Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Corticosteroids for systemic use, glucocorticoids.
ATC code: H02AB09
 Mechanism of action
Hydrocortisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally-occurring and synthetic, which are readily absorbed from the gastro-intestinal tract.

Pharmacodynamic effects
Hydrocortisone is believed to be the principal corticosteroid secreted by the adrenal cortex.
Naturally-occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. 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.

Clinical efficacy and safety

Paediatric population
The pivotal study was an open-label single-dose single-centre trial in 24 paediatric patients aged less than 6 years requiring replacement therapy for adrenal insufficiency due to CAH, primary adrenal failure or hypopituitarism. The study consisted of three consecutive cohorts, the first including 12 patients aged 2 to less than 6 years, the second including 6 patients aged 28 days to less than 2 years, and the third including 6 neonates aged from birth to less than 28 days.

Of these 24 patients, 23 had a diagnosis of CAH and 1 had a diagnosis of hypopituitarism including hypothyroidism. 1 patient had renal hypoplasia, 1 patient atopic dermatitis and 1 patient had rhinitis. The study used a single dose of Alkindi granules equivalent to the previous morning’s dose of each patient’s usual glucocorticoid treatment. The Alkindi dose range administered was 1 mg - 4 mg.
Parents/carers (and where possible children) assessed the palatability of Alkindi after administration using a 5-item Likert scale.

As this was a single-dose study, the primary efficacy assessment was serum cortisol at 60 minutes.
In all 24 patients Alkindi was found to increase cortisol values from baseline as expected: median baseline cortisol 14.1 nmol/l (range 14.1 - 104.5), median Cmax 535.2 nmol/l (range 346.2 - 1445.1).

Alkindi was positively assessed in terms of palatability. Among parents and carers asked about their child’s experience of taking the medication (n=23), 82.6% agreed/strongly agreed that their child found swallowing Alkindi easy; 65.2% agreed/strongly agreed that their child showed a positive reaction after Alkindi administration; 95.5% would be happy to give their child Alkindi in the future; and 95.5% said that they would prefer Alkindi for their child’s treatment over their usual hydrocortisone formulation. Six of the 12 children in Cohort 1 (age range 2.6 to 4.7 years) responded to an adjusted palatability questionnaire. ≥50% subjects reported that the taste, feel in mouth and ease of swallowing were very good and that they were likely to take the medicinal product again.
68.8% of healthy adult volunteers have described the taste as neutral.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following oral administration, hydrocortisone is rapidly absorbed from the gastro-intestinal tract and the oral Alkindi 4x5 mg was approximately 87 % bioavailable when compared to intravenous hydrocortisone in dexamethasone-suppressed healthy adult male volunteers.

The coadministration of Alkindi with soft food (yoghurt and fruit puree) has been studied in vitro with no significant effect on dissolution seen.
An in vivo study in healthy volunteers showed no significant difference in overall exposure when Alkindi was dosed fed or fasted.

Distribution
90% or more of circulating hydrocortisone is reversibly bound to protein.

The binding is accounted for by two protein fractions. One, corticosteroid-binding globulin is a glycoprotein; the other is albumin.

Biotransformation
Hydrocortisone is metabolised in the liver and most body tissues to hydrogenated and degraded forms such as tetrahydrocortisone and tetrahydrocortisol which are excreted in the urine, mainly conjugated as glucuronides, together with a very small proportion of unchanged hydrocortisone.

The terminal half-life of hydrocortisone is about 1.5 hours following intravenous and oral dosing of hydrocortisone tablets and Alkindi in dexamethasone-suppressed healthy adult male volunteers.

No studies have been conducted in patients with hepatic or renal impairment.