Modeling Nikkomycin Z dosing and pharmacology in murine pulmonary coccidioidomycosis preparatory to phase 2 clinical trials

Lisa F. Shubitz, Hien T. Trinh, Robert H. Perrill, C. Michael Thompson, Nathan J. Hanan, John N. Galgiani, David E. Nix

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Nikkomycin Z (NikZ) is a chitin synthase inhibitor with activity against Coccidioides species that is being developed as a first-in-class orphan product for treatment of coccidioidomycosis. It has previously been shown to reduce lethal respiratory infections in mice to undetectable levels when treatment is begun 48 hours after infection. The studies described here focus on bracketing NikZ doses for phase 2 and 3 clinical trials, using an established mouse respiratory infection as a model and starting treatment 120 hours after infection. A dose of 80 mg/kg/day, divided into 2 doses, nearly eradicated infection, and larger doses did not improve fungal clearance. Increasing the duration of treatment from 1 week to 3 weeks resulted in a greater percentage of culture-negative mice. Comparative data show that plasma levels of NikZ that nearly eradicate Coccidioides in mice are achievable in patients and provide a plausibly effective dose range for initial phase 2 clinical studies.

Original languageEnglish (US)
Pages (from-to)1949-1954
Number of pages6
JournalJournal of Infectious Diseases
Volume209
Issue number12
DOIs
StatePublished - Jun 15 2014

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Keywords

  • Mouse
  • anti-fungal drugs
  • coccidioidomycosis
  • experimental infection
  • nikkomycin Z
  • pharmacokinetics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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