PHARMACOKINETICS OF 3 DOSES OF ONCE-WEEKLY FLUCONAZOLE (150, 300, AND450 MG) IN DISTAL SUBUNGUAL ONYCHOMYCOSIS OF THE TOENAIL

Background: Preliminary clinical data suggest that fluconazole is effe ctive in the treatment of patients with onychomycosis. To design optim um dosage regimens, a better understanding of fluconazole's distributi on into and elimination from nails is needed. Objective: The purpose o f this study was to determine plasma and toenail concentrations of flu conazole. Methods: In this multicenter, randomized, double-blind inves tigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients wi th onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail cl ippings from both affected and healthy nails were obtained for flucona zole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was d iscontinued. Results: Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median tim e to reach steady-state fluconazole concentrations in healthy nails wa s 4 to 5 months in the three fluconazole dose groups. In affected nail s, steady-state fluconazole concentrations were achieved more slowly w ith a median time of 6 to 7 months. At the 8-month assessment, affecte d toenail fluconazole concentrations were higher than corresponding pl asma fluconazole concentrations, with ratios of 1.31 to 1.50 in the th ree active treatment groups. Toenail concentrations of fluconazole dec lined slowly after treatment was discontinued, with elimination half-l ives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, r espectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects. Conclusion: Fluconazole penetrates healthy and diseased nails rapidly, yielding de tectable concentrations after two weekly doses. Once it penetrates nai l, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a onc e-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis.