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Pharmacokinetics of antifungal agents in onychomycoses
1Laboratory of Pharmacology, University Hospital Center, Caen, France.
Abstract:
Onychomycosis is caused by infection by fungi, mainly dermatophytes and nondermatophyte yeasts or moulds; it affects the fingernails and, more frequently, the toenails. Dermatophytes are responsible for about 90 to 95% of fungal infections. Trichophyton rubrum is the most common dermatophyte; Candida albicans is the major nondermatophyte yeast. Although topical therapy of onchomycosis does not lead to systemic adverse effects or interactions with concomitantly taken drugs, it does not provide high cure rates and requires complete compliance from the patient. At present there are 3 oral antifungal medications that are generally used for the short term treatment of onychomycosis: itraconazole, terbinafine and fluconazole. The persistence of these active drugs in nails allows weekly administration, reduced treatment or a pulse regimen. Good clinical and mycological efficacies are obtained with itraconazole 100 to 200 mg daily, terbinafine 250mg daily for 3 months, or fluconazole 150 mg weekly for at least 6 months. Itraconazole is a synthetic triazole with a broad spectrum of action. It is well absorbed when administered orally and can be detected in nails 1 to 2 weeks after the start of therapy. The nail : plasma ratio stabilises at around 1 by week 18 of treatment. Itraconazole is still detectable in nails 27 weeks after stopping administration. Nail concentrations are higher than the minimum inhibitory concentration (MIC) for most dermatophytes and Candida species from the first month of treatment. The elimination half-life of itraconazole from nails is long, ranging from 32 to 147 days. Terbinafine is a synthetic allylamine that is effective against dermatophytes. Terbinafine is well absorbed from the gastrointestinal tract, and the time to reach effective concentrations in nail is 1 to 2 weeks. The half-life is from 24 to 156 days, explaining the observed persistence of terbinafine in nails for longer than 252 days. Fluconazole is a bis-triazole broad spectrum antifungal with high oral bioavailability. The uptake of fluconazole by nail increases with the length of treatment, and nail : plasma ratios are generally 1.5 to 2 at steady state. Fluconazole concentrations exceed the MIC for Candida species soon after the start of treatment. Fluconazole concentrations fall slowly after the drug is stopped, with a half-life of 50 to 87 days, and fluconazole is still detectable in nails 5 months after the end of treatment. All these drugs are potent inhibitors of cytochrome P450 (CYP) enzymes and may increase the plasma concentrations of concomitantly used drugs. Itraconazole inhibits CYP3A4. Fluconazole inhibits CYP3A4, but to a lesser degree than itraconazole, CYP2C9 and CYP2C19. Terbinafine inhibits CYP2D6.
Insights
Oral antifungal medications like itraconazole, terbinafine, and fluconazole offer effective treatment for fungal nail infections (onychomycosis). These drugs persist in nails, allowing for convenient dosing schedules and achieving good clinical outcomes.
Area of Science:
- Mycology
- Dermatology
- Pharmacology
Background:
- Onychomycosis is a common fungal infection affecting fingernails and toenails, primarily caused by dermatophytes.
- Topical treatments for onychomycosis have limitations in cure rates and require strict patient adherence.
- Oral antifungal medications provide an alternative treatment with systemic efficacy.
Purpose of the Study:
- To review the efficacy and pharmacokinetic properties of oral antifungal agents for onychomycosis.
- To compare the characteristics of itraconazole, terbinafine, and fluconazole in treating fungal nail infections.
- To highlight the persistence of these drugs in nail tissue and their implications for treatment regimens.
Main Methods:
- Review of existing literature on oral antifungal treatments for onychomycosis.
- Analysis of pharmacokinetic data, including drug absorption, distribution in nail tissue, and elimination half-life.
- Comparison of clinical and mycological efficacy rates for itraconazole, terbinafine, and fluconazole.
Main Results:
- Itraconazole, terbinafine, and fluconazole demonstrate good clinical and mycological efficacy in treating onychomycosis.
- These oral antifungals exhibit significant persistence in nail tissue, with long elimination half-lives.
- Drug concentrations in nails often exceed minimum inhibitory concentrations (MICs) for causative fungi.
- All three medications are potent inhibitors of cytochrome P450 (CYP) enzymes, necessitating caution with drug interactions.
Conclusions:
- Oral antifungal therapy with itraconazole, terbinafine, or fluconazole is effective for onychomycosis.
- The prolonged presence of these drugs in nails supports intermittent or pulse dosing strategies.
- Potential for drug interactions due to CYP enzyme inhibition should be considered during treatment.