Ingenol mebutate

The mechanism of action of ingenol mebutate for use in actinic keratosis remains to be fully characterised. In vivo and in vitro models have shown a dual mechanism of action for the effects of ingenol mebutate: 1) induction of local lesion cell death and 2) promoting an inflammatory response characterised by local production of proinflammatory cytokines and chemokines and infiltration of immunocompetent cells.

Pharmacodynamic effects

Results from two clinical studies on biological effects of ingenol mebutate have shown that topical administration induced epidermal necrosis and a profound inflammatory response in both epidermis and the upper dermis of the treated skin, dominated by infiltrating T cells, neutrophils and macrophages. Necrosis in the dermis was rarely observed.

Gene expression profiles of skin biopsies from the treated areas is suggestive of inflammatory responses and response to wounding, which is consistent with the histology assessments. Non-invasive examination of the treated skin by reflectance confocal microscopy have shown that the skin changes induced by ingenol mebutate were reversible, with almost complete normalisation of all measured parameters on day 57 after treatment, which is supported also by clinical findings and studies in animals.

The systemic pharmacokinetic profile of ingenol mebutate and its metabolites has not been characterised in humans due to the absence of quantifiable whole blood levels following cutaneous administration.

Absorption

No systemic absorption was detected at or above the lower limit of detection (0.1 ng/mL) when ingenol mebutate 500 mcg/g from 4 tubes was applied to an area of 100 cm² on the dorsal forearm in actinic keratosis patients once daily for 2 consecutive days.

In vitro study results demonstrate that ingenol mebutate does not inhibit or induce human cytochrome P450 isoforms.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and genotoxicity.

The non-clinical safety studies demonstrate that cutaneous administration of ingenol mebutate gel is well tolerated with any skin irritation being reversible and a negligible risk of systemic toxicity under the recommended conditions of use.

In rats, ingenol mebutate was not associated with fetal developmental effects at IV doses up to 5 mcg/kg/day (30 mcg/m²/day). In rabbits there were no major abnormalities. Minor fetal abnormalities or variants were observed in the fetuses of treated dams at doses of 1 mcg/kg/day (12 mcg/m²/day).