Summary. In vitro susceptibility to the sordarin derivative GM 237354 and amphotericin B were tested in a total of 190 Cryptococcus neoformans clinical isolates from different geographical areas of Spain and South American countries. Minimal inhibitory concentrations (MICs) were obtained using the NCCLS reference microbroth dilution method and analysed according the serotypes of Cr. neoformans. The MICs for amphotericin B were lower than 1.0 μg ml−1 (MIC90% 0.5 μg ml−1, MIC50% 0.125 μg ml−1) but five isolates showed MICs of 2.0 μg ml−1 to GM 237354 (MIC90% 1.0 μg ml−1, MIC50% 0.5 μg ml−1). Cryptococcus neoformans var. gattii serotype B, was significantly less susceptible than A and AD serotypes (P=0.047 and P=0.022, respectively).

01 Oct 2001·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Animal Pharmacokinetics and Interspecies Scaling of Sordarin Derivatives following Intravenous Administration

Q2 · MEDICINE

Article

Author: Gargallo-Viola, D. ; Aviles, P. ; San Roman, R. ; Gómez De Las Heras, F. ; Pateman, A. ; Guillén, M. J.

ABSTRACT Sordarin derivatives constitute a new group of synthetic antifungal agents that selectively inhibit fungal protein synthesis. They have demonstrated in vitro activity against the most important fungal pathogens, both yeast and filamentous. This new family of compounds has also shown in vivo activity against murine Candida albicans, Histoplasma capsulatum , and Coccidioides immitis experimental infections, as well as against Pneumocystis carinii pneumonia in rats. After intravenous dosing in animals, both the area under the concentration-time curve and the elimination half-life were highest in Cynomolgus monkeys, followed by those in rats, mice, and rabbits. The volume of distribution at steady state for sordarin derivatives was similar in all species tested. The clearance in rats and mice was higher than for other species. GM 237354, a sordarin derivative, was characterized by high serum protein binding in mouse, rat, and monkey serum (unbound fraction, ≤5%). An indirect evaluation of the effect of liver function upon the metabolism of this class of compounds has been made in animals with impaired liver function such as Gunn rats, as well as in allometric studies that showed better correlations of half-life to liver blood flow than to animal body weight. Linearity of the main pharmacokinetic parameters was demonstrated after intravenous dosing of the representative compound GM 193663 at 10 and 20 mg/kg of body weight in rats. Allometry was used to determine whether human pharmacokinetic parameters can be predicted from animal data by regression analysis against body weight and liver blood flow. All these results have demonstrated that the human pharmacokinetics of sordarin derivatives can be forecast from animal data.

01 Oct 2001·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Gargallo-Viola, D. ; Aviles, P. ; Gómez De Las Heras, F. ; San Roman, R. ; Falcoz, C. ; Guillén, M. J.

ABSTRACT The antifungal effect of GM 237354, a sordarin derivative, was studied in an in vitro pharmacokinetic (PK)-pharmacodynamic dynamic system (bioreactor) which reproduces PK profiles observed in a previously described model of drug efficacy against murine systemic candidiasis. Immunocompetent mice infected intravenously with 10 5 CFU of Candida albicans were treated with GM 237354 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 concentrations measured in vivo by 0.05, the free fraction determined in vitro by equilibrium dialysis. In the bioreactor the inoculum was ≈10 6 CFU/ml; and a one-compartment PK model was used to reproduce the PK profiles of free and total GM 237354 in serum obtained in mice, and clearance 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 free 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 available on in vitro-in vivo correlations have been obtained with antibiotics. The good in vitro-in vivo correlation obtained with an antifungal agent shows that the in vitro dynamic system could constitute a powerful investigational tool prior to assessment of the efficacy of an anti-infective agent in animals and humans.

100 Deals associated with GM-237354

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Indication	Highest Phase	Country/Location	Organization	Date
Candidiasis	Preclinical	-	GSK Plc	-
Coccidioidomycosis	Preclinical	-	GSK Plc	-
Histoplasmosis	Preclinical	-	GSK Plc	-
Mycoses	Preclinical	US	GSK Plc	-
Protozoan Infections	Preclinical	-	GSK Plc	-

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