TABLETS

Mean peak plasma levels of approximately 3.5 mcg/ml are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal. Subsequent plasma elimination is biphasic with half-life of 2 hours during the first 10 hours and 8 hours thereafter. Following absorption from the gastrointestinal tract, ketoconazole is converted into several inactive metabolites. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation. About 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged drug. The major route of excretion is through the bile into the intestinal tract. In vitro, the plasma protein binding is about 99%, mainly to the albumin fraction. Only a negligible proportion of ketoconazole reaches the cerebral-spinal fluid. Ketoconazole is weak dibasic agent and thus requires acidity for dissolution and absorption.

Ketoconazole Tablets are active against clinical infections withBlastomyces dermatitidis, Candida spp., Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Phialophora spp. Ketoconazole Tablets are also active againstTrichophyton spp., Epidermophyton spp., and Microsporum spp. Ketoconazole is also active in vitro against a variety of fungi and yeast. In animal models, activity has been demonstrated against Candida spp., Blastomyces dermatitidis, Histoplasma capsulatum, Malassezia furfur, Coccidioides immitis, and Cryptococcus neoformans.

Mode of Action

In vitro studies suggest that Ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes.

SHAMPOO

When ketoconazole 2% shampoo was applied dermally to intact or abraded skin of rabbits for 28 days at doses up to 50 mg/kg and allowed to remain one hour before being washed away, there were no detectable plasma ketoconazole levels using an assay method having a lower detection limit of 5 ng/ml. Ketoconazole was not detected in plasma in 39 patients who shampooed 4-10 times per week for 6 months or in 33 patients who shampooed 2-3 times per week for 3-26 months (mean: 16 months).

Twelve hours after a single shampoo, hair samples taken from six patients showed that high amounts of ketoconazole were present on the hair but only about 5% had penetrated into the hair keratin. Chronic shampooing (twice weekly for two months) increased the ketoconazole levels in the hair keratin to 20%, but did not increase levels on the hair. There were no detectable plasma levels.

An exaggerated use washing test on the sensitive antecubital skin of 10 subjects twice daily for five consecutive days showed that the irritancy potential of ketoconazole 2% shampoo was significantly less than that of 2.5% selenium sulfide shampoo.

A human sensitization test, a phototoxicity study, and a photoallergy study conducted in 38 male and 22 female volunteers showed no contact sensitization of the delayed hypersensitivity type, no phototoxicity and no photoallergic potential due to ketoconazole 2% shampoo.

Mode of Action

Interpretations of in vivo studies suggest that ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. It is postulated that the therapeutic effect of ketoconazole in dandruff is due to the reduction ofPityrosporum ovale (Malassezia ovale), but this has not been proven. Support for this hypothesis comes from a 4-week double-blind, placebo controlled clinical trial in which the decrease in P. ovale on the scalp was significantly greater with ketoconazole (36 patients) than with placebo (20 patients) and was comparable to that with selenium sulfide (42 patients). In the same study, ketoconazole and selenium sulfide reduced the severity of adherent dandruff significantly more than placebo did. Ketoconazole produced significantly higher proportions of patients with at least 50% reductions in adherent dandruff (50% vs. 15%) and in loose dandruff (67% vs. 15%) than did the placebo.

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