Pharmacokinetics of nikkomycin Z following multiple doses in healthy subjects.

Abstract

Nikkomycin Z is an investigational antifungal agent that inhibits chitin synthesis. The drug shows promise against endemic fungi such as Coccidioides spp. The purpose of this study was to determine the pharmacokinetics and safety when administered as multiple, ascending doses in healthy subjects. Healthy adult volunteers received nikkomycin Z in oral doses ranging from 250 mg twice daily to 750 mg three times a day for 14 days. An intensive pharmacokinetic study was conducted after the first dose (day 1) and after the last dose (day 14). Subjects were also monitored for safety and tolerance but were not confined to the facility continuously. Doses were tracked by self-reporting and were observed prior to intensive pharmacokinetic studies. On day 14, the mean (sd) maximal concentration ranged from 3.70 (1.08) to 6.89 (1.59) mg/L, and mean time of maximal concentration ranged from 2.3 to 3.0 h. The mean area under the time curve from time 0 to end of the dosing interval (8 or 12 h) was 17.3 (5.2) mg h/L for 250 mg twice daily, 28.5 (9.5) for 500 mg twice daily, 34.5 (10.9) for 750 mg twice daily, and 35.6 (8.4) for 750 mg thrice daily. The mean half-life ranged from 1.94 to 2.18 h. Bioavailability was less than proportional to dose for the 750 mg doses. Nikkomycin Z was well tolerated, and the study was completed without any serious safety concerns. This study supports continued development of nikkomycin Z as a potential therapeutic for the treatment of coccidioidomycosis.