CLINICAL PHARMACOLOGY
Mechanism of Action
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs such as prednisolone are primarily used for their potent anti-inflammatory effects in disorders of many organ systems.
Glucocorticoids such as prednisolone cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.
Prednisolone is a synthetic adrenocortical steroid drug with predominantly glucocorticoid properties. Some of these properties reproduce the physiological actions of endogenous glucocorticosteroids, but others do not necessarily reflect any of the adrenal hormones' normal functions; they are seen only after administration of large therapeutic doses of the drug. The pharmacological effects of prednisolone which are due to its glucocorticoid properties include: promotion of gluconeogenesis; increased deposition of glycogen in the liver; inhibition of the utilization of glucose; anti-insulin activity; increased catabolism of protein; increased lipolysis; stimulation of fat synthesis and storage; increased glomerular filtration rate and resulting increase in urinary excretion of urate (creatinine excretion remains unchanged); and increased calcium excretion.
Depressed production of eosinophils and lymphocytes occurs, but erythropoiesis and production of polymorphonuclear leukocytes are stimulated. Inflammatory processes (edema, fibrin deposition, capillary dilatation, migration of leukocytes and phagocytosis) and the later stages of wound healing (capillary proliferation, deposition of collagen, cicatrization) are inhibited.
Prednisolone can stimulate secretion of various components of gastric juice. Suppression of the production of corticotropin may lead to suppression of endogenous corticosteroids. Prednisolone has slight mineralocorticoid activity, whereby entry of sodium into cells and loss of intracellular potassium is stimulated. This is particularly evident in the kidney, where rapid ion exchange leads to sodium retention and hypertension.
Pharmacokinetics
Absorption
The maximum serum concentration of Flo-Pred occurs within 1 to 2 hrs following a single dose of oral administration. Food intake prolongs the time to peak concentration, but does not affect the extent of absorption significantly.
Distribution
Prednisolone is reported to be 70-90% protein-bound in the plasma and the volume of distribution is reported as 0.22 - 0.7 L/kg.
Metabolism
Prednisolone is reported to be metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates.
Excretion
Flo-Pred is eliminated from the plasma with a half-life of 2 to 3 hours.
Oral administration of single dose of 15 mg/5 mL of Flo-Pred, 15 mg/5 mL Prednisolone USP syrup, and 3× 5 mg Prednisolone USP tablets in 24 adult volunteers yielded comparable pharmacokinetic data:
Table 1. Comparison of Mean Pharmacokinetic Parameters (%CV) in Healthy Volunteers Following a Single Dose of 15 mg/5 mL of Flo-Pred, 15 mg/5 mL Prednisolone USP Syrup, and 3× 5 mg Prednisolone USP Tablets DoseAdministered under fasting conditions.
(15 mg prednisolone base equivalent) | AUC0-∞ (ng∙hr/mL)
(%CV) | Cmax (ng ∙ hr/mL)Mean values of 24 normal volunteers.
(%CV) |
|---|
| Flo-Pred Suspension | 1999.4 (60.0) | 321.1 (52.0) |
| Prednisolone Syrup | 1872.7 (50.4) | 362.4 (37.8) |
| Prednisolone Tablet | 1968.4 (54.6) | 326.9 (43.5) |
The systemic availability, metabolism and elimination of prednisolone after administration of single weight-based doses (0.8 mg/kg) of intravenous (IV) prednisolone and oral prednisone were reported in a study of 19 younger adult (aged 23 to 34 years) and 12 geriatric (65 to 89 years) subjects. Results showed that the systemic availability of total and unbound prednisolone, as well as interconversion between prednisolone and prednisone were independent of age. The mean unbound fraction of prednisolone was higher, and the steady-state volume of distribution (Vss) of unbound prednisolone was reduced in elderly patients. Plasma Prednisolone concentrations were higher in elderly subjects, and the higher AUCs of total and unbound prednisolone were most likely reflective of an impaired metabolic clearance, evidenced by reduced fractional urinary clearance of 6b-hydroxyprednisolone. Despite these findings of higher total and unbound prednisolone concentrations, elderly subjects had higher AUCs of cortisol, suggesting that the elderly population is less sensitive to suppression of endogenous cortisol or their capacity for hepatic inactivation of cortisol is diminished.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Flo-Pred was not formally evaluated in carcinogenicity studies. Review of the published literature identified carcinogenicity studies of prednisolone at doses which were less than the typical clinical doses. In a 2-year study, male Sprague-Dawley rats administered prednisolone in drinking water at a dose of 368 mcg/kg/day (equivalent to 3.5 mg/day in a 60 kg individual based on a mg/m2 body surface area comparison) developed increased incidences of hepatic adenomas. Lower doses were not studied and therefore a no effect level could not be identified. In an 18-month study, intermittent oral gavage administration of prednisolone did not induce tumors in female Sprague-Dawley rats when given 1, 2, 4.5 or 9 times per month at 3 mg/kg prednisolone (equivalent to 29 mg in a 60 kg individual based on a mg/m2 body surface area comparison).
Flo-Pred was not formally evaluated for genotoxicity. However, in published studies prednisolone was not mutagenic with or without metabolic activation in the Ames bacterial reverse mutation assay using Salmonella typhimurium and Escherichia coli, or in a mammalian cell gene mutation assay using mouse lymphoma L5178Y cells, according to current evaluation standards. In a published chromosomal aberration study in Chinese Hamster Lung (CHL) cells, a slight increase was seen in the incidence of structural chromosomal aberrations with metabolic activation at the highest concentration tested, however, the effect appears to be equivocal. Prednisolone was not genotoxic in an in vivo micronucleaus assay in the mouse though the study design did not meet current criteria.
Flo-Pred was not formally evaluated in fertility studies. However, menstrual irregularities have been described with clinical use [see Adverse Reactions (6) ].
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