Ingenol Mebutate
Ingenol Mebutate
Ingenol mebutate, Ingenol-3-angulate or PEP005 is commonly known with the trade name of PICATO of Leo pharmaceuticals. It is a topical gel used under strict regulations to treat Actinic Keratosis (AK) for a short duration therapy and to lower the recurrence rate of AK compared to the available drugs (Soyer H.P,Prowl T.W,Jemec G.B.E. 2015).This gel has been approved by The U.S. Food and Drug Administration (FDA),Therapeutic Goods Administration (TGA) and European Medicines Agency (EMA) (U.S Food and Drug Administration n.d.) It has a dual mechanism of action; those are rapid lesion necrosis and specific neutrophil-mediated, antibody-dependent cellular cytotoxicity. …show more content…
(Rosen RH, Gupta AK, Tyring SK. 2011)
AK which is also known as Solar Keratosis is a pre cancer patch of thick, scaly skin found mostly among the fair skinned people who are frequently exposed to sun. The Ultra Violet rays of sun and usage of indoor tanning beds may cause this skin condition. If AK is left untreated it may turn into squamous cell carcinoma and melanoma.
Picato is supplied as a 0.015% or 0.05% gel for topical administration. The recommended dose for actinic keratosis on the face and scalp is 0.015% applied to the affected area once daily for three consecutive days. The recommended dose for actinic keratosis on the trunk and extremities is 0.05% applied to the affected area once daily for two consecutive days. (Fallen RS, Gooderham M. 2012)
The exact mechanism of action of ingenol mebutate in actinic keratosis is still unknown yet it is presumed to involve as an inducer of apoptosis by targeting Protein Kinase C alpha and delta (PKC α and δ) types in humans. The PKC family consists of signaling isoenzymes that regulates cellular activities like cell proliferation, differentiation, apoptosis and antineoplastic . These effects are applied upon myeloid leukemia cells, melanoma cells, basal cell carcinoma cells and other tumor cells. Drug actions are facilitated by ligand binding and general function of the drug is described as Zinc-Ion binding and Protein serine/threonine kinase activity to PKC α and PKC δ respectively. (National Center for Biotechnology Information n.d.)
Hence Picato is a topical treatment; the systematic absorption is less than 0.1ng/mL practically the measurement explains that Picato is not absorbed through skin. Ingenol mebutate has no interaction with other oral drugs. There is no route of elimination, clearance quantity, metabolism, and biological half life indicated as it is a topical treatment.
Figure1 : Chemical Structure of Ingenol Mebutate (Ingenol Mebutate 2015)
Chemical formula is Ingenol Mebutate is C25H34O6 and according to the chemical properties of Ingenol Mebutate it exhibit the rule of 5.Molecular Weight is 430.53386 g/mol, Hydrogen bond donor count is 3 and Hydrogen bond acceptor count is 6 and the LogP value is 2.
(National Center for Biotechnology Information n.d.)
Drug Discovery
Ingenol mebutate is the active ingredient in the sap of the plant Euphorbia peplus in Australia.It is a diterpene ester, it is the active form of the drug and not considered as a prodrug. It is obtained from the aerial parts of the plants followed by extraction and purification. This plant has being used in traditional herbal remedy to a variety of ailments, including skin cancers and keratosis (Nielsch U;Fuhrmann U;Jaroch S. 2004) .Component extraction research of this plant resulted in the identification of a number of diterpene esters which all were capable of producing an inflammation reaction, of which ingenol mebutate was identified as the cytotoxic compound. (Rizk AM, Hammouda FM, Evans FJ …show more content…
1985)
The efficacy of this sap was confirmed in a clinical study of three daily treatments of 48 lesions that included intra epidermal carcinoma, basal cell carcinoma, and squamous cell carcinoma.
The complete clinical clearance of more than 50% of lesions after a mean follow-up time of 15 months supported further clinical development of ingenol mebutate (Berman 2012)
Drug Development
In the process of drug development, lead identification of 25 compounds with similar bioactivity was identified. (National Center for Biotechnology Information n.d.)
Regulatory Approvals
Ingenol Mebutate is identified as a New Molecular Entity (NME) by Center of Drug Evaluation and Research (CDER) of FDA in 23/01/2012 under the FDA application No (NDA) 202833 .It is reviewed as a Standard Review Drug by FDA. (U.S Food and Drug Administration n.d.)
Pharmocovigilance studies
Post marketing cases submitted to the FDA Adverse Event Reporting System (FAERS) for Picato
gel.
Ingenol mebutate, Ingenol-3-angulate or PEP005 is commonly known with the trade name of PICATO of Leo pharmaceuticals. It is a topical gel used under strict regulations to treat Actinic Keratosis (AK) for a short duration therapy and to lower the recurrence rate of AK compared to the available drugs (Soyer H.P,Prowl T.W,Jemec G.B.E. 2015).This gel has been approved by The U.S. Food and Drug Administration (FDA),Therapeutic Goods Administration (TGA) and European Medicines Agency (EMA) (U.S Food and Drug Administration n.d.) It has a dual mechanism of action; those are rapid lesion necrosis and specific neutrophil-mediated, antibody-dependent cellular cytotoxicity. …show more content…
(Rosen RH, Gupta AK, Tyring SK. 2011)
AK which is also known as Solar Keratosis is a pre cancer patch of thick, scaly skin found mostly among the fair skinned people who are frequently exposed to sun. The Ultra Violet rays of sun and usage of indoor tanning beds may cause this skin condition. If AK is left untreated it may turn into squamous cell carcinoma and melanoma.
Picato is supplied as a 0.015% or 0.05% gel for topical administration. The recommended dose for actinic keratosis on the face and scalp is 0.015% applied to the affected area once daily for three consecutive days. The recommended dose for actinic keratosis on the trunk and extremities is 0.05% applied to the affected area once daily for two consecutive days. (Fallen RS, Gooderham M. 2012)
The exact mechanism of action of ingenol mebutate in actinic keratosis is still unknown yet it is presumed to involve as an inducer of apoptosis by targeting Protein Kinase C alpha and delta (PKC α and δ) types in humans. The PKC family consists of signaling isoenzymes that regulates cellular activities like cell proliferation, differentiation, apoptosis and antineoplastic . These effects are applied upon myeloid leukemia cells, melanoma cells, basal cell carcinoma cells and other tumor cells. Drug actions are facilitated by ligand binding and general function of the drug is described as Zinc-Ion binding and Protein serine/threonine kinase activity to PKC α and PKC δ respectively. (National Center for Biotechnology Information n.d.)
Hence Picato is a topical treatment; the systematic absorption is less than 0.1ng/mL practically the measurement explains that Picato is not absorbed through skin. Ingenol mebutate has no interaction with other oral drugs. There is no route of elimination, clearance quantity, metabolism, and biological half life indicated as it is a topical treatment.
Figure1 : Chemical Structure of Ingenol Mebutate (Ingenol Mebutate 2015)
Chemical formula is Ingenol Mebutate is C25H34O6 and according to the chemical properties of Ingenol Mebutate it exhibit the rule of 5.Molecular Weight is 430.53386 g/mol, Hydrogen bond donor count is 3 and Hydrogen bond acceptor count is 6 and the LogP value is 2.
(National Center for Biotechnology Information n.d.)
Drug Discovery
Ingenol mebutate is the active ingredient in the sap of the plant Euphorbia peplus in Australia.It is a diterpene ester, it is the active form of the drug and not considered as a prodrug. It is obtained from the aerial parts of the plants followed by extraction and purification. This plant has being used in traditional herbal remedy to a variety of ailments, including skin cancers and keratosis (Nielsch U;Fuhrmann U;Jaroch S. 2004) .Component extraction research of this plant resulted in the identification of a number of diterpene esters which all were capable of producing an inflammation reaction, of which ingenol mebutate was identified as the cytotoxic compound. (Rizk AM, Hammouda FM, Evans FJ …show more content…
1985)
The efficacy of this sap was confirmed in a clinical study of three daily treatments of 48 lesions that included intra epidermal carcinoma, basal cell carcinoma, and squamous cell carcinoma.
The complete clinical clearance of more than 50% of lesions after a mean follow-up time of 15 months supported further clinical development of ingenol mebutate (Berman 2012)
Drug Development
In the process of drug development, lead identification of 25 compounds with similar bioactivity was identified. (National Center for Biotechnology Information n.d.)
Regulatory Approvals
Ingenol Mebutate is identified as a New Molecular Entity (NME) by Center of Drug Evaluation and Research (CDER) of FDA in 23/01/2012 under the FDA application No (NDA) 202833 .It is reviewed as a Standard Review Drug by FDA. (U.S Food and Drug Administration n.d.)
Pharmocovigilance studies
Post marketing cases submitted to the FDA Adverse Event Reporting System (FAERS) for Picato
gel.