Methods: MIC was determined as outlined in CLSI M38-A2. Plasma PK was measured after 4 d of oral doses in neutropenic ICR mice without fungal inoculation. In vivo antifungal activity was determined in a tail-vein IA model in neutropenic mice inoculated with A. fumigatus (AF) ATCC 204305 (N=10 per dose). Two separate studies were conducted, with oral VT-1598 treatment starting either 48 h prior (prophylaxis) or 5 h post-inoculation (delayed), with 4 days of post-inoculation dosing, and kidney fungal burden measured 1 d post last dose by both CFU and qPCR. Drug control was 10 mg/kg AmBisome i.v.
Results: The MIC for VT-1598 against AF 204305 was 0.25 μg/ml. The plasma PK of VT-1598 was linearly proportional between the 5 and 40 mg/kg once-daily doses, with AUCs of 155 and 1033 μg*h/ml for the two doses, respectively. VT-1598 was similarly effective in reducing fungal burden when given in delayed treatment compared to prophylaxis, and both studies demonstrated a full dose response (i.e., no to full reduction of fungal burden). When comparing fungal burdens of each dose group to the fungal burden at the start of treatment, the dose of VT-1598 to achieve fungal stasis ranged from 20.5-25.9 mg/kg and to achieve a 1-log10 fungal kill ranged from 30.9 -50.5 mg/kg. Using the previously measured mouse plasma binding (>99.9%), the free AUC /MIC values for stasis and 1-log10 kill ranged from 2.1-2.7 and 3.2-5.2, respectively. These values are within the range of 1-11 that have been reported for posaconazole and isavuconazole (Lepak, AAC, 2013).
Conclusion: VT-1598 had potent antifungal activity in a murine model of IA. The PK/PD relationship was the same as clinically used mold-active CYP51 agents, suggesting it could have similar clinical efficacy. If correct, the tetrazole-based greater selectivity may significantly differentiate VT-1598 from current IA therapies.
E. P. Garvey,
Viamet Pharmaceuticals, Inc.:
P. Warn, Evotec (UK) Ltd.: Employee , Salary .
C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee , Salary .
R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Board Member and Employee , Salary .