Ketoconazole

Pharmacokinetics

The oral absorption of ketoconazole is influenced by the acidity of the stomach contents, and the concomitant administration of histamine H ₂ receptor antagonists, proton pump inhibitors, antacids, or food affects its absorption [ ]. A high carbohydrate meal ingested with ketoconazole reduces total drug absorption, while a high lipid meal increases it. Erratic absorption is particularly apparent in patients with AIDS. Peak serum concentrations are seen within 2–3 hours. The half-life is about 8 hours. CSF penetration is less than 10%. Ketoconazole is extensively metabolized in the liver and excreted in the bile in an inactive form; less than 1% of the active drug is excreted in the urine. Clearance is not significantly altered by renal dialysis.

Higher doses of ketoconazole affect cortisol/cortisone and androgen/testosterone substrates. This finding has led to the use of ketoconazole in Cushing’s disease and prostate cancer, but the phenomenon is also responsible for some of its adverse effects, especially those associated with higher doses and prolonged use [ ]. The potency of ketoconazole in inhibiting P450 isoenzymes (such as CYP3A4) is a cause of interactions with several other drugs.

Use in non-infective conditions

The efficacy of ketoconazole 400 mg qds in the early treatment of acute lung injury and acute respiratory distress syndrome has been investigated in a randomized, double-blind, placebo-controlled trial in 234 patients [ ]. Ketoconazole had no effects on mortality, lung function, or the duration of mechanical ventilation.

Because of its potent inhibitory effects on adrenal steroidogenesis by interference with cytochrome CYP450, ketoconazole controls hypercortisolism when surgery is contraindicated or unsuccessful. The effects of oral ketoconazole 200–1200 mg qds for 65–83 months in three patients who had residual or recurrent Cushing’s disease after surgical treatment have been reported [ ]. The dosage of ketoconazole was adjusted according to the clinical response and 24-hour urinary excretion of free cortisol. All three patients had good clinical and biochemical responses to therapy with ketoconazole and there were no adverse reactions.

General adverse effects and adverse reactions

Gastrointestinal complaints, including anorexia, nausea, gastralgia, and constipation are the most frequent adverse effects of ketoconazole. Hepatotoxicity, varying in degree from mild disturbances of liver function tests to hepatitis and rare cases of fulminating hepatic necrosis, has been reported. Some cases have been reported in the first weeks of treatment, but duration of treatment is of importance and in prolonged courses of treatment, monitoring is advisable. With the use of high doses, especially for longer periods of time, the effects of interference with hormonal balance should be watched for. Adrenal insufficiency has been reported even with low-dose treatment. Pruritus and skin reactions have been reported, but do not in general cause major problems. Hypersensitivity reactions are rare. Tumor-inducing effects have not been reported.

Cardiovascular

Ketoconazole has been reported to be prodysrhythmic [ ].

• A 63-year-old woman with coronary artery disease developed a markedly prolonged QT interval and torsade de pointes after taking ketoconazole for a fungal infection. Her QT interval returned to normal on withdrawal of ketoconazole. There were no mutations in her genes that encode cardiac IK _r channel proteins.

The authors concluded that because it blocks inward rectifier potassium channels (IK _r ) channels, ketoconazole alone can prolong the QT interval and induce torsade de pointes. This calls for attention when ketoconazole is given to patients with risk factors for the long QT syndrome.

Respiratory

Patients undergoing esophagectomy are at increased risk of acute lung injury, perhaps related to increased concentrations of thromboxane in the postpulmonary circulation. In 38 consecutive patients undergoing esophagectomy, perioperative ketoconazole, which inhibits thromboxane synthesis, reduced the incidence of acute lung injury [ ].

Nervous system

Headache, dizziness, nervousness, and somnolence have been reported [ ]. The incidences are low. Encephalopathy can occur as a result of severe liver damage.

Sensory systems

Psychiatric

In one patient taking a high dosage for prostate cancer, weakness was associated with mental disturbances, notably confabulation and disorientation in time and space [ ].

Endocrine

Reductions in serum and urinary cortisol concentrations have been reported in patients taking ketoconazole and signs of hypoadrenalism have been seen during high-dose treatment. However, it is not clear whether the asthenia syndrome described in the past (severe muscle weakness, most pronounced in the legs, fatigue, apathy, and anorexia) is related to hypoadrenalism. In some cases, hypoadrenalism has been described shortly after the start of low-dose treatment. Substitution therapy may be required, since simple withdrawal of ketoconazole may not redress hormonal balance quickly enough.

Various studies have shown that ketoconazole interferes with 17- and 20-hydroxylases and inhibits mitochondrial 11-α-hydroxylase and cytochrome P450-dependent steroid hydroxylase enzymes [ , ].

Because of its effects on the pituitary/adrenal system, ketoconazole has been used in the long-term control of hypercortisolism of either pituitary or adrenal origin [ ]. In seven patients with Cushing’s disease and one with an adrenal adenoma, ketoconazole 600–800 mg/day for 3–13 months produced rapid persistent clinical improvement [ ]. Plasma dehydroepiandrosterone sulfate concentrations and urinary 17-ketosteroid and cortisol excretion fell soon after the start of treatment, and remained normal or nearly so throughout treatment. Urinary tetrahydro-11-deoxycortisol excretion rose significantly. Plasma cortisol concentrations fell. Plasma ACTH concentrations did not change and individual plasma ACTH and cortisol increments in response to CRH were comparable before and during treatment. The cortisol response to insulin-induced hypoglycemia improved in one patient and was restored to normal in another. The patients recovered normal adrenal suppressibility in response to a low dose of dexamethasone during ketoconazole treatment.

Ketoconazole inhibits adrenal 11-β-hydroxylase and 17,20-lyase, and prevents the expected rise in ACTH secretion in patients with Cushing’s disease [ , ]. It may, however, cause such a rapid reduction in serum cortisol concentrations that a crisis is precipitated, and patients’ adrenal function should be carefully monitored. While ketoconazole (400–800 mg/day) may be a good alternative to other adrenal steroid inhibitors, patients should be observed for signs of hepatotoxicity. Acute adrenal crisis occasionally occurs [ ].

Because ketoconazole has antiandrogenic properties, it is particularly suitable for women, in whom it has few effects on menstruation and does not cause hirsutism. In men, however, long-term inhibition of androgen production can be disruptive, especially if it leads to gynecomastia and hypogonadism. Combination with aminoglutethimide and metyrapone has been advocated in order to avoid these effects [ ].

Gynecomastia was occasionally observed in men when ketoconazole first became available. Ketoconazole has a marked effect on steroid concentrations, including a change in the testosterone/estradiol ratio, and this is most likely to be the basis of the gynecomastia. A lowering of testosterone serum concentrations and a reduced response of testosterone concentrations to human gonadotropin have been shown [ ]. Various studies have shown suppression of testosterone, androstenedione, and dehydroepiandrosterone, with reciprocal increases in gonadotrophins.

Ketoconazole (400 mg/day) has been used for the treatment of hirsutism and acne in women, but adverse effects, such as headache, nausea, loss of scalp hair, hepatitis, and biochemical changes, were impressive [ ].

Hematologic

Fatal aplastic anemia has been reported during ketoconazole therapy [ ].

Eosinophilia (20 × 10 ⁹ /l) occurred in a 26-week-old premature child after transdermal administration of ketoconazole for 6 days of application and again after rechallenge [ ].

Gastrointestinal

Nausea, mild gastrointestinal symptoms, and vomiting can occur in patients taking ketoconazole; diarrhea has been reported, but the incidence is low [ ]. The incidence of gastrointestinal complaints is higher with the use of daily doses above 800 mg [ ].

Liver

Mild and often transient rises in serum liver enzyme activities are not uncommon in patients taking ketoconazole; the incidence is reported to be about 10–15% [ , ], a higher incidence than was originally thought [ ]. The newer figures probably represent a greater awareness of the risk rather than a true increase; it is possible, however, that the use of higher doses plays a role [ ].

The incidence of symptomatic hepatic injury associated with ketoconazole is estimated to be about one in 10 000 treated cases [ ]. Biochemically, the pattern was hepatocellular in 54%, cholestatic in 16%, and mixed cholestatic-hepatocellular in 30%. Histology (14 cases) showed a predominantly hepatocellular pattern in 57%, with extensive centrilobular necrosis and mild to moderate bridging [ , ]. Lethal cases of toxic hepatitis and a case necessitating transplantation have been reported [ , , ].

• A girl developed fatal liver failure while taking ketoconazole for Cushing’s syndrome [ ]. The authors proposed using metyrapone when temporary control of hypercortisolism is required in childhood and adolescence.

A cohort study of the risk of acute liver injury among users of oral antifungal drugs has been performed in the general population of the General Practice Research Database in the UK [ ]. The cohort included 69 830 patients, free from liver and systemic diseases, who had received at least one prescription for oral griseofulvin, fluconazole, itraconazole, ketoconazole, or terbinafine between 1991 and 1996. Five cases of acute liver injury occurred during the use of oral antifungal drugs. Two of the patients were taking ketoconazole, another two itraconazole, and one terbinafine. The incidence rates of acute liver injury were 134 (CI = 37, 488) per 100 000 person-months for ketoconazole, 10 (CI = 2.9, 38) for itraconazole, and 2.5 (CI = 0.4, 14) for terbinafine. One case was associated with past use of fluconazole. Ketoconazole was the antifungal drug that was associated with the highest relative risk, 228 (CI = 34, 933) compared with the risk among non-users, followed by itraconazole and terbinafine, with relative risks of 18 (CI = 2.6, 73) and 4.2 (CI = 0.2, 25) respectively.

Skin

The risk of serious skin disorders has been estimated in 61 858 users, aged 20–79 years, of oral antifungal drugs identified in the UK General Practice Research Database [ ]. They had received at least one prescription for oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine. The background rate of serious cutaneous adverse reactions (corresponding to non-use of oral antifungal drugs) was 3.9 per 10 000 person-years (95% CI = 2.9, 5.2). Incidence rates for current use were 15 per 10 000 person-years (1.9, 56) for itraconazole, 11.1 (3.0, 29) for terbinafine, 10 (1.3, 38) for fluconazole, and 4.6 (0.1, 26) for griseofulvin. Cutaneous disorders associated with the use of oral antifungal drugs in this study were all mild.

Pruritus and occasional rashes can occur in patients taking ketoconazole [ ]. Rare cases of a fixed drug eruption have been reported [ ].

Musculoskeletal

• Muscle weakness and diffuse myalgia were reported in a 17-year-old man with multiple endocrine neoplasia syndrome type 1 taking ketoconazole for oral candidiasis. The electromyogram showed a distinct myopathic pattern. Withdrawal of the ketoconazole was followed by rapid improvement [ ].

In rats, high doses (80 mg/kg) caused syndactyly in one experiment [ ]. There are insufficient data to determine whether there might be a harmful effect in humans.

Breasts

Gynecomastia due to ketoconazole is described above under Endocrine.

Lactation

Ketoconazole can be found in the milk of lactating dogs receiving ketoconazole; However, infant exposure to ketoconazole in human milk has been calculated to be 0.4% on average (maximum 1.4%) of that expected from therapeutic doses given directly to infants [ ].