Levecortix-100/Levecortix-250 Mechanism of Action

Pharmacology: Pharmacodynamics: Levecortix-100: Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory actions as Hydrocortisone. It is a glucocorticosteroid. Used in pharmacological doses, its actions suppress the clinical manifestations of disease in a wide range of disorders.
Levecortix-250: Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids.
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders of many organ systems.
Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory actions as hydrocortisone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The highly water-soluble sodium succinate ester of hydrocortisone permits the immediate intravenous administration of high doses of hydrocortisone in a small volume of diluent and is particularly useful where high blood levels of hydrocortisone are required rapidly. Following the intravenous injection of hydrocortisone sodium succinate, demonstrable effects are evident within one hour and persist for a variable period.
Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune response to diverse stimuli.
The relative potency of methylprednisolone sodium succinate and hydrocortisone sodium succinate, as indicated by depression of eosinophil count, following intravenous administration, is five lo one. This is consistent with the relative oral potency of methylprednisolone and hydrocortisone.
Pharmacokinetics: Levecortix-100: Hydrocortisone is readily absorbed from the gastrointestinal tract and peak blood concentrations are attained in about an hour. The biological half-life is about 100 minutes. It is more than 90% bound to plasma proteins. Following intramuscular injection, the absorption of the water-soluble sodium phosphate and sodium succinate esters is rapid, while absorption of Hydrocortisone free alcohol and its lipid-soluble esters is slower. Absorption of Hydrocortisone acetate after intra-articular or soft-tissue injection is also slow. Hydrocortisone is absorbed through the skin, particularly in denuded areas. Hydrocortisone is metabolised in the liver and most body tissues to hydrogenated and degraded forms such as tetrahydrocortisone and tetrahydrocortisol. These are excreted in the urine, mainly conjugated as glucuronides, together with a very small proportion of unchanged hydrocortisone. Hydrocortisone readily crosses the placenta.
Levecortix-250: Absorption: Following administration of 5, 10, 20, and 40 mg single intravenous doses of hydrocortisone sodium succinate in healthy male subjects, mean peak values obtained at 10 minutes after dosing were 312, 573, 1095, and 1854 ng/mL, respectively. Hydrocortisone sodium succinate is rapidly absorbed when administered intramuscularly.
Distribution: Hydrocortisone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. The volume of distribution at steady state for hydrocortisone ranged from approximately 20 to 40 L. Hydrocortisone binds to the glycoprotein transcortin (i.e., corticosteroid binding globulin) and albumin. The plasma protein binding of hydrocortisone in humans is approximately 92%.
Metabolism: Hydrocortisone (i.e., cortisol) is metabolized by 11β-HSD2 to cortisone, and further to dihydrocortisone and tetrahydrocortisone. Other metabolites include dihydrocortisol, 5α-dihydrocortisol, tetrahydrocortisol, and 5α-tetrahydrocortisol. Cortisone can be converted to cortisol through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Hydrocortisone is also metabolized by CYP3A4 to 6β-hydroxycortisol (6β-OHF), and 6β-OHF varied from 2.8% to 31.7% of the total metabolites produced, demonstrating large inter-individual variability.
Excretion: Excretion of the administered dose is nearly complete within 12 hours. When hydrocortisone sodium succinate is administered intramuscularly, it is excreted in a pattern similar to that observed after intravenous injection.