Ketoconazole was patented in 1977 by Belgian pharmaceutical company Janssen, and came into medical use in 1981.[14] It is available as a generic medication and formulations that are applied to the skin are over the counter in the United Kingdom.[12] In 2021, it was the 161st most commonly prescribed medication in the United States, with more than 3million prescriptions.[15][16] The formulation that is taken by mouth was withdrawn in the European Union and in Australia in 2013,[17][18] and in China in 2015.[19] In addition, its use was restricted in the United States and Canada in 2013.[18]
Medical uses
Topical antifungal
Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), jock itch, and tinea versicolor.[20] Topical ketoconazole is also used as a treatment for dandruff (seborrheic dermatitis of the scalp) and for seborrheic dermatitis on other areas of the body, perhaps acting in these conditions by suppressing levels of the fungus Malassezia furfur on the skin.[20][21][22]
Systemic antifungal
Ketoconazole has activity against many kinds of fungi that may cause human disease, such as Candida, Histoplasma, Coccidioides, and Blastomyces (although it is not active against Aspergillus), chromomycosis and paracoccidioidomycosis.[23][13] First made in 1977,[20] ketoconazole was the first orally-active azole antifungal medication.[23] However, ketoconazole has largely been replaced as a first-line systemic antifungal medication by other azole antifungal agents, such as fluconazole and/or itraconazole, because of ketoconazole's greater toxicity, poorer absorption, and more limited spectrum of activity.[23][24]
Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections.[25]
Off-label uses
Hair loss
Ketoconazole 2% gel
Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor such as finasteride or dutasteride has been used off label to treat androgenic alopecia. It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.[26]
Limited clinical studies suggest ketoconazole shampoo used either alone[27][28] or in combination with other treatments[29] may be useful in reducing hair loss in some cases.[30]
In July 2013, the US Food and Drug Administration (FDA) issued a warning that taking ketoconazole by mouth can cause severe liver injuries and adrenal gland problems: adrenal insufficiency and worsening of other related to the gland conditions.[13] It recommends oral tablets should not be a first-line treatment for any fungal infection. It should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated.[13] As contraindication it should not be used in people with acute or chronic liver disease.[13]
The topical formulations have not been associated with liver damage, adrenal problems, or drug interactions. These formulations include creams, shampoos, foams, and gels applied to the skin, unlike the ketoconazole tablets, which are taken by mouth.[13]
Pregnancy
Ketoconazole is categorized as pregnancy category C in the US.[38] Research in animals has shown it to cause teratogenesis when administered in high doses.[38] A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.[39]
Overdose
In the event of an overdose of oral ketoconazole, treatment should be supportive and based on symptoms.[6]Activated charcoal may be administered within the first hour following overdose of oral ketoconazole.[6]
Interactions
The concomitant use of the following medications is contraindicated with ketoconazole tablets:[6][36]
Ritonavir is known for increasing activity of the ketoconazole so it is recommended to reduce dosage.[6]
There is also a list of drugs which significantly decrease systemic exposure to the ketoconazole and drugs whose systemic exposure is increased by the ketoconazole.[6][36]
Resistance to ketoconazole has been observed in a number of clinical fungal isolates, including Candida albicans. Experimentally, resistance usually arises as a result of mutations in the sterol biosynthesis pathway. Defects in the sterol 5-6 desaturase enzyme reduce the toxic effects of azole inhibition of the 14-alpha demethylation step. Multidrug-resistance (MDR) genes can also play a role in reducing cellular levels of the drug. As azole antifungals all act at the same point in the sterol pathway, resistant isolates are normally cross-resistant to all members of the azole family.[40][41]
Antihormonal activity
As an antiandrogen, ketoconazole operates through at least two mechanisms of action. First, and most notably, high oral doses of ketoconazole (e.g. 40 mg three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels.[25][42] It produces this effect through inhibition of 17α-hydroxylase and 17,20-lyase, which are involved in the synthesis and degradation of steroids, including the precursors of testosterone.[25] Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer.[43] Second, ketoconazole is an androgen receptorantagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the androgen receptor. This effect is thought to be quite weak however, even with high oral doses of ketoconazole.[44]
Ketoconazole is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers.[10] The cis-(2S,4R) isomer was more potent in inhibiting progesterone 17α,20-lyase than its enantiomer (IC50 values of 0.05 and 2.38 μM, respectively) and in inhibiting 11β-hydroxylase (IC50 values of 0.152 and 0.608 μM, respectively). Both isomers were relatively weak inhibitors of human placental aromatase.[9]
Oral ketoconazole has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200 mg/day.[47][48][49] Numerous small studies have investigated the effects of oral ketoconazole on hormone levels in humans.[50] It has been found in men to significantly decrease testosterone and estradiol levels and to significantly increase luteinizing hormone, progesterone, and 17α-hydroxyprogesterone levels, whereas levels of androstenedione, follicle-stimulating hormone, and prolactin were unaffected.[50][51][48] The ratio of testosterone to estradiol is also decreased during oral ketoconazole therapy in men.[48] Suppression of testosterone levels by ketoconazole is generally partial and has often been found to be transient.[50] Better effects on suppression of testosterone levels have been observed in men when ketoconazole is combined with a GnRH agonist to suppress the hypothalamic–pituitary–gonadal axis, which prevents compensatory upregulation of luteinizing hormone secretion and consequent activation of gonadal testosterone production.[48] In premenopausal women with polycystic ovary syndrome, ketoconazole has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol.[49][52] Studies in postmenopausal women with breast cancer have found that ketoconazole significantly decreases androstenedione levels, slightly decreases estradiol levels, and does not affect estrone levels.[53] This indicates minimal inhibition of aromatase by ketoconazole in vivo in humans.[53] Ketoconazole has also been found to decrease levels of endogenouscorticosteroids, such as cortisol, corticosterone, and aldosterone, as well as vitamin D.[54][48]
Ketoconazole has been found to inhibit the activity of the cation channel TRPM5.[55]
Pharmacokinetics
When administered orally, ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption. Absorption can be increased by taking it with an acidic beverage, such as cola.[56] Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.
Ketoconazole was discovered in 1976 at Janssen Pharmaceuticals.[59] It was patented in 1977,[14] followed by introduction in the United States in July 1981.[18][8][60][14] Following its introduction, ketoconazole was the only systemic antifungal available for almost a decade.[18] Ketoconazole was introduced as the prototypical medication of the imidazole group of antifungals.[61] Oral ketoconazole has been replaced with oral fluconazole or itraconazole for many mycoses.[61]
Due to incidence of serious liver toxicity, the use of oral ketoconazole was suspended in France in July 2011, following review.[18] This event triggered an evaluation of oral ketoconazole throughout the rest of the European Union.[18][62] In 2013, oral ketoconazole was withdrawn in the European Union and Australia, and strict restrictions were placed on the use of oral ketoconazole in the United States and Canada.[18] Oral ketoconazole is indicated for use in these countries when the indication is a severe or life-threatening systemic infection and alternatives are unavailable.[18] However, topical ketoconazole, which does not distribute systemically, is safe and widely used still.[18]
Ketoconazole HRA was approved for use in the European Union for treatment of Cushing's syndrome in November 2013.[7][63]
Society and culture
Generic names
Ketoconazole is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[57][58][64][65]
Brand names
Ketoconazole has been marketed under a large number of brand names.[57][58][64][65]
Availability
Ketoconazole is available widely throughout the world.[58][65]
As of March 2019, oral levoketoconazole (developmental code name COR-003, tentative brand name Recorlev) is phase IIIclinical trials for the treatment of Cushing's syndrome.[67] Oral levoketoconazole may have a lower risk of liver toxicity than oral ketoconazole.[68]
Veterinary use
Ketoconazole is sometimes prescribed as an antifungal by veterinarians for use in pets, often as unflavored tablets that may need to be cut to smaller size for correct dosage.[69]
^Marks DH, Prasad S, De Souza B, Burns LJ, Senna MM (December 2019). "Topical Antiandrogen Therapies for Androgenetic Alopecia and Acne Vulgaris". Am J Clin Dermatol. 21 (2): 245–254. doi:10.1007/s40257-019-00493-z. PMID31832993. S2CID209331373.
^"MedScape". Ectopic Cortisol Production Derived From Malignant Testicular Masses: Treatment and Management. Nature Publishing Group. Archived from the original on 13 May 2018. Retrieved 18 April 2015.
^Zelefsky MJ, Eastham JA, Sartor OA, Kantoff P (2008). DeVita VT, Lawrence TS, Rosenberg SA (eds.). Cancer: Principles & Practice of Oncology (8th ed.). Philadelphia: Lippincott Williams & Wilkins. p. 1443. ISBN9780781772075.
^Loli P, Berselli ME, Tagliaferri M (December 1986). "Use of ketoconazole in the treatment of Cushing's syndrome". The Journal of Clinical Endocrinology and Metabolism. 63 (6): 1365–71. doi:10.1210/jcem-63-6-1365. PMID3023421.
^Duret C, Daujat-Chavanieu M, Pascussi JM, Pichard-Garcia L, Balaguer P, Fabre JM, et al. (July 2006). "Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor". Molecular Pharmacology. 70 (1): 329–39. doi:10.1124/mol.105.022046. PMID16608920. S2CID21455699.
^Feldman D (November 1986). "Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis". Endocrine Reviews. 7 (4): 409–20. doi:10.1210/edrv-7-4-409. PMID3536461.
^Tarbit MH, Robertson WR, Lambert A (1990). "Hepatic and Endocrine Effects of Azole Antifungal Agents". Chemotherapy of Fungal Diseases. Handbook of Experimental Pharmacology. Vol. 96. pp. 205–229. doi:10.1007/978-3-642-75458-6_10. ISBN978-3-642-75460-9. ISSN0171-2004.
^Heeres J, Backx LJ, Mostmans JH, Van Cutsem J (August 1979). "Antimycotic imidazoles. part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent". Journal of Medicinal Chemistry. 22 (8): 1003–5. doi:10.1021/jm00194a023. PMID490531.
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