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 have multiple effects in multiple tissues through actions on the intracellular steroid receptors.

Pharmacodynamic effects

Hydrocortisone is a glucocorticoid and the synthetic form of endogenously produced cortisol.
Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastro-intestinal tract. Cortisol is 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

A study in 122 participants with genetically diagnosed 21-hydroxylase deficiency randomised to Efmody or continuation of standard care with blinded titration of dose and regular overnight profiles failed to meet its primary endpoint of superiority in change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) profile for 17-hydroxyprogesterone 17-OHP. The 17-OHP SDS was lower in the Efmody cohort than standard therapy at 4 and 12 weeks. At 24 weeks the 17- OHP SDS was lower in the morning period (07:00 hrs to 15:00 hrs) but not in the evening or overnight (see also Figure 1 for the geometric mean 24-hour profile of 17-OHP after 24 weeks intensive treatment). A reduction in the 17-OHP area under the curve occurred in both groups, with greater reduction in the Efmody cohort. The percentage of patients with controlled 09:00 hrs 17-OHP (<36nmol/l) was 50% at baseline and at 24 weeks was 91% in the Efmody cohort and 71% in the standard therapy cohort. Efmody patients suffered no adrenal crises (compared to 3 in the control arm) Efmody-S P C-0923                                                                    Efmody-5_10 mg-SPC and had fewer sick day episodes where increased dosing due to stress was required was required (26 vs 36 in the control arm) despite reporting more episodes of intercurrent infective or gastro-intestinal illness. Glucocorticoid daily dose, measured as a hydrocortisone equivalent dose, increased in most subjects during the study (see Table 2).

Table 2. Glucocorticoid daily dose changes during the phase 3 study DIUR-005 
Dose                    Hydrocortisone modified- Standard glucocorticoid group release hard capsules group
Baseline      24 weeks     Baseline       24 weeks
All
(hydrocortisone dose equivalents)*
Median daily dose (mg)         25.0            30.0            25.0              31.3 On hydrocortisone at baseline
Median daily dose (mg)         20.0            25.0           23.75              25.0 On prednis(ol)one at baseline
Median daily dose (mg)          30             27.5            26.6              32.8 On dexamethasone at baseline
Median daily dose (mg)          30              30              40                40 
Figure 1. End of study geometric mean 24-hour profile of 17-OHP after 24 weeks intensive treatment with either Efmody (closed circles) or standard therapy (open circles).
17-OHP nmol/l



Standard GC 24 weeks                                Efmody 24 weeks

A safety extension study of 91 patients with titration by investigators was characterised by dose reductions with median daily dose of Efmody at 18 months interim analysis (n=50) being 20 mg (from a median baseline daily dose of 30 mg) with 17-OHP levels remaining in the clinically determined optimal range and androstenedione at or below the reference range for normal individual.

In the safety assessment of clinical studies, differences between the treatment arms in treatment related AE’s were reported (by preferred term [PT]). The most notable differences between the Efmody and standard glucocorticoid therapy pools, respectively, were observed for headache (7.5% vs 1.6%), Efmody-S P C-0923                                                                   Efmody-5_10 mg-SPC increased appetite (5.8% vs 3.3%), weight increase (including abnormal weight gain) (9.2% vs1.6%), decreased appetite (5.0% vs 0%) and nausea (4.2% vs 1.6%).”

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following a single oral administration in fasted dexamethasone-suppressed healthy adults, the rate of absorption of hydrocortisone from Efmody 20 mg was delayed and reduced compared to immediate release hydrocortisone tablets 20 mg, as reflected by a lower Cmax and a significantly longer Tmax for Efmody (median Tmax for serum cortisol of 4.5 hours and 0.88 hours for Efmody and hydrocortisone tablets respectively). Efmody appeared to be more bioavailable relative to immediate release hydrocortisone tablets, with overall exposure to serum cortisol and derived free cortisol approximately 19% and 13% higher respectively for Efmody.

In the same population, food (high fat meal started 30 minutes before dosing) was found to delay and reduce the rate of absorption of hydrocortisone from Efmody 20 mg, as reflected by a longer Tmax (median Tmax for serum cortisol of 6.75 hours and 4.5 hours for fed and fasted subjects respectively) and lower Cmax (reduced by approximately 20% in fed subjects). Overall exposure appeared similar in fed and fasted subjects (90% confidence intervals for the fed/fasted ratio of the geometric least square mean of AUC0-t and AUC0-inf were within 80-125%). This effect is therefore not considered clinically significant.

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. Hydrocortisone is both metabolised by and a regulator of CYP3A4.

Elimination

In the fasted dexamethasone-suppressed healthy adult population described above, terminal elimination half-life values were similar for Efmody and hydrocortisone tablets (geometric mean t1/2 for serum cortisol of 1.38 hours and 1.40 hours respectively). Clearance appeared higher for hydrocortisone tablets relative to Efmody (geometric mean CL/F for serum cortisol of 22.24 L/h and 18.48 L/h respectively).

Paediatrics

The pharmacokinetics of Efmody have not been studied in the paediatric population.
Other populations
No studies have been conducted in patients with hepatic or renal impairment.