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Antimicrobial Agents and Chemotherapy, June 2009, p. 2517-2521, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01609-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Nikkomycin Z after Single Rising Oral Doses{triangledown}

David E. Nix,1* Robert R. Swezey,5 Richard Hector,4 and John N. Galgiani1,2,3

Valley Fever Center for Excellence, Colleges of Pharmacy,1 Medicine, University of Arizona, Tucson, Arizona,2 Southern Arizona VA Health Care System, Tucson, Arizona,3 University of California San Francisco Institute for Global Health, San Francisco, California,4 SRI International, Menlo Park, California5

Received 4 December 2008/ Returned for modification 8 February 2009/ Accepted 28 March 2009

Nikkomycin Z is an antifungal drug that inhibits chitin synthase. This agent is under development as an orphan product for treatment of coccidioidomycosis. Safety and pharmacokinetics of nikkomycin Z were evaluated in healthy male subjects following single, rising oral doses ranging from 250 mg to 2,000 mg. A total of 12 subjects were recruited and divided into two groups. Group 1 (n = 6) received two out of three doses of 250 mg, 1,000 mg, or 1,750 mg and a placebo randomly in place of one of the doses. Group 2 (n = 6) received two out of three doses of 500 mg, 1,500 mg, or 2,000 mg and a placebo in place of one of the doses. Subjects were confined to the study unit overnight prior to dosing, and 12 blood samples were collected over 24 h postdosing while subjects were confined. Subjects returned for additional blood samples and safety evaluations at 48 h and 72 h after each dose. There was a 2-week washout period between doses. Plasma drug concentrations were determined using a validated high-performance liquid chromatography method. Nikkomycin Z was absorbed after oral administration, reaching a maximum concentration in serum of 2.21 µg/ml at 2 h postdose and an area under the concentration-time curve from 0 h to infinity of 11.3 µg·h/ml for the 250-mg dose. Pharmacokinetics appeared linear over the range of 250 to 500 mg; however, relative bioavailability was about 62 to 70% for the 1,000-mg dose and 42 to 47% for doses between 1,500 and 2,000 mg. The mean terminal half-life ranged from 2.1 to 2.5 h and was independent of dose. No serious or dose-related adverse events were observed. This study provides a basis for pharmacokinetic simulations and continued studies of nikkomycin Z administered in multiple doses.

* Corresponding author. Mailing address: University of Arizona College of Pharmacy, P.O. Box 210-207, Tucson, AZ 85721-0207. Phone: (520) 626-4814. Fax: (520) 626-7355. E-mail: nix{at}pharmacy.arizona.edu

{triangledown} Published ahead of print on 6 April 2009.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2517-2521, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01609-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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