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SOLU-CORTEF (Hydrocortisone sodium succinate for injection USP) Action And Clinical Pharmacology

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Action And Clinical Pharmacology

SOLU-CORTEF contains sterile hydrocortisone sodium succinate, which is the sodium succinate ester of hydrocortisone, a glucocorticoid. Hydrocortisone sodium succinate is highly soluble, which permits the intravenous administration of high doses in a small volume of diluent. This is particularly useful in situations where high blood levels of hydrocortisone are required rapidly.

Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory actions as hytdrocortisone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. Following the intravenous injection of SOLU-CORTEF, experimental evidence of its effects has been noted within a few minutes and persists for a variable period. SOLU-CORTEF may be administered by intravenous infusion, or by intramuscular injection. The preferred method for initial emergency use is intravenous injection.

Naturally occurring glucocorticoids (hydrocortisone and cortisone), 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.

The relative potency of methylprednisolone sodium succinate (SOLU-MEDROL) and hydrocortisone sodium succinate (SOLU-CORTEF), as indicated by depression of eosinophil count, following intravenous administration, is five to one. This is consistent with the relative oral potency of methylprednisolone and hydrocortisone.

Pharmacokinetics

The pharmacokinetics of hydrocortisone in healthy male subjects demonstrated nonlinear kinetics when a single intravenous dose of hydrocortisone sodium succinate higher than 20 mg was administered, and the corresponding pharmacokinetic parameters of hydrocortisone are presented in Table 3.

Table 3. Mean (SD) hydrocortisone pharmacokinetic parameters following single intravenous doses
 
AUC0-∞ = Area under the curve from time zero to infinity.

Healthy Male Adults (21-29 years; N = 6)

Dose (mg)

5

10

20

40

Total Exposure (AUC0-∞; ng·h/mL)

410 (80)

790 (100)

1480 (310)

2290 (260)

Clearance (CL; mL/min/m2)

209 (42)

218 (23)

239 (44)

294 (34)

Volume of Distribution at Steady State (Vdss; L)

20.7 (7.3)

20.8 (4.3)

26.0 (4.1)

37.5 (5.8)

Elimination Half-life (t1/2; hr)

1.3 (0.3)

1.3 (0.2)

1.7 (0.2)

1.9 (0.1)

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 (Table 3). 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 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.

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