In vivo efficacy of VT-1129 against experimental cryptococcal meningitis with the use of a loading dose-maintenance dose administration strategy

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

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

VT-1129 is a novel fungal enzyme-specific Cyp51 inhibitor with potent cryptococcal activity. Because of its long half-life (6 days in mice) and our desire to quickly reach potent efficacy, we evaluated a VT-1129 loading dose-maintenance dose strategy against cryptococcal meningitis. VT-1129 plasma and brain pharmaco-kinetics were first studied in healthy mice, and these data were used to model loading dose-maintenance dose regimens to generate different steady-state concentrations. Mice were inoculated intracranially with Cryptococcus neoformans, and oral treatment began 1 day later. Treatment consisted of placebo or one of three VT-1129 loading dose-maintenance dose regimens, i.e., loading dose of 1, 3, or 30 mg/kg on day 1, followed by once-daily maintenance doses of 0.15, 0.5, or 5 mg/kg, respectively. In the fungal burden arm, therapy continued for 14 days and brains were collected on day 15 for fungal burden assessments. In the survival arm, treatment continued for 10 days, after which mice were monitored without therapy until day 30. VT-1129 plasma and brain concentrations were also measured. All VT-1129 doses significantly improved survival and reduced fungal burdens, compared to placebo. VT-1129 plasma and brain levels correlated with fungal burden reductions (R2 0.72 and R2 0.67, respectively), with a plasma concentration of 1 g/ml yielding a reduction of 5 log10 CFU/g. With the highest loading dose-maintenance dose regimen, fungal burdens were undetectable in one-half of the mice in the fungal burden arm and in one-fourth of the mice in the survival arm, 20 days after the final dose. These data support a loading dose-maintenance dose strategy for quickly reaching highly efficacious VT-1129 concentrations for treating cryptococcal meningitis.

Original languageEnglish (US)
Article numbere01315-18
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number11
DOIs
StatePublished - Nov 2018

Keywords

  • Cryptococcal meningitis
  • Cryptococcus neoformans
  • In vivo efficacy
  • Loading dose
  • Maintenance dose
  • Murine model
  • VT-1129

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'In vivo efficacy of VT-1129 against experimental cryptococcal meningitis with the use of a loading dose-maintenance dose administration strategy'. Together they form a unique fingerprint.

  • Cite this

    Wiederhold, N. P., Xu, X., Wang, A., Najvar, L. K., Garvey, E. P., Ottinger, E. A., Alimardanov, A., Cradock, J., Behnke, M., Hoekstra, W. J., Brand, S. R., Schotzinger, R. J., Jaramillo, R., Olivo, M., Kirkpatrick, W. R., & Pattersona, T. F. (2018). In vivo efficacy of VT-1129 against experimental cryptococcal meningitis with the use of a loading dose-maintenance dose administration strategy. Antimicrobial agents and chemotherapy, 62(11), [e01315-18]. https://doi.org/10.1128/AAC.01315-18