Pharmacokinetics of nikkomycin Z after single rising oral doses.
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 microg/ml at 2 h postdose and an area under the concentration-time curve from 0 h to infinity of 11.3 microg x 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.
Nix
David E
DE
University of Arizona College of Pharmacy, P.O. Box 210-207, Tucson, AZ 85721-0207, USA. nix@pharmacy.arizona.edu
Swezey
Robert R
RR
Hector
Richard
R
Galgiani
John N
JN
D000284:Administration, Oral; D000328:Adult; D000617:Aminoglycosides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D006801:Humans; D008297:Male
D000617:Aminoglycosides; D000935:Antifungal Agents; C011952:nikkomycin