Pharmacokinetics of three doses of once-weekly fluconazole (150, 300, and 450 mg) in distal subungual onychomycosis of the toenail
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1 SUPPORTED BY AN EDUCATIONAL GRANT FROM U.S. PHARMACEUTICALS, PFIZER INC. 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 treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding 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 maximum 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 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 discontinued. 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 concentrations 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 characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis. (J Am Acad Dermatol 1998;38:S103-9.) The newer oral antifungal agents terbinafine, itraconazole, and fluconazole look promising in the treatment of onychomycosis, 1,2 although no From Oregon Health Sciences University, Portland, Oregon. Reprint requests: Phoebe Rich, MD, 2222 NW Lovejoy, Suite 419, Portland, OR Copyright 1998 by the American Academy of Dermatology, Inc /98/$ /0/90461 standard dosage regimen has been determined. A variety of treatment schedules have been investigated, 1 and most of the studies evaluating the pharmacokinetics 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- S103
2 S104 Rich et al. Journal of the American Academy of Dermatology June 1998 tions achieved, and the persistence of drug in the nail plate after discontinuing therapy. Fungal infections of the toenail are difficult to treat because of the unique properties of the nail unit. 1,2 To be effective, an antifungal drug must penetrate the affected nail tissue (the nail bed or the nail unit) and persist in high concentrations until the infecting pathogen is eradicated. Because topical antifungal agents fail to penetrate the hard keratin of the nail plate, they are usually ineffective in patients with onychomycosis. 8 Although pharmacokinetic data for the older oral antifungal agents griseofulvin and ketoconazole are scant, it is assumed that these drugs penetrate into the nail plate via the nail matrix. 9 Therefore therapy with these drugs must be given until the entire nail plate is clinically cured, which can take up to 18 months for toenails. 10 In contrast, pharmacokinetic data for itraconazole 3,11,12 and terbinafine 4-7,13 indicate that these newer agents reach the nail plate via diffusion through the nail bed, producing therapeutic concentrations in distal nail more quickly. On the basis of its favorable pharmacokinetic profile, 14 good penetration into nails is predicted for fluconazole. Oral absorption of fluconazole is rapid and nearly complete (>90% bioavailability), regardless of gastric ph or the presence of food, thereby resulting in high plasma concentrations. In contrast to itraconazole or terbinafine, protein binding of active drug is minimal (about 11%), so that most fluconazole circulates as free drug. 15 Because of the low extent of plasma protein binding, any factor causing a slight change in the binding would not be expected to change the pharmacologic effect or pharmacokinetics of the drug. 16 Tissue distribution of fluconazole is extensive, and the volume of distribution of the drug is approximately equivalent to total body water. 17 Fluconazole is also unique because it is the only azole antifungal that is not metabolized to any great extent. About 80% of a fluconazole dose is excreted unchanged in the urine. 18 In previous studies, fluconazole was also found to penetrate nails readily. Hay 19 found that after only a single 50 mg dose of fluconazole, the mean concentration of the drug in nine subjects reached 1.31 µg/gm in nails 2 hours after the first dose, which was higher than in plasma (0.76 µg/ml), and increased by day 14 to 1.80 µg/gm. In a study of 18 subjects, Faergemann and Laufen 20 found the fluconazole concentration in healthy toenails was already above that in serum after 1 month of onceweekly 150 mg doses (3.09 µg/gm) and rose to 8.54 µg/gm after 6 months of treatment, whereas serum concentrations remained stable. Toenail concentrations of fluconazole could still be measured 6 months after treatment ended. Similar pharmacokinetic results were seen in a study reported earlier in 10 subjects dosed with 150 mg once weekly with fluconazole in Sweden. 21 The purpose of this study was to determine corresponding toenail and plasma concentrations of fluconazole in a larger population of patients being treated for onychomycosis with 150, 300, or 450 mg oral fluconazole once weekly. PATIENTS AND METHODS Study design A subset of 151 subjects from a randomized, doubleblind, fixed-dose, parallel-group, placebo-controlled multicenter study 22 investigating the efficacy and safety of once-weekly fluconazole in the treatment of onychomycosis participated in this pharmacokinetic study. The study protocol was approved by the institutional review boards at the participating treatment facilities. Of the 15 sites participating in the clinical study, nine participated in the pharmacokinetic portion: Investigators were instructed to enroll as many patients as were willing for the pharmacokinetic study. Subjects were randomly assigned to treatment with fluconazole 150, 300, or 450 mg once weekly, or matching placebo once weekly, according to a computer-generated randomization schedule. They were instructed to take their dose orally on the same day each week. Of note, patients who required treatment with any of the following medications were not allowed to participate in the study because of potential drug interactions with fluconazole: Cimetidine, hydrochlorothiazide, rifampin, warfarin, phenytoin, cyclosporine, terfenadine, astemizole, or loratadine. Written informed consent was obtained from each subject before participation in the pharmacokinetic investigation. Study procedures Subjects participating in the pharmacokinetic investigation followed the same schedule of visits as described in the clinical study. 22 During treatment, monthly visits were scheduled at which patients were evaluated for safety and efficacy. At these visits, fluconazole toenail and plasma samples were taken as described below to assess pharmacokinetics. Additional safety visits were scheduled 2 and 6 weeks after the start of treatment. The pharmacokinetic assessment was also carried out at the 2-week safety visit. Therapy was
3 Journal of the American Academy of Dermatology Volume 38, Number 6, Part 2 Rich et al. S105 discontinued when either the toenail selected as target for the efficacy study was clinically normal and the pathogen eradicated for two consecutive monthly visits or when 12 months of study drug therapy had been completed, whichever occurred earlier. Subjects who were clinically cured or improved at the end of therapy entered a 6-month blinded follow-up period and were assessed for safety, efficacy, and pharmacokinetics at 2, 4, and 6 months after treatment. Method of assessment A 10 ml blood sample for the determination of plasma fluconazole concentrations was collected at each monthly visit except the 4- and 6-month follow-up visits. Previous pharmacokinetic studies showed that, after multiple dosing, the plasma C max of fluconazole occurred around 2 to 6 hours after dosing, 14 so visits were scheduled within 2 to 6 hours after ingestion of the weekly dose of study drug to obtain plasma with fluconazole concentrations near C max. Distal toenail clippings were obtained just after blood sampling at each visit. At each visit for each individual, all clippings from toenails not used in the clinical and mycologic evaluation that were found to be affected by onychomycosis were placed in one pool, and all toenails found to be healthy at baseline were placed in another. Nails retained the healthy or affected designation throughout the study, including the posttreatment follow-up period. Each pool was assayed separately for fluconazole. Subjects were asked not to trim or cosmetically treat the nails during the study period. Just before nail samples were obtained, the toenails were swabbed clean with alcohol. Nail samples were then obtained by clipping the distal sections of all nontarget toenails as close to the skin as possible without causing discomfort to the subject. Analytical methods Plasma samples were assayed in duplicate for fluconazole at Corning Hazleton Wisconsin (Madison, WI), by means of reversed-phase high-performance liquid chromatography on a Zorbax RX C8 column using UV absorbency detection. The study sample concentrations of fluconazole were calculated from a weighted (1/concentration 2 ) linear regression of the standard curves, which ranged from 50 to 20,000 ng/ml. For the standard of 50 ng/ml (the lower limit of quantitation), the mean ± standard deviation back-calculated concentration, the relative standard deviation, and the deviation of the mean from theoretical concentration were 50.2 ± 1.37 ng/ml, 2.7%, and 0.3%, respectively. The low deviation of the mean concentration from theoretical for the determined quality control concentrations and the mean between-day variabilities for the quality control samples indicated that the fluconazole plasma assay was accurate and precise. Samples from subjects given placebo were not analyzed. In addition, samples from six subjects in two of the active treatment groups were excluded because measurable concentrations of fluconazole were detected in plasma samples at baseline. Toenail samples were assayed in duplicate for fluconazole at Corning Hazleton Wisconsin (Madison, WI), by means of a validated gas chromatographic system with a mass spectrometric detector. The amount of fluconazole in study samples was calculated from a weighted (1/concentration 2 ) linear regression of the standard curves, which ranged from 2.5 to 50 ng of fluconazole per sample. The concentration of fluconazole in nail study samples was calculated by dividing the amount of fluconazole determined in the assay by the weight of the nail sample. For the standard of 2.5 ng fluconazole (the lower limit of quantitation), the mean ± standard deviation back-calculated weight, the relative standard deviation, and the deviation of the mean from theoretical concentration were 2.52 ± ng fluconazole, 4.1%, and 0.8%, respectively, again indicating that the fluconazole nail assay was accurate and precise. Samples from subjects given placebo were not analyzed. In addition, samples from six subjects in two of the active treatment groups were excluded because measurable concentrations of fluconazole were detected in nail samples at baseline. Parameter calculations All pharmacokinetic calculations and estimates were performed separately for affected and healthy nails. To assess dose-proportionality, nail concentrations (amount of fluconazole in nail sample divided by weight of nail sample) were normalized to the 150 mg dose for each subject. The half-life in nails was determined by linear regression of log nail concentration versus time using the end-of-treatment and follow-up data. The half-life was calculated as (ln 2.0)/slope. The time to reach steady state for an individual was estimated by examination of individual concentrationtime plots in conjunction with statistical criteria based on regression of concentration against study month. A sequence of simple linear regression models on study month was fitted to the concentrations. The first analysis included all concentrations beginning at month 0.5 and each successive iteration eliminated the earliest month from the previous analysis. A minimum of three concentrations was required for each analysis. Although no rigorous algorithm was defined, several components from this sequence of analyses were evaluated in judging the steady-state time. In order of consideration these were (1) the first month for which the p-value for regression
4 S106 Rich et al. Journal of the American Academy of Dermatology June 1998 Table I. Number of subjects studied Fluconazole 150 mg 300 mg 450 mg Placebo Total Received treatment Participated in pharmacokinetic investigation Pharmacokinetic parameters analyzed was less than 10%, (2) the month at which the slope changed from positive to zero or negative, (3) the month at which consecutive concentration means appeared to level off, and (4) the month at which the residual mean square was similar to the total variance. The concentration of fluconazole at steady state (C SS ) was calculated as the average of all concentrations measured on and after the steady-state month. Cases in which steady state was not achieved according to these criteria during the observation period were not included in the comparative analysis of mean steady-state concentrations. Statistical analysis Means and standard deviations were calculated for plasma and nail concentrations at each time point during treatment and follow-up. For each dose, concentrations of fluconazole in affected nail were compared with concentrations in healthy nail at each study month by means of a two-sided paired t-test. Median time to steady state for each dose was obtained from the Kaplan-Meier estimate of the cumulative distribution of month to steady state. The distributions of steady-state times were compared among doses by means of the logrank statistic. A 5% level of significance was used for all statistical analyses. Dose-normalized concentrations at each study month were compared across fluconazole doses by means of the F-statistic from a one-way ANOVA. Nail concentrations were considered dose-proportional if the mean normalized concentrations were not significantly different among doses. To determine whether clinical response to treatment was related to fluconazole nail concentration, logistic regression analyses were conducted for clinical response at end of therapy versus steady-state fluconazole concentration in affected nail. For mycologic response, logistic regression of mycologic outcome against fluconazole concentration in affected nail at first month of eradication was conducted. For the analyses, clinical response outcomes of improvement and failure were combined to produce a dichotomous response variable; outcomes of persistence were assigned the maximum nail concentration that the subject achieved for the analysis of mycologic response. The global clinical response (considering all toenails) was cross-tabulated against steady-state concentration range (categorized as 5.0, 5.0 to 7.5, or 7.5 µg/gm) and a Mantel-Haenszel chi-square for nonzero correlation was computed. RESULTS Subjects who received treatment and were included in the pharmacokinetic assessment are summarized in Table I by treatment group. A total of 151 subjects gave consent to participate in the pharmacokinetic investigation. Samples from the 36 subjects who received placebo were not analyzed. No significant differences in demographic characteristics or disease severity among treatment groups were found at baseline. The demographic characteristics of the subjects in the pharmacokinetic study were very similar to those in the complete study population. 22 Most of the subjects in the pharmacokinetic study were male (76.1%), with the mean age in the four treatment groups ranging from 46.5 to 47.8 years and mean weight ranging from 78.0 to 81.5 kg. Fluconazole was found in both healthy and affected nails at the time of the earliest sample (after two weekly doses) in nearly all subjects. Only 6 of the 115 patients (5.2%) receiving fluconazole in the study (three receiving 150 mg, two receiving 300 mg, and one receiving 450 mg fluconazole) had no fluconazole in healthy or affected nails. Healthy nail concentrations were significantly higher than affected nail concentrations, indicating a slower uptake of the drug in diseased nails. At 2 weeks, healthy toenail concentrations were 44%, 30%, and 24%, respectively, of plasma concentrations (Fig. 1). Affected toenail concentrations were somewhat lower: 18%, 17%, and 17% of plasma concentrations for the 150, 300, and 450 mg doses, respectively. After the 2-week visit, plasma concentrations of fluconazole remained constant for the remainder
5 Journal of the American Academy of Dermatology Volume 38, Number 6, Part 2 Rich et al. S107 A B C Fig. 1. Mean toenail and plasma concentrations of fluconazole over time by dose group. A, 150 mg/wk. B, 300 mg/wk. C, 450 mg/wk. of the treatment time, indicating that plasma levels were consistent throughout the study. However, nail concentrations continued to rise, reaching steady state at median times of 5, 5, and 4 months for the 150, 300, and 450 mg doses, respectively, for healthy nails. Steady state was attained later in affected nails. In these nails, the median steadystate times were 6.5, 6, and 7 months for the 150, 300, and 450 mg doses, respectively. In healthy nails at 8 months, after steady state was achieved in all nails at all dose levels, concentrations were 202%, 191%, and 166% of plasma concentrations for the 150, 300, and 450 mg doses, respectively. Affected nail concentrations remained lower than healthy nail concentrations at 8 months. They were 150%, 140%, and 131% of plasma concentrations for the 150, 300, and 450 mg doses, respectively. Fluconazole concentrations in toenails declined slowly during the follow-up period after treatment (Fig. 1). Measurable concentrations of fluconazole (0.53, 1.09, and 2.88 µg/gm in the 150, 300, and 450 mg dose groups, respectively) were still present in the affected toenails of most subjects 6 months after the drug was discontinued. As shown in Table II, the estimated elimination half-life of fluconazole in healthy toenails ranged from 2 to 3 months, whereas that for affected toenails ranged from 2 to 4 months. Clinical and mycologic responses for all subjects are presented elsewhere. 16 In the present study, a significant correlation (r 2 = 0.116, p = 0.008) was observed between affected toenail steady-state fluconazole concentration and clinical response at the end of therapy. A significant correlation (p = 0.016) also was found for the cross-tabulation of global clinical response (based on response of all infected toenails) and affected toenail steady-state fluconazole concentration. Below a steady-state concentration of 7.5 µg/gm, global response was somewhat low. Below 5.0 µg/gm, 3 of 28 patients (11%) reported all nails clear. Only 3 of 32 patients (9%) with steady-state nail concentrations between 5.0 and 7.5 µg/gm reported all nails clear. However, at a steady-state concentration above 7.5 µg/gm, 16 of 44 patients (36%) reported all nails clear. No such correlation, however, was found between mycologic outcome and steady-state fluconazole concentration in affected toenails. DISCUSSION Along with high cure rates, low recurrence rates, and a favorable safety profile, pharmacoki-
6 S108 Rich et al. Journal of the American Academy of Dermatology June 1998 Table II. Summary of pharmacokinetic parameters for fluconazole in healthy and affected toenails Healthy toenail Affected toenail Parameter 150 mg 300 mg 450 mg 150 mg 300 mg 450 mg C ss (µg/gm) Median time to C ss (months) Mean t 1/2 ± SD (months) 1.81 ± ± ± ± ± ± 2.63 C ss, Steady-state concentration; t1, elimination half-life. /2 netic properties have been identified as important criteria in the evaluation of the ideal antifungal drug. 2 The results of our study clearly demonstrated that orally administered fluconazole was present in infected toenails as early as the second week of treatment. The concentrations of fluconazole present at the initial 2-week assessment, as well as throughout the treatment and posttreatment periods, were well above the minimum inhibitory concentration demonstrated for dermatophytes (0.05 to 0.39 µg/ml) and nondermatophytes (0.78 to 1.56 µg/ml). 23 The early presence of fluconazole in the distal nail suggests that the drug enters the nail plate across the whole nail bed and is not just taken up by newly forming nail in the matrix region. In an earlier study, higher mycologic cure rates were observed in patients treated with itraconazole 200 mg/day compared with those who received 100 mg/day. 12 Because itraconazole nail concentrations were higher in the 200 mg/day dose group, the authors concluded that antifungal drug concentration in nail may be a good index of efficacy in fungal nail infections. Our study is the first to evaluate systematically a potential correlation between antifungal drug concentration within the nail and efficacy. The correlation between affected nail steady-state concentration and clinical outcomes is a strong indication that there is a relationship between nail concentration and response, and the rapid penetration and slow release of fluconazole in nail is an important factor in the overall success of the drug. Rapid penetration into nail also has been observed for itraconazole and terbinafine. One study reported that itraconazole was present in fingernails of healthy volunteers after 7 days of 100 mg/day. 3 However, in a study with onychomycosis patients, 11 itraconazole was not detected in infected fingernails or toenails in 20% (4/20) of patients after 1 month of 100 mg/day itraconazole. In contrast, in the present study only 5.2% of subjects had undetectable concentrations of fluconazole after two weekly doses. This may explain the high cure rate obtained with fluconazole for both toenail and fingernail onychomycosis. In addition to rapid penetration, therapeutic fluconazole concentrations were maintained in affected nails once steady state had been reached. The correlation between treatment outcome and steady-state concentration for all nails showed that, at a steady-state concentration above 7.5 µg/gm, 36% (16/44) patients had all nails clear, dramatically more than among those with steadystate concentrations below 7.5 µg/gm. Only 9% (3/32) of patients with a lower steady-state concentration had all nails clear. Patients receiving the middle dose (300 mg once weekly) had an average steady-state concentration of 8.69 µg/gm (Table II), well above 7.5 µg/gm. The long persistence of fluconazole after treatment is likely to be important in preventing relapse of the infection and also may explain the continued improvement seen in some patients even after treatment was discontinued. Although the long half-life in nail is indicative of the high affinity of fluconazole for the nail, the fact that fluconazole concentrations decrease in nails with a measurable half-life indicates that the binding is not irreversible. This suggests that there is a level of free fluconazole available in the nail and nail bed during and after therapy. The pharmacokinetic profile of fluconazole makes this drug an attractive option in the treatment of onychomycosis. REFERENCES 1. Zaias N, Glick B, Rebell G. Diagnosing and treating onychomycosis. J Fam Pract 1996;42: Odom RB. New therapies for onychomycosis. J Am Acad Dermatol 1996;35:S Cauwenbergh G, Degreef H, Heykants J, et al.
7 Journal of the American Academy of Dermatology Volume 38, Number 6, Part 2 Rich et al. S109 Pharmacokinetic profile of orally administered itraconazole in human skin. J Am Acad Dermatol 1988;18: Faergemann J, Zehender H, Denouël J, Millerioux L. Levels of terbinafine in plasma, stratum corneum, dermis-epidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once per day for four weeks. Acta Derm Venereol 1993;73: Faergemann J, Zehender H, Millerioux L. Levels of terbinafine in plasma, stratum corneum, dermis-epidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once daily for 7 and 14 days. Clin Exp Dermatol 1994;19: Kovarik JM, Mueller EA, Zehender H, Denouel J, Caplain H, Millerioux L, et al. Multiple-dose pharmacokinetics and distribution in tissue of terbinafine and metabolites. Antimicrob Agents Chemother 1995;39: Finley AY. Pharmacokinetics of terbinafine in the nail. J Dermatol Treat 1992;3(suppl 1): Hay RJ. Onychomycosis. Agents of choice. Dermatol Clin 1993;11: Zaias N. Onychomycosis. Dermatol Clin 1985;3: Barranco V. New approaches to the diagnosis and management of onychomycosis. Int J Dermatol 1994;33: Matthieu L, De Doncker P, Cauwenbergh G, Woestenborghs R, van de Velde V, Janssen PA, et al. Itraconazole penetrates the nail via the nail matrix and the nail bed an investigation in onychomycosis. Clin Exp Dermatol 1991;16: Willemsen M, De Doncker P, Willems J, et al. Posttreatment itraconazole levels in the nail. J Am Acad Dermatol 1992;26: Dykes PJ, Thomas R, Finlay AY. Determination of terbinafine in nail samples during systemic treatment for onychomycosis. Br J Dermatol 1990;123: Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 1990;12(suppl 3):S Grant SM, Clissold SP. Fluconazole, a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs 1990;39: Debruyne D, Ryckelynck J-P. Clinical pharmacokinetics of fluconazole. Clin Pharmacokinet 1993;24: Perry CM, Whittington R, McTavish D. Fluconazole: an update of its antimicrobial activity, pharmacokinetic properties, and therapeutic use in vaginal candidiasis. Drugs 1995;49: Warnock DW. New pharmacological concepts in antimycotic treatment. J Eur Acad Dermatol Venereol 1993;2: S Hay RJ. Pharmacokinetic evaluation of fluconazole in skin and nails. Int J Dermatol 1992;31(suppl 2): Faergemann J, Laufen H. Levels of fluconazole in normal and diseased nails during and after treatment of onychomycoses in toe-nails with fluconazole 150 mg once weekly. Acta Dermatol Venereol (Stockh) 1996;76: Fräki J, Heikkila H, Kero M, Kuokkanen K, Oksman R, Rautanen T, et al. Dermatology Abstract 14, Scher RK, Breneman D, Rich P, Savin RC, Feingold DS, Konnikov N, et al. Once-weekly fluconazole (150 mg, 300 mg, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol 1998;38:S Oyeka CA, Gugnani HC. In vitro activity of seven azole compounds against some clinical isolates of nondermatophyte filamentous fungi and some dermatophytes. Mycopathologia 1990;110:
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