In Vivo Efficacy of VT-1129 against Experimental Cryptococcal Meningitis with the Use of a Loading Dose-Maintenance Dose Administration Strategy.

Paradigms and Technologies
Therapeutic Approaches

Abstract

VT-1129 is a novel fungal-specific Cyp51 inhibitor with potent cryptococcal activity. Because of its long half-life (>6 days in mice) and the desire to quickly reach potent efficacy, we evaluated a VT-1129 loading dose-maintenance dose (LD-MD) strategy against cryptococcal meningitis. VT-1129 plasma and brain pharmacokinetics were first studied in healthy mice, and these data were used to model LD-MD doses to generate different steady-state concentrations. Mice were inoculated intracranially with C. neoformans, and oral treatment began 1 day later. Treatment consisted of placebo, three VT-1129 LD-MD groups: LD of 1, 3, or 30 mg/kg on day 1, followed by MD of 0.15, 0.5, or 5 mg/kg once daily, respectively. In the fungal burden arm, therapy continued for 14 days, and brains were collected on day 15 for fungal burden assessment. In the survival arm, treatment continued for 10 days after which mice were monitored off-therapy until day 30. VT-1129 plasma and brain concentrations were also measured. Each VT-1129 dose significantly improved survival and reduced fungal burden compared to placebo. VT-1129 plasma and brain levels correlated with fungal burden reductions (R2 = 0.72 and 0.67, respectively), with plasma concentration of 1 μg/mL yielding a reduction of ∼5 log10 CFU/g. With the highest LD-MD dose, fungal burden was undetectable in half of the mice in the fungal burden arm, and in a quarter of the mice in the survival arm, 20 days after final dose. These data support an LD-MD strategy for quickly reaching highly efficacious VT-1129 concentrations in treating cryptococcal meningitis.

Authors

Wiederhold, Nathan P; Xu, Xin; Wang, Amy; Najvar, Laura K; Garvey, Edward P; Ottinger, Elizabeth; Alimardanov, Asaf; Cradock, Jim; Behnke, Mark; Hoekstra, William J; Brand, Stephen R; Schotzinger, Robert J; Jaramillo, Rosie; Olivo, Marcos; Kirkpatrick, William R; Patterson, Thomas F;

External Links