U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C25H34O6
Molecular Weight 430.5348
Optical Activity UNSPECIFIED
Defined Stereocenters 8 / 8
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of INGENOL MEBUTATE

SMILES

C/C(/[H])=C(/C)\C(=O)O[C@@]1([H])C(=C[C@@]23[C@]([H])(C)C[C@]4([H])[C@]([H])([C@]([H])(C=C(CO)[C@]([H])([C@]12O)O)C3=O)C4(C)C)C

InChI

InChIKey=VDJHFHXMUKFKET-WDUFCVPESA-N
InChI=1S/C25H34O6/c1-7-12(2)22(29)31-21-13(3)10-24-14(4)8-17-18(23(17,5)6)16(20(24)28)9-15(11-26)19(27)25(21,24)30/h7,9-10,14,16-19,21,26-27,30H,8,11H2,1-6H3/b12-7-/t14-,16+,17-,18+,19-,21+,24+,25+/m1/s1

HIDE SMILES / InChI

Description
Curator's Comment:: http://www.dermnetnz.org/topics/ingenol-mebutate-gel/; http://www.ncbi.nlm.nih.gov/pubmed/25115145; https://www.ncbi.nlm.nih.gov/pubmed/?term=24672213; http://www.ncbi.nlm.nih.gov/pubmed/?term=26225771;

Ingenol mebutate is a substance found in the sap of the plant Euphorbia peplus. Ingenol mebutate gel was developed as a short-course topical therapy for actinic keratosis and non-melanoma skin cancer. It was approved under the trade name Picato by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the topical treatment of actinic keratosis in two gel formulations of different strengths for use on either the face and scalp (0.015%) or the trunk and extremities (0.05%). Ingenol mebutate may offer several advantages over other AK treatments currently on the market, including a shorter duration of use, faster resolution of lesions, and a favorable side-effect profile. It was shown in several randomized, double-blind, vehicle-controlled studies that applied topically for 2 to 3 days ingenol mebutate gel is effective for treatment of actinic keratoses. The mechanism of action by which Picato gel induces cell death in treating AK lesions is unknown. It is presumed to involve primary necrosis then neutrophil-mediated inflammation and antibody-dependent cell death of residual disease cells. Also ingenol mebutate activates various protein kinase C (PKC) isoforms, thereby inducing apoptosis in some tumor cells, including myeloid leukemia cells, melanoma cells, and basal cell carcinoma cells. The PKC family consists of signaling isoenzymes that regulate many cell processes including proliferation, differentiation, and apoptosis. Ingenol mebutate (PEP005) has also been found to be useful for reactivating latent HIV virus in cells taken from individuals who have tested negative for signs of the disease following extended courses of anti-retroviral drugs, raising the possibility that this drug may be used to expose the last traces of virus, and thus potentially provide a permanent cure for HIV infection. Research is ongoing to determine whether the effects observed in vitro are also seen in animal models, with a view to eventual human trials for this application.

Approval Year

Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Curative
PICATO

Approved Use

Indicated for the topical treatment of actinic keratosis.

Launch Date

1.32727675E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
0.332 nM
0.127 mg 1 times / day multiple, topical
dose: 0.127 mg
route of administration: Topical
experiment type: MULTIPLE
co-administered:
INGENOL MEBUTATE blood
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
1.43 ng × h/mL
0.127 mg 1 times / day multiple, topical
dose: 0.127 mg
route of administration: Topical
experiment type: MULTIPLE
co-administered:
INGENOL MEBUTATE blood
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
0.015 % 1 times / day multiple, topical
Recommended
Dose: 0.015 %, 1 times / day
Route: topical
Route: multiple
Dose: 0.015 %, 1 times / day
Sources: Page: p. 52
unhealthy, 61 years
n = 1
Health Status: unhealthy
Age Group: 61 years
Sex: M
Population Size: 1
Sources: Page: p. 52
Disc. AE: Eye pain, Application site pain...
AEs leading to
discontinuation/dose reduction:
Eye pain (severe, 1 patient)
Application site pain (severe, 1 patient)
Periorbital edema (severe, 1 patient)
Sources: Page: p. 52
0.25 % 1 times / day multiple, topical
Highest studied dose
Dose: 0.25 %, 1 times / day
Route: topical
Route: multiple
Dose: 0.25 %, 1 times / day
Sources: Page: p. 53
unhealthy
n = 1
Health Status: unhealthy
Condition: superficial basal cell carcinoma
Population Size: 1
Sources: Page: p. 53
Disc. AE: Lymphangitis...
AEs leading to
discontinuation/dose reduction:
Lymphangitis (1 patient)
Sources: Page: p. 53
0.05 % 1 times / day multiple, topical
Recommended
Dose: 0.05 %, 1 times / day
Route: topical
Route: multiple
Dose: 0.05 %, 1 times / day
Sources: Page: p. 53
unhealthy
n = 1
Health Status: unhealthy
Condition: nodular basal cell carcinoma
Population Size: 1
Sources: Page: p. 53
Disc. AE: Erythema, Skin exfoliation...
AEs leading to
discontinuation/dose reduction:
Erythema (1 patient)
Skin exfoliation (1 patient)
Sources: Page: p. 53
AEs

AEs

AESignificanceDosePopulation
Application site pain severe, 1 patient
Disc. AE
0.015 % 1 times / day multiple, topical
Recommended
Dose: 0.015 %, 1 times / day
Route: topical
Route: multiple
Dose: 0.015 %, 1 times / day
Sources: Page: p. 52
unhealthy, 61 years
n = 1
Health Status: unhealthy
Age Group: 61 years
Sex: M
Population Size: 1
Sources: Page: p. 52
Eye pain severe, 1 patient
Disc. AE
0.015 % 1 times / day multiple, topical
Recommended
Dose: 0.015 %, 1 times / day
Route: topical
Route: multiple
Dose: 0.015 %, 1 times / day
Sources: Page: p. 52
unhealthy, 61 years
n = 1
Health Status: unhealthy
Age Group: 61 years
Sex: M
Population Size: 1
Sources: Page: p. 52
Periorbital edema severe, 1 patient
Disc. AE
0.015 % 1 times / day multiple, topical
Recommended
Dose: 0.015 %, 1 times / day
Route: topical
Route: multiple
Dose: 0.015 %, 1 times / day
Sources: Page: p. 52
unhealthy, 61 years
n = 1
Health Status: unhealthy
Age Group: 61 years
Sex: M
Population Size: 1
Sources: Page: p. 52
Lymphangitis 1 patient
Disc. AE
0.25 % 1 times / day multiple, topical
Highest studied dose
Dose: 0.25 %, 1 times / day
Route: topical
Route: multiple
Dose: 0.25 %, 1 times / day
Sources: Page: p. 53
unhealthy
n = 1
Health Status: unhealthy
Condition: superficial basal cell carcinoma
Population Size: 1
Sources: Page: p. 53
Erythema 1 patient
Disc. AE
0.05 % 1 times / day multiple, topical
Recommended
Dose: 0.05 %, 1 times / day
Route: topical
Route: multiple
Dose: 0.05 %, 1 times / day
Sources: Page: p. 53
unhealthy
n = 1
Health Status: unhealthy
Condition: nodular basal cell carcinoma
Population Size: 1
Sources: Page: p. 53
Skin exfoliation 1 patient
Disc. AE
0.05 % 1 times / day multiple, topical
Recommended
Dose: 0.05 %, 1 times / day
Route: topical
Route: multiple
Dose: 0.05 %, 1 times / day
Sources: Page: p. 53
unhealthy
n = 1
Health Status: unhealthy
Condition: nodular basal cell carcinoma
Population Size: 1
Sources: Page: p. 53
Overview

OverviewOther

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
no
no
no
no
no
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Characterization of the interaction of ingenol 3-angelate with protein kinase C.
2004 May 1
Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate.
2006 Dec 1
HIV type 1 inhibition by protein kinase C modulatory compounds.
2006 Sep
PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study.
2009 Feb
Ingenol mebutate gel for actinic keratosis.
2012 Mar 15
Patents

Sample Use Guides

For application of up to one contiguous skin area of approximately 25 cm^2 (5 cm x 5 cm) using one unit dose tube. For actinic keratosis on the face or scalp apply Picato gel, 0.015% to the affected area once daily for 3 consecutive days. For actinic keratosis on the trunk or extremities apply Picato gel 0.05% to the affected area once daily for 2 consecutive days
Route of Administration: Topical
In Vitro Use Guide
Unknown
Name Type Language
INGENOL MEBUTATE
DASH   INN   MART.   ORANGE BOOK   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
INGENOL MEBUTATE [MART.]
Common Name English
2-BUTENOIC ACID, 2-METHYL-, (1AR,2S,5R,5AS,6S,8AS,9R,10AR)-1A,2,5,5A,6,9,10,10A-OCTAHYDRO-5,5A-DIHYDROXY-4-(HYDROXYMETHYL)-1,1,7,9-TETRAMETHYL-11-OXO-1H-2,8A-METHANOCYCLOPENTA(A)CYCLOPROPA(E)CYCLODECEN-6-YL ESTER, (2Z)-
Common Name English
INGENOL MEBUTATE [ORANGE BOOK]
Common Name English
PEP005
Code English
AGN 204332
Code English
INGENOL MEBUTATE [USAN]
Common Name English
INGENOL MEBUTATE [WHO-DD]
Common Name English
PEP-005
Code English
(1AR,2S,5R,5AS,6S,8AS,9R,10AR)-5,5A-DIHYDROXY-4-(HYDROXYMETHYL)-1,1,7,9-TETRAMETHYL-11-OXO-1A,2,5,5A,6,9,10,10A-OCTAHYDRO-1H-2,8A-METHANOCYCLOPENTA(A)CYCLOPROPA(E)CYCLODECEN-6-YL (2Z)-2-METHYLBUT-2-ENOATE
Common Name English
INGENOL MEBUTATE [VANDF]
Common Name English
PICATO
Brand Name English
INGENOL MEBUTATE [MI]
Common Name English
INGENOL MEBUTATE [INN]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C274
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
WHO-VATC QD06BX02
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
EMA ASSESSMENT REPORTS PICATO (AUTHORIZED: KERATOSIS, ACTINIC)
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
WHO-ATC D06BX02
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
NDF-RT N0000184015
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
Code System Code Type Description
NDF-RT
N0000009176
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY Increased Cellular Death [PE]
EVMPD
SUB32495
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
INN
9006
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
HSDB
8308
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
PUBCHEM
6918670
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
DRUG BANK
DB05013
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
NCI_THESAURUS
C48398
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
MERCK INDEX
M11695
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
ChEMBL
CHEMBL1863513
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
RXCUI
1242806
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY RxNorm
FDA UNII
7686S50JAH
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
CAS
75567-37-2
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
DRUG CENTRAL
4226
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY
IUPHAR
7443
Created by admin on Sat Jun 26 01:51:03 UTC 2021 , Edited by admin on Sat Jun 26 01:51:03 UTC 2021
PRIMARY