title: Modeling nikkomycin Z dosing and pharmacology in murine pulmonary coccidioidomycosis preparatory to phase 2 clinical trials.
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.
authors.affiliation: School of Animal and Comparative Biomedical Sciences Valley Fever Center for Excellence.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Shubitz
authors.affiliation: Valley Fever Center for Excellence.
authors.forename: Hien T
authors.initials: HT
authors.lastname: Trinh
authors.affiliation: Valley Fever Center for Excellence.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Perrill
authors.affiliation: Valley Fever Center for Excellence School of Pharmacy Practice and Science.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Thompson
authors.affiliation: School of Pharmacy Practice and Science.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Hanan
authors.affiliation: Valley Fever Center for Excellence Department of Medicine, University of Arizona, Tucson.
authors.forename: John N
authors.initials: JN
authors.lastname: Galgiani
authors.affiliation: Valley Fever Center for Excellence School of Pharmacy Practice and Science Department of Medicine, University of Arizona, Tucson.
authors.forename: David E
authors.initials: DE
authors.lastname: Nix
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D003047:Coccidioidomycosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D017711:Nonlinear Dynamics
chemical_list: D000617:Aminoglycosides; D000935:Antifungal Agents; C011952:nikkomycin
keywords: Mouse; anti-fungal drugs; coccidioidomycosis; experimental infection; nikkomycin Z; pharmacokinetics