Pharmacokinetics of nikkomycin Z after single rising oral doses - PubMed (original) (raw)

Randomized Controlled Trial

. 2009 Jun;53(6):2517-21.

doi: 10.1128/AAC.01609-08. Epub 2009 Apr 6.

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Randomized Controlled Trial

Pharmacokinetics of nikkomycin Z after single rising oral doses

David E Nix et al. Antimicrob Agents Chemother. 2009 Jun.

Abstract

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.

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Figures

FIG. 1.

FIG. 1.

Mean concentration (in micrograms per milliliter) of nikkomycin versus time for the two subject groups (n = 4 per dose level). The left panel includes data for subjects who received doses of 250 mg (○), 1,000 mg (□), and 1,750 mg (Δ) (group 1). The right panel includes data for doses of 500 mg (○), 1,500 mg (□), and 2,000 mg (Δ) (group 2).

FIG. 2.

FIG. 2.

Dose proportionality of nikkomycin Z based on the _C_max (left) and AUC0-∞ (right). Crossbars represent mean values for each dose level.

FIG. 3.

FIG. 3.

Goodness of fit for the selected population pharmacokinetic model. Observed plasma drug concentrations are shown versus the predicted concentrations. The solid line represents the line of identity.

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