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 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 approximately 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.
Aviles
P
P
GlaxoSmithKline S.A., Parque Tecnológico de Madrid, 28760 Tres Cantos, Madrid, Spain.
Falcoz
C
C
Guillén
M J
MJ
San Roman
R
R
Gómez De Las Heras
F
F
Gargallo-Viola
D
D
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D007192:Indenes; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013223:Statistics as Topic; D016896:Treatment Outcome
D000935:Antifungal Agents; D001798:Blood Proteins; C412609:GM237354; D007192:Indenes; C003329:sordarin