Modeling Nikkomycin Z Dosing and Pharmacology in Murine Pulmonary Coccidioidomycosis Preparatory to Phase 2 Clinical Trials

Nikkomycin Z (NikZ) is a chitin synthase inhibitor with activity against Cocddioides 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 treatm...

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Bibliographic Details
Published in:The Journal of infectious diseases 2014-06, Vol.209 (12), p.1949-1954
Main Authors: Shubitz, Lisa F., Trinh, Hien T., Perrill, Robert H., Thompson, C. Michael, Hanan, Nathan J., Galgiani, John N., Nix, David E.
Format: Article
Language:English
Subjects:
Aminoglycosides - administration & dosage
Aminoglycosides - blood
Aminoglycosides - pharmacokinetics
Animals
Antifungal Agents - administration & dosage
Antifungal Agents - blood
Antifungal Agents - pharmacokinetics
Biological and medical sciences
Coccidioidomycosis
Coccidioidomycosis - drug therapy
Disease Models, Animal
Dogs
Dosage
Dose-Response Relationship, Drug
Drug design
Female
Fever
Fundamental and applied biological sciences. Psychology
Fungal infections
Fungal spores
FUNGI
Human mycoses
Humans
Infections
Infectious diseases
Major and Brief Reports
Medical sciences
Mice
Microbiology
Mycoses
Nonlinear Dynamics
Pharmacokinetics
Placebos
Tropical mycoses
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Summary:Nikkomycin Z (NikZ) is a chitin synthase inhibitor with activity against Cocddioides 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 culturenegative mice. Comparative data show that plasma levels of NikZ that nearly eradicate Cocddioides in mice are achievable in patients and provide a plausibly effective dose range for initial phase 2 clinical studies.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiu029