title: Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and -resistant Candida albicans in a murine model of vaginal candidiasis.
abstract: Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 of ≤0.015 and MIC90 of 0.12 μg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 of 8 and MIC90 of 64 μg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (P < 0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC of 64 μg/ml) but fully sensitive in vitro to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 μg/ml) and moderately resistant to fluconazole (MIC of 8 μg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 μg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC.
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA egarvey@viamet.com.
authors.forename: E P
authors.initials: EP
authors.lastname: Garvey
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Hoekstra
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Schotzinger
authors.affiliation: Wayne State University, Detroit, Michigan, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Sobel
authors.affiliation: LSU Health Sciences Center School of Dentistry, New Orleans, Louisiana, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Lilly
authors.affiliation: LSU Health Sciences Center School of Dentistry, New Orleans, Louisiana, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Fidel
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects*; D002181:Candidiasis, Vulvovaginal / Q000188:drug therapy*; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use*; D051379:Mice; D011725:Pyridines / Q000627:therapeutic use*; D013777:Tetrazoles / Q000627:therapeutic use*; D014621:Vagina / Q000382:microbiology*
chemical_list: D000935:Antifungal Agents; D011725:Pyridines; D013777:Tetrazoles; C000599187:VT-1161; D015725:Fluconazole