Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Shire Services BVBA, Rue Montoyer 47, B 1000 Brussels, Belgium
Pharmacotherapeutic group: Corticosteroids for systemic use, glucocorticoids
ATC code: H02AB09
Hydrocortisone is a glucocorticoid and the synthetic form of endogenously produced cortisol. Glucocorticoids are important steroids for intermediary metabolism, immune function, musculoskeletal and connective tissue and the brain. Cortisol is the principal glucocorticoid secreted by the adrenal cortex.
Naturally-occurring glucocorticoids (hydrocortisone and cortisol), which also have salt-retaining properties, are used as replacement therapy in adrenal insufficiency. They are also used for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition they modify the body’s immune responses to diverse stimuli.
The pivotal study was a randomised, two-period 12-week crossover multi-centre trial in 64 patients with primary adrenal insufficiency, 11 of whom had concomitant diabetes mellitus and 11 had hypertension. The study compared modified-release tablets given once daily with conventional tablets given three times daily using the same daily dose of hydrocortisone (20 to 40 mg).
Compared to conventional tablets given three times daily, once daily modified-release tablets resulted in an increased cortisol exposure during the first four hours after intake in the morning but reduced exposure in the late afternoon/evening and over the 24-hour period (Figure 1).
Figure 1. Observed mean serum cortisol concentration versus clock time following single and multiple dosing in primary adrenal insufficiency patients (n=62) after oral administration of Plenadren given once daily and hydrocortisone thrice daily:
Following oral administration, hydrocortisone is rapidly and well absorbed from the gastrointestinal tract and the absorption has been reported to be more than 95% for an oral 20 mg dose (tablets). Hydrocortisone is a class II active substance according to the biopharmaceutical classification system (BCS) with a high intestinal permeability and a low dissolution rate, especially at higher doses. The modified-release tablet has an outer coating layer that provides an immediate release of the drug and an extended release core. The immediate-release part provides a rapid onset of absorption and the extended release part provides a more extended plasma profile of cortisol. The bioavailability (AUC0-24h) is 20% lower with the modified-release tablet compared to the same daily dose of hydrocortisone given as conventional tablets three times daily. When the oral dose is increased the total plasma exposure of cortisol increased less than proportional. The exposure increased three-fold when the dose of hydrocortisone modified-release increased from 5 mg to 20 mg.
The absorption rate of hydrocortisone was reduced after food intake resulting in a delay in the time to maximal concentration in plasma from on average less than 1 hour to over 2.5 hours. On the other hand, the extent of absorption and bioavailability was approximately 30% higher for the 20 mg tablet after food intake compared to fasting and there was no absorption failure or dose dumping.
In plasma, cortisol is bound to corticosteroid-binding globulin (CBG, also called transcortin) and albumin. The binding is about 90%.
The terminal half-life has been reported to be about 1.5 hours following intravenous and oral dosing of hydrocortisone tablets. The terminal half-life of cortisol following administration of Plenadren was about 3 hours and formulation release controlled. This terminal half-life is similar to the pharmacokinetics of endogenous cortisol that also is secretion-controlled.
Hydrocortisone (cortisol) is a lipophilic drug that is eliminated completely via metabolism with a low clearance and accordingly low intestinal and hepatic extraction ratios.
Hydrocortisone is eliminated completely by metabolism by 11ßHSD type 1 and type 2 enzymes and CYP 3A4 in the liver and in peripheral tissue. CYP 3A4 is involved in the clearance of cortisol by the formation of 6β-hydroxycortisol which is excreted in urine. The transport of cortisol across membranes is expected to be mediated mainly by passive diffusion and therefore renal and biliary clearances are negligible.
A small amount of cortisol is excreted in the urine unchanged (<0.5% of the daily production), meaning that cortisol is eliminated completely by metabolism. Since severe renal impairment may affect medicinal products completely eliminated via metabolism, dose adjustment may be needed.
No study has been performed in patients with hepatic impairment, however data in the literature for hydrocortisone support that no dose adjustment is required in mild to moderate hepatic impairment. In case of severe hepatic impairment, the functional liver mass decreases and thus the metabolising capacity for hydrocortisone. This may require dose individualisation.
No pharmacokinetic data are available in children or adolescents.
Animal experiments have shown that prenatal exposure to very high doses of glucocorticoids can induce malformations (cleft palate, skeletal malformations). Animal studies have also shown that prenatal exposure to high doses of glucocorticoids (but lower than teratogenic doses) may be associated with increased risk of intrauterine growth retardation, cardiovascular disease in adulthood and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour.
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