetic-pharmacodynamic model and influence of protein binding

The antifungal effect of GM 237354, a sordarin derivative, was studied in a n in vitro pharmacokinetic (PK)pharmacodynamic dynamic system (bioreactor) which reproduces PK profiles observed in a previously described model of dr ug efficacy against murine systemic candidiasis. Immunocompetent mice infec ted intravenously with 10(5) CFU of Candida albicans were treated with GM 2 37354 at 2.5, 10, and 40 mg/kg of body weight every 8 h subcutaneously for 7 days. Free concentrations in serum were calculated by multiplying total c oncentrations measured in vivo by 0.05, the free fraction determined in vit ro by equilibrium dialysis. In the bioreactor the inoculum was approximate to 10(6) CFU/ml; and a one-compartment PK model was used to reproduce the P K profiles of free and total GM 237354 in serum obtained in mice, and clear ance of C. albicans was measured over 48 h. A good correlation was observed when the in vivo fungal kidney burden and the area under the survival time curve were compared with the in vitro broth "burden," although only when f ree in vivo levels in serum were reproduced in vitro. GM 237354 displayed a 3-log decrease effect both in vivo and in vitro. The very few reports avai lable on in vitro-in vivo correlations have been obtained with antibiotics. The good in vitro-in vivo correlation obtained with an antifungal agent sh ows that the in vitro dynamic system could constitute a powerful investigat ional tool prior to assessment of the efficacy of an anti-infective agent i n animals and humans.