Pharmacokinetics of Antifungal Agents in Onychomycoses

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.

Collaborative Evaluation of Optimal Antifungal Susceptibility Testing Conditions for Dermatophytes

“…This agrees with previous reports, which showed the efficacy in vitro of this allylamine (3,17,18). However, for ITC we obtained MICs that were within the range of expected concentrations in nail with daily oral doses of 100 to 200 mg (4,19). Similar results were obtained by Korting et al (18), who tested numerous isolates of T. rubrum and T. mentagrophytes from patients with tinea unguium, also by a microdilution method.…”

“…For localized nonextensive lesions, topical therapies with clotrimazole (CLT) are generally used. For tinea unguium, scalp ringworm, extensive infections, or skin lesions with folliculitis, systemic antifungal treatment is necessary (1,4,23,26). Oral drugs such as itraconazole (ITC) and terbinafine (TRB) are the antifungal agents currently most used to treat severe infections (4,23).…”

“…For tinea unguium, scalp ringworm, extensive infections, or skin lesions with folliculitis, systemic antifungal treatment is necessary (1,4,23,26). Oral drugs such as itraconazole (ITC) and terbinafine (TRB) are the antifungal agents currently most used to treat severe infections (4,23). Some novel compounds, such as UR-9825, posaconazole, voriconazole, or ravuconazole, also appear to be promising candidates for the treatment of dermatophytosis (2,10,28).…”

Determination of Posaconazole Levels in Toenails of Adults with Onychomycosis following Oral Treatment with Four Regimens of Posaconazole for 12 or 24 Weeks

“…The CV% of posaconazole exposure in toenails was higher than that in plasma (51% to 137% for the toenail C max versus 50% to 76% for the plasma C min ). Posaconazole diffusion into the nail plate, presumably via the nail plate bed, is likely to be consistent with that observed for other systemically administered antifungals, such as terbinafine, itraconazole, and fluconazole (1,2,5). Levels of posaconazole in the nail remained high after treatment was discontinued, probably because posaconazole accumulated in the nail matrix via systemic absorption during treatment.…”

Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy

“…Absorption rates vary from Ͼ80% for flucytosine, fluconazole, and voriconazole and 70 to 80% for terbinafine to 55% for itraconazole (capsule), 8 to 48% for posaconazole (in animals), and 48 to 74% for ravuconazole (in animals), Ͻ10% for amphotericin B, and Ͻ0.2% for caspofungin and the other echinocandins (Table 1) (54,60,62,74,101,102). The absorption of antifungal agents may be strongly affected by conditions such as overall immunosuppression, hypochlorhydria, and concomitant chemotherapy (58,60). Absorption may also vary among healthy individuals even under the same dietary conditions (93,281).…”