Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Laboratoire HRA Pharma, 15 rue Béranger, 75003 Paris, France
Pharmacotherapeutic group: Imidazole derivatives
ATC code: J02AB02
Ketoconazole is a steroidogenesis inhibitor. Ketoconazole is an imidazole derivative that is a potent inhibitor of cortisol synthesis resulting from its ability to inhibit several cytochrome P450 enzymes in the adrenal glands. Ketoconazole inhibits primarily the activity of 17α-hydroxylase, but it also inhibits 11-hydroxylation steps, and at higher doses the cholesterol side-chain cleavage enzyme. Therefore, ketoconazole is an inhibitor of cortisol and aldosterone synthesis. Ketoconazole is also a potent inhibitor of androgens synthesis, inhibiting the activity of C17-20 lyase in the adrenals and also in Leydig cells.
Apart from adrenal blocking effect, ketoconazole may also have direct effects on corticotropic tumour cells in patients with Cushing’s disease.
The efficacy and safety of ketoconazole in the treatment of Cushing’s syndrome from all causes have been described through several published retrospective studies, chart reviews and case reports. Control of cortisol levels, either in serum/plasma or urine, was used to assess the efficacy of the treatment, along with the evaluation of clinical symptoms of Cushing’s syndrome. More than 800 patients have been treated with ketoconazole with variable treatment duration and modalities. About 200 patients were treated for more than 6 months and some of them were treated for several years.
Urinary free cortisol (UFC) levels were normalised in about 50% of patients on ketoconazole. Response rates varied between 43 and 80% depending on the studies and the criteria to define a response. About 75% of patients achieved a decrease of more than 50% of UFC levels on ketoconazole, compared to pre-treatment levels.
Ketoconazole has been used both as sole medical therapy and in combination with other drugs, mainly with metyrapone, in patients with more severe disease or in those not completely responding to a single agent or in those requiring a dose reduction of at least one of the drugs to improve tolerance. Ketoconazole has also been used with other therapies including surgery and pituitary radiation. Overall, ketoconazole was shown to be an effective drug for normalising cortisol levels in all causes of Cushing’s syndrome and, if tolerated, ketoconazole treatment can be maintained for a long period.
In approximately 10 to 15 % of ketoconazole treated patients, an “escape phenomenon” is observed and reinforces the need for a long-term clinical and biochemical follow-up of these patients. If such a phenomenon occurs, a further dose increase may be required to maintain cortisol levels within the normal range.
Data from 535 patients with Cushing’s disease treated with ketoconazole, along with 13 individual case reports are available in the literature. In a retrospective study conducted in several French centres, 200 patients with Cushing’s disease were followed between 1995 and 2012. At the last visit, 78 patients (49.3%) were controlled, 37 patients (23.4%) had partial control with at least 50% decrease of UFC (without normalisation), and 43 patients (27.2%) had unchanged UFC levels. At the last follow-up, clinical signs were improved in 74/134 patients (55.2%), hypertension in 36/90 patients (40), hypokalaemia in 10/26 patients (38.4%), and diabetes mellitus in 23/39 patients (59%).
Data from 91 patients with the ectopic ACTH syndrome treated with ketoconazole were reviewed, along with 18 individual case reports. In a Canadian study, of the 12 assessable patients (out of 15), 10 showed a reduction in urinary free cortisol levels, but only five had complete resolution on ketoconazole doses 400 to 1200 mg/day. Clinical improvement in hypokalaemia, metabolic alkalosis, diabetes mellitus, and hypertension occurred even in the absence of complete hormonal response.
Data from 17 patients with adrenal tumours and from 2 patients with primary nodular adrenocortical hyperplasia (NAH) treated with ketoconazole are available in the literature along with 17 individual case reports of patients with benign or malignant tumours or NAH and 2 paediatric cases of McCune Albright syndrome. Improvement of clinical symptoms was noted in most patients after initiation of treatment. However in patients with adrenal cortical carcinoma, improvement of hypercortisolism on ketoconazole was limited in some cases.
Data on 24 paediatric patients with endogenous Cushing’s syndrome treated with ketoconazole are available in the literature, among which 16 were aged over 12 years old and 8 were aged less than 12 years old.
Treatment with ketoconazole in paediatric patients allowed normalisation of urinary free cortisol levels and clinical improvement, including recovering of growth rate and gonadal function, normalisation of blood pressure, Cushing’s syndrome features and weight loss in most of the cases. The doses used in adolescents above 12 years old were similar to the doses used in adults' patients with endogenous Cushing’s syndrome.
Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption. Mean peak plasma concentrations of approximately 3.5 μg/ml are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal.
Cmax and AUC increase more than proportionally with dose. At steady state, mean peak concentrations of 1.7µg/mL to 15.6µg/mL were reported for total daily doses of 200mg to 1200mg.
In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Ketoconazole is widely distributed into tissues; however, only a negligible proportion of ketoconazole reaches the cerebral-spinal fluid.
Ketoconazole is extensively metabolised to a large number of inactive metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of ketoconazole.
The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation.
Ketoconazole is a potent inhibitor of CYP3A4 and P-gp. Ketoconazole has not been demonstrated to induce its own metabolism.
Plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. The half-life of ketoconazole increases with dose and duration of treatment. At doses >400 mg/day, half-lives of 3 to 10 hours have been reported. 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.
Based on limited data, pharmacokinetics parameters (AUC, Cmax and half-life) of ketoconazole for doses of 5 to 10 mg/kg/days, corresponding approximately to daily doses of 200-800 mg, are similar in paediatric and adult population.
The pharmacokinetics of ketoconazole were not significantly different in patients with renal failure compared to healthy subjects.
No formal evaluation of the effect of age on the pharmacokinetics of Ketoconazole HRA has been performed. There are no data suggesting a need for a specific dose adjustment in this population.
In vitro data indicate that ketoconazole is a potent inhibitor of OATP1B1, OATP1B3, OAT3, OCT1 and OCT2 and to a lesser extent of OAT1 and BSEP. Inhibition of these different transporters at clinically relevant concentrations of ketoconazole cannot be excluded.
The toxicological profile of ketoconazole has been established from long term studies in rats and dogs.
Bone fragility and broken legs were reported in rats but were not observed in other species.
Consistent with the pharmacological action of ketaconazole, effects were observed on adrenal and gonads in rats and dogs.
Elevated liver enzymes and histological changes in the liver consisting in dose–related lipofuscin accumulation in hepatocytes were reported in rats and dogs after repeated administration of ketoconazole.
Electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QT interval. However no modifications of ECG were recorded in dogs at daily doses up to 40 mg/kg administered for 12 months.
Ketoconazole was not genotoxic in vitro and in vivo. However, the genotoxic potential was not properly determined for the proposed dosing regimen in the treatment of endogenous Cushing’s syndrome. Ketoconazole is not carcinogenic.
In reproduction studies, ketoconazole impaired fertility in males and females. Doses of 25 mg/kg and higher in male rats and dogs produced sperm abnormalities and decreased fertility in rats. Ketoconazole at doses up to 40 mg/kg had no effects on female fertility in the rat, whilst doses of 75 mg/kg and higher decreased the pregnancy rate and the number of implantation sites. Doses of 80 and 160 mg/kg inhibited ovulation in immature rats. Ketoconazole at doses of 40 mg/kg/day and higher produces evidence of embryotoxicity and teratogenicity in rats and rabbits. Observed teratogenic effects were mainly skeletal anomalies, including cleft palate, brachydactylia, ectrodactylia and syndactylia. Treatment of juvenile rats for 30 day beginning at 21 days of age delayed the puberty onset. Effects on human reproduction cannot be excluded.
Studies in pregnant rats and in guinea pigs with 3H-ketoconazole indicate that ketoconazole crosses the placenta.
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