Safety and PK of Nikkomycin Z for Coccidioides Pneumonia Treatment

Every year there are 50,000 new U.S. cases of coccidioidomycosis (Valley Fever). The majority of these illnesses occur as a result of endemic exposure in Arizona and California. The benefits of antifungal therapy for uncomplicated disease are not currently established. Current therapies for serious and complicated forms of coccidioidomycosis are only partially effective and in themselves are unable to eradicate the fungus from sites of infection, commonly resulting in breakthrough infection and/or relapse. Nikkomycin Z is effective in the mouse model and results in improved microbiological response over fluconazole.

The goals of this study include: 1) Evaluating the safety and tolerance of nikkomycin Z following administration of multiple doses (50 mg Q 12 h to 750 mg Q 8 h) for two week and 2) Evaluating the pharmacokinetics of nikkomycin Z after single and multiple doses in relationship to dose. The study will include patients with uncomplicated Coccidioides pneumonia (mild illness) which will allow exploratory analysis of efficacy and dose response based on biomarkers.

• nikkomycin Z (Drug): Stage I: Multiple rising doses. Doses packaged on a unit dose basis in 50 and 250 mg capsules. Subjects take 1-3 capsules per dosing block for 14 days unless ADE or study withdrawal. Dose escalation unless a dose-limiting adverse effect is noted. Subjects assigned to BID dosing will receive 28 doses and subjects assigned to TID dosing will receive 42 doses. * 50 mg BID (n=4) vs placebo capsule BID (n=1) * 50 mg BID (n=4) vs 250 mg BID (n=4) vs Placebo capsule BID (n=2) * 250 mg BID (n=4) vs 500 mg BID (n=4) vs Placebo capsule BID (n=2) * 500 mg BID (n=4) vs Placebo capsule BID (n=1) At least 4 subjects complete lower dose before randomization includes next higher dose. Stage II will be a single dose level selected based on pharmacodynamics and safety from Stage I for 20 additional subjects using 4:1 randomization.
• Placebo (Drug): Placebo comparator

Primary outcomes

• Concentration of Nikkomycin Z in the Blood Over Time (AUC) [0, 0.25, 0.5, 0.75, 1.0, 1.5, 2 , 3, 4, 6, 8 and 12 h hours post-dose on Day 1 and Day 14]
• Highest Concentration of Nikkomycin Z in the Blood (Cmax) [0, 0.25, 0.5, 0.75, 1.0, 1.5, 2 , 3, 4, 6, 8 and 12 h hours post-dose on Day 1 and Day 14]

Sex: All, ages: 18 Years to 50 Years

Inclusion Criteria:

* Age >= 18 years and <= 50 years
* Male or Female (if female, must have a negative pregnancy test and agree to use an acceptable contraception method)
* Able to understand study and give written informed consent
* Have a respiratory illness with at least one of the following: Cough, chest pain dyspnea or tachypnea, sputum production, or fever/chills/night sweats
* Have a new or suspected new pulmonary infiltrate on Chest X-ray
* Have a positive coccidioidal serology by EIA or immunodiffusion

Exclusion Criteria:

* Patients under the age of 18 years or over 50 years
* Patients with a prior history of confirmed coccidioidal infection
* Laboratory diagnosis of another etiology for the inclusion-defining illness
* Inability to comprehend study and provide informed consent
* History of or current evidence of major organ disease
* Concomitant use of prednisone and other corticosteroids not permitted
* Concomitant immunosuppressive therapy is not permitted
* Concomitant antibacterial therapy is not permitted

Participant flow

Outcome results

• Concentration of Nikkomycin Z in the Blood Over Time (AUC) (Primary), Mean, mg*hr/L: A - First Dose Level (n=5) 3.444 +/- 0.710; B - Second Dose Level (n=10) 19.923 +/- NA; C - Third Dose Level (n=10) ; D - Fourth Dose Level (n=5)
• Highest Concentration of Nikkomycin Z in the Blood (Cmax) (Primary), Mean, mg/L: A - First Dose Level (n=5) 0.710 +/- 0.188; B - Second Dose Level (n=10) 3.748 +/- NA; C - Third Dose Level (n=10) ; D - Fourth Dose Level (n=5)

Adverse events

Other adverse events by term

Limitations and caveats: Early termination leading to small numbers of subjects analyzed

• David E Nix, Pharm D, Principal investigator, University of Arizona