Advantan Mechanism of Action

Pharmacotherapeutic group: Corticosteroids, potent (group III). ATC code: D07AC14.
Pharmacology: Pharmacodynamics: After topical application, Methylprednisolone aceponate (Advantan) cream, ointment and fatty ointment suppress inflammatory and allergic skin reactions as well as reactions associated with hyperproliferation, leading to regression of the objective symptoms (erythema, edema, weeping) and the subjective complaints (itching, smarting, pain).
It is known that methylprednisolone aceponate itself binds to the intracellular glucocorticoid receptor and this is especially true for the principal metabolite 6α-methylprednisolone-17-propionate, which is formed after cleavage of the ester in the skin.
The steroid receptor complex binds to certain regions of DNA, thereby triggering a series of biological effects.
Binding of the steroid receptor complex results in induction of macrocortin synthesis. Macrocortin inhibits the release of arachidonic acid and thus the formation of inflammatory mediators such as prostaglandins and leukotrienes.
The immunosuppressive action of glucocorticoids can be explained by inhibition of cytokine synthesis and an antimitotic effect, which so far is not well understood.
Inhibition of the synthesis of vasodilating prostaglandins or potentiation of the vasoconstrictive effect of adrenaline finally results in the vasoconstrictive activity of glucocorticosteroids.
Pharmacokinetics: Methylprednisolone aceponate becomes available from the formulation base. The concentration in the stratum corneum and living skin decreases from the outside to the inside.
Methylprednisolone aceponate is hydrolized in the epidermis and dermis to the main metabolite 6α-methylprednisolone-17-propionate which binds more firmly to the corticoid receptor than the parent drug, an indication of a bioactivation in the skin. The rate and extent of percutaneous absorption of a topical corticoid depends on a series of factors: chemical structure of the compound, the composition of the vehicle, the concentration of the compound in the vehicle, the conditions of exposure (area treated, duration of exposure, open or occlusion) and the skin status (kind and severity of skin disease, anatomical site etc.).
Percutaneous absorption of methylprednisolone aceponate from the cream, ointment and fatty ointment formulations has been investigated in healthy volunteers. The percutaneous absorption after open application of the Methylprednisolone aceponate (Advantan) fatty ointment (2 x 20 g daily) for 5 days was estimated to 0.34% corresponding to a corticoid load of approximately 2 µg/kg/day. The respective figures after open application of the Methylprednisolone aceponate (Advantan) ointment (2 x 20 g daily) for 8 days were 0.65% (absorption) or 4 µg/kg/day (load). Under occlusive conditions the daily application of 2 x 20 g Methylprednisolone aceponate (Advantan) cream for 8 days led to a mean percutaneous absorption of ca. 3 % corresponding to a systemic corticoid load of ca. 20 µg/kg/day. The percutaneous absorption of methylprednisolone aceponate through skin pre-damaged by removal of the stratum corneum resulted in distinctly higher absorption (13-27% of the dose). In adult psoriatic and atopic patients, percutaneous absorption of methylprednisolone aceponate from the fatty ointment was about 2.5%. In three atopic children (9-10 years of age), percutaneous absorption of methylprednisolone aceponate from the fatty ointment was about 0.5-2% and thus not higher than that compared to adults.
After reaching the systemic circulation, the primary hydrolysis product of methylprednisolone aceponate, 6α-methyl-prednisolone-17-propionate is quickly conjugated with glucuronic acid and as a result, inactivated. The metabolites of methylprednisolone aceponate (main metabolite: 6α-methyl prednisolone-17-propionate-21-glucuronide) are eliminated primarily via the kidneys with a half-life of about 16 hours. Following i.v. administration, excretion with the urine and feces was complete within 7 days. No accumulation of drug substance or metabolites takes place in the body.
Toxicology: Preclinical safety data: In systemic tolerance studies following repeated subcutaneous and dermal administration methylprednisolone aceponate showed the action profile of a typical glucocorticoid. It can be concluded from these results that following therapeutic use of Methylprednisolone aceponate (Advantan) cream, ointment and fatty ointment no side-effects other than those typical of glucocorticoids are to be expected even under extreme conditions such as application over a large surface and/or occlusion.
Embryotoxicity studies with Methylprednisolone aceponate (Advantan) cream, ointment and fatty ointment led to results typical for glucocorticoids, i.e. embryolethal and/or teratogenic effects are induced in the appropriate test system. In view of these findings, particular care should be taken when prescribing Methylprednisolone aceponate (Advantan) cream, ointment and fatty ointment during pregnancy. The results of epidemiological studies are summarized under "Use in Pregnancy & Lactation".
Neither in vitro investigations for detection of gene mutations on bacteria and mammalian cells nor in vitro and in vivo investigations for detection of chromosome and gene mutations gave any indication of a genotoxic potential of methylprednisolone aceponate.
Specific tumorigenicity studies using methylprednisolone aceponate have not been carried out.
Knowledge concerning the structure, the pharmacological effect mechanism and the results from systemic tolerance studies with long-term administration do not indicate any increase in the risk of tumor occurrence. As systemically effective immunosuppressive exposure is not reached with dermal application of Methylprednisolone aceponate (Advantan) cream, ointment and fatty ointment under the recommended conditions of use, no influence on the occurrence of tumors is to be expected.
In investigations of the local tolerance of methylprednisolone aceponate and Methylprednisolone aceponate (Advantan) formulations on the skin and the mucosa no findings other than the topical side-effects known for glucocorticoids were recorded.
Methylprednisolone aceponate showed no sensitizing potential on the skin of the guinea-pig.