Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail

R. C. Savin, L. Drake, D. Babel, D. M. Stewart, Phoebe Rich, M. R. Ling, D. Breneman, R. K. Scher, A. G. Martin, D. M. Pariser, R. J. Pariser, C. N. Ellis, S. Kang, D. Friedman, H. I. Katz, C. J. McDonald, J. Muglia, G. Webster, B. E. Elewski, J. J. LeydenA. D. Bucko, E. H. Tschen, Jon Hanifin, M. R. Morman, J. L. Shupack, N. Levine, N. J. Lowe, W. F. Bergfeld, C. Camisa, D. S. Feingold, N. Konnikov, R. B. Odom, R. Aly, D. L. Greer, J. Hilbert

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. Objective: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. Methods: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. Results: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steadystate concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. Conclusion: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global out-comes.

Original languageEnglish (US)
JournalJournal of the American Academy of Dermatology
Volume38
Issue number6 II
StatePublished - 1998
Externally publishedYes

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Onychomycosis
Fluconazole
Nails
Pharmacokinetics
Placebos
Therapeutics
Arthrodermataceae
Mycoses
Controlled Clinical Trials
Pharmaceutical Preparations
Solubility

ASJC Scopus subject areas

  • Dermatology

Cite this

Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail. / Savin, R. C.; Drake, L.; Babel, D.; Stewart, D. M.; Rich, Phoebe; Ling, M. R.; Breneman, D.; Scher, R. K.; Martin, A. G.; Pariser, D. M.; Pariser, R. J.; Ellis, C. N.; Kang, S.; Friedman, D.; Katz, H. I.; McDonald, C. J.; Muglia, J.; Webster, G.; Elewski, B. E.; Leyden, J. J.; Bucko, A. D.; Tschen, E. H.; Hanifin, Jon; Morman, M. R.; Shupack, J. L.; Levine, N.; Lowe, N. J.; Bergfeld, W. F.; Camisa, C.; Feingold, D. S.; Konnikov, N.; Odom, R. B.; Aly, R.; Greer, D. L.; Hilbert, J.

In: Journal of the American Academy of Dermatology, Vol. 38, No. 6 II, 1998.

Research output: Contribution to journalArticle

Savin, RC, Drake, L, Babel, D, Stewart, DM, Rich, P, Ling, MR, Breneman, D, Scher, RK, Martin, AG, Pariser, DM, Pariser, RJ, Ellis, CN, Kang, S, Friedman, D, Katz, HI, McDonald, CJ, Muglia, J, Webster, G, Elewski, BE, Leyden, JJ, Bucko, AD, Tschen, EH, Hanifin, J, Morman, MR, Shupack, JL, Levine, N, Lowe, NJ, Bergfeld, WF, Camisa, C, Feingold, DS, Konnikov, N, Odom, RB, Aly, R, Greer, DL & Hilbert, J 1998, 'Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail', Journal of the American Academy of Dermatology, vol. 38, no. 6 II.
Savin, R. C. ; Drake, L. ; Babel, D. ; Stewart, D. M. ; Rich, Phoebe ; Ling, M. R. ; Breneman, D. ; Scher, R. K. ; Martin, A. G. ; Pariser, D. M. ; Pariser, R. J. ; Ellis, C. N. ; Kang, S. ; Friedman, D. ; Katz, H. I. ; McDonald, C. J. ; Muglia, J. ; Webster, G. ; Elewski, B. E. ; Leyden, J. J. ; Bucko, A. D. ; Tschen, E. H. ; Hanifin, Jon ; Morman, M. R. ; Shupack, J. L. ; Levine, N. ; Lowe, N. J. ; Bergfeld, W. F. ; Camisa, C. ; Feingold, D. S. ; Konnikov, N. ; Odom, R. B. ; Aly, R. ; Greer, D. L. ; Hilbert, J. / Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail. In: Journal of the American Academy of Dermatology. 1998 ; Vol. 38, No. 6 II.
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abstract = "Background: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. Objective: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. Methods: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. Results: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30{\%} to 33{\%} of steadystate concentrations had been achieved in healthy nails and 22{\%} to 29{\%} in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. Conclusion: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global out-comes.",
author = "Savin, {R. C.} and L. Drake and D. Babel and Stewart, {D. M.} and Phoebe Rich and Ling, {M. R.} and D. Breneman and Scher, {R. K.} and Martin, {A. G.} and Pariser, {D. M.} and Pariser, {R. J.} and Ellis, {C. N.} and S. Kang and D. Friedman and Katz, {H. I.} and McDonald, {C. J.} and J. Muglia and G. Webster and Elewski, {B. E.} and Leyden, {J. J.} and Bucko, {A. D.} and Tschen, {E. H.} and Jon Hanifin and Morman, {M. R.} and Shupack, {J. L.} and N. Levine and Lowe, {N. J.} and Bergfeld, {W. F.} and C. Camisa and Feingold, {D. S.} and N. Konnikov and Odom, {R. B.} and R. Aly and Greer, {D. L.} and J. Hilbert",
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TY - JOUR

T1 - Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail

AU - Savin, R. C.

AU - Drake, L.

AU - Babel, D.

AU - Stewart, D. M.

AU - Rich, Phoebe

AU - Ling, M. R.

AU - Breneman, D.

AU - Scher, R. K.

AU - Martin, A. G.

AU - Pariser, D. M.

AU - Pariser, R. J.

AU - Ellis, C. N.

AU - Kang, S.

AU - Friedman, D.

AU - Katz, H. I.

AU - McDonald, C. J.

AU - Muglia, J.

AU - Webster, G.

AU - Elewski, B. E.

AU - Leyden, J. J.

AU - Bucko, A. D.

AU - Tschen, E. H.

AU - Hanifin, Jon

AU - Morman, M. R.

AU - Shupack, J. L.

AU - Levine, N.

AU - Lowe, N. J.

AU - Bergfeld, W. F.

AU - Camisa, C.

AU - Feingold, D. S.

AU - Konnikov, N.

AU - Odom, R. B.

AU - Aly, R.

AU - Greer, D. L.

AU - Hilbert, J.

PY - 1998

Y1 - 1998

N2 - Background: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. Objective: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. Methods: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. Results: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steadystate concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. Conclusion: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global out-comes.

AB - Background: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. Objective: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. Methods: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. Results: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steadystate concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. Conclusion: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global out-comes.

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