What is mechanism of action?

mechanism of action is P-Glycoprotein Inhibitors [MoA], Cytochrome P450 3A4 Inhibitors [MoA] or Cytochrome P450 3A5 Inhibitors [MoA]

Ketoconazole

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Ketoconazole Prescribing Information

Ketoconazole shampoo, 2%, is indicated for the treatment of tinea (pityriasis) versicolor caused by or presumed to be caused by

Pityrosporum orbiculare

(also known as

Malassezia furfur

M. orbiculare

Note: Tinea (pityriasis) versicolor may give rise to hyperpigmented or hypopigmented patches on the trunk which may extend to the neck, arms and upper thighs. Treatment of the infection may not immediately result in normalization of pigment to the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental sun exposure. Although tinea versicolor is not contagious, it may recur because the organism that causes the disease is part of the normal skin flora.

Clinical Trials Experience

In 11 double-blind trials in 264 patients using ketoconazole shampoo, 2%, for the treatment of dandruff or seborrheic dermatitis, an increase in normal hair loss and irritation occurred in less than 1% of patients. In three open-label safety trials in which 41 patients shampooed 4-10 times weekly for six months, the following adverse experiences each occurred once: abnormal hair texture, scalp pustules, mild dryness of the skin, and itching. As with other shampoos, oiliness and dryness of hair and scalp have been reported. In a double-blind, placebo-controlled trial in which patients with tinea versicolor were treated with either a single application of ketoconazole shampoo, 2%, (n=106), a daily application for three consecutive days (n=107), or placebo (n=105), drug-related adverse events occurred in 5 (5%), 7 (7%) and 4 (4%) of patients, respectively. The only events that occurred in more than one patient in any one of the three treatment groups were pruritus, application site reaction, and dry skin; none of these events occurred in more than 3% of the patients in any one of the three groups.

Post-marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency. The following adverse drug reactions have been identified during post-marketing experience with ketoconazole shampoo, 2%: there have been reports of hair discoloration and abnormal hair texture, itching, skin burning sensation, contact dermatitis, hypersensitivity, angioedema, alopecia, rash, urticaria, skin irritation, dry skin, and application site reactions.

Ketoconazole shampoo, 2%, is a red-orange liquid for topical application, containing the broad spectrum synthetic antifungal agent ketoconazole in a concentration of 2% in an aqueous suspension. It also contains: sodium laureth sulfate, disodium laureth sulfosuccinate, cocamide diethanolamide, hydrochloric acid, PEG-120 methyl glucose dioleate, imidurea, sodium chloride, sodium hydroxide, fragrance, FD&C red No. 40, and purified water.

Ketoconazole is

cis

-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1

-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine and has the following structural formula:

Tinea (pityriasis) versicolor is a non-contagious infection of the skin caused by

Pityrosporum orbiculare (Malassezia furfur)

. This commensal organism is part of the normal skin flora. In susceptible individuals the condition is often recurrent and may give rise to hyperpigmented or hypopigmented patches on the trunk which may extend to the neck, arms and upper thighs. Treatment of the infection may not immediately result in restoration of pigment to the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental skin exposure. The rate of recurrence of infection is variable.

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).

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 shampoo, 2%, 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 photoallergenic potential due to ketoconazole shampoo, 2%.

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, but not proven, that the therapeutic effect of ketoconazole in tinea (pityriasis) versicolor is due to the reduction of

Pityrosporum orbiculare (Malassezia furfur)

and that the therapeutic effect in dandruff is due to the reduction of

Pityrosporum ovale

. Support for the therapeutic effect in tinea versicolor comes from a three-arm, parallel, double-blind, placebo controlled study in patients who had moderately severe tinea (pityriasis) versicolor. Successful response rates in the primary efficacy population for each of both three-day and single-day regimens of ketoconazole shampoo, 2%, were statistically significantly greater (73% and 69%, respectively) than a placebo regimen (5%). There had been mycological confirmation of fungal disease in all cases at baseline. Mycological clearing rates were 84% and 78%, respectively, for the three-day and one-day regimens of the 2% shampoo and 11% in the placebo regimen. While the differences in the rates of successful response between either of the two active treatments and placebo were statistically significant, the difference between the two active regimens was not.

Microbiology:

Ketoconazole is a broad spectrum synthetic antifungal agent which inhibits the growth of the following common dermatophytes and yeasts by altering the permeability of the cell membrane: dermatophytes:

Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Microsporum canis, M. audouini, M. gypseum

and

Epidermophyton floccosum;

yeasts:

Candida albicans, C. tropicalis, Pityrosporum ovale (Malassezia ovale)

and

Pityrosporum orbiculare (M. furfur)

. Development of resistance by these microorganisms to ketoconazole has not been reported.

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