Pharmacokinetics and pharmacology of terbinafine and itraconazole.

BACKGROUND: Two new systemic antifungal agents, terbinafine and itraconazole, have expanded the choices for treatment of onychomycosis. The pharmacokinetic and pharmacologic properties provide the basis of their activity and are related to their efficacy and safety in dermatophyte infections.

OBJECTIVE: We describe the pharmacodynamics, pharmacokinetics, and pharmacology of terbinafine and itraconazole and the features that form a framework for comparing their efficacy. PHARMACODYNAMICS: Both terbinafine and itraconazole ultimately block ergosterol synthesis; terbinafine disrupts fungal cell wall synthesis earlier (squalene to squalene epoxide) than does itraconazole (lanosterol to ergosterol). In vitro, terbinafine exposure results in a toxic accumulation of squalene and decreased production of ergosterol. Minimal inhibitory concentrations (MICs) of terbinafine for dermatophytes are essentially equal to minimal fungicidal concentrations (MFCs). However, the MFCs of itraconazole are much higher than the MICs. PHARMACOLOGIC PROFILE: Both itraconazole and terbinafine penetrate keratinizing tissue; levels reached in nail plate exceed those in plasma. Therapeutic levels of the itraconazole persist in nails for up to 6 months after discontinuation of 3 months of therapy (200 mg/day) and during various pulsed cycles. After discontinuation of 1 month of therapy, terbinafine persists at therapeutic levels in the nail. Itraconazole has an affinity for mammalian cytochrome P-450 enzymes as well as for fungal P-450-dependent enzyme, and thus has the potential for clinically important interactions (e.g., astemizole, terfenadine, rifampin, oral contraceptives, H2 receptor antagonists, warfarin, cyclosporine). Terbinafine is not metabolized through this system and has little potential for drug-drug interactions.

CONCLUSION: The low MFCs exhibited by terbinafine for dermatophytes may be important in its clinical efficacy and low relapse rates. The safety profile of terbinafine directly reflects its mechanism of action.