S103 From Oregon Health Sciences University, Portland, Oregon. Reprint requests: Phoebe Rich, MD, 2222 NW Lovejoy, Suite 419, Portland, OR 97210. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/0/90461 The newer oral antifungal agents — terbinafine, itraconazole, and fluconazole — look promising in the treatment of onychomycosis, 1,2 although no standard dosage regimen has been determined. A variety of treatment schedules have been investi- gated, 1 and most of the studies evaluating the phar- macokinetics of these drugs in nails have involved small numbers of healthy volunteers 3-6 or patients with diseased fingernails only. 7 More information is needed regarding the rate of antifungal drug movement through the nail plate, the concentra- Pharmacokinetics of three doses of once-weekly fluconazole (150, 300, and 450 mg) in distal subungual onychomycosis of the toenail Phoebe Rich, MD, Richard K. Scher, MD, Debra Breneman, MD, Ronald C. Savin, MD, David Stuart Feingold, MD, Nellie Konnikov, MD, Jerome L. Shupack, MD, Sheldon Pinnell, MD, Norman Levine, MD, Nicholas J. Lowe, MD, Raza Aly, PhD, Richard B. Odom, MD, Donald L. Greer, PhD, Manuel R. Morman, PhD, MD, Alicia D. Bucko, DO, Eduardo H. Tschen, MD, Boni E. Elewski, MD, Edgar B. Smith, MD, and James Hilbert, PhD Portland, Oregon; New York, New York; Cincinnati and Cleveland, Ohio; New Haven and Groton, Connecticut; Boston, Massachusetts; Durham, North Carolina; Tucson, Arizona; Santa Monica and San Francisco, California; New Orleans, Louisiana; Rutherford, New Jersey; Albuquerque, New Mexico; and Galveston, Texas Background: Preliminary clinical data suggest that fluconazole is effective in the treat- ment of patients with onychomycosis. To design optimum dosage regimens, a better under- standing of fluconazole’s distribution into and elimination from nails is needed. Objective: The purpose of this study was to determine plasma and toenail concentrations of fluconazole. Methods: In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maxi- mum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determi- nations 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 dis- continued. Results: Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concen- trations were still present in toenails at 6 months after treatment in most subjects. Conclusion: Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic charac- teristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis. (J Am Acad Dermatol 1998;38:S103-9.) SUPPORTED BY AN EDUCATIONAL GRANT FROM U.S. PHARMACEUTICALS, PFIZER INC.