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

1327276800000
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
experiment_type: multiple
dose_type: Recommended
co-adm with
    data_source:
    https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
    unhealthy, 61 years
    population: unhealthy
    age: 61 years
    sex: M
    food_status:
    n:
    data_source:
    https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
    Disc. AE: Eye pain, Application site pain...
    AEs leading to
    discontinuation/dose reduction:​
    Eye pain (severe1 times / day)
    Application site pain (severe1 times / day)
    Periorbital edema (severe1 times / day)

    data_source:
    https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
    0.25 % 1 times / day multiple, topical
    Highest studied dose
    dose: 0.25 % 1 times / day
    route: topical
    experiment_type: multiple
    dose_type: Highest studied dose
    co-adm with
      data_source:
      https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
      unhealthy
      population: unhealthy
      age:
      sex:
      food_status:
      n:
      data_source:
      https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
      Disc. AE: Lymphangitis...
      AEs leading to
      discontinuation/dose reduction:​
      Lymphangitis (1 times / day)

      data_source:
      https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
      0.05 % 1 times / day multiple, topical
      Recommended
      dose: 0.05 % 1 times / day
      route: topical
      experiment_type: multiple
      dose_type: Recommended
      co-adm with
        data_source:
        https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
        unhealthy
        population: unhealthy
        age:
        sex:
        food_status:
        n:
        data_source:
        https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
        Disc. AE: Erythema, Skin exfoliation...
        AEs leading to
        discontinuation/dose reduction:​
        Erythema (1 times / day)
        Skin exfoliation (1 times / day)

        data_source:
        https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
        AEs

        AEs

        AESignificanceDosePopulation
        Application site pain severe,1 pts%
        Disc. AE
        0.015 % 1 times / day multiple, topical
        Recommended
        dose: 0.015 % 1 times / day
        route: topical
        experiment_type: multiple
        dose_type: Recommended
        co-adm with
          data_source:
          https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
          unhealthy, 61 years
          Eye pain severe,1 pts%
          Disc. AE
          0.015 % 1 times / day multiple, topical
          Recommended
          dose: 0.015 % 1 times / day
          route: topical
          experiment_type: multiple
          dose_type: Recommended
          co-adm with
            data_source:
            https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
            unhealthy, 61 years
            Periorbital edema severe,1 pts%
            Disc. AE
            0.015 % 1 times / day multiple, topical
            Recommended
            dose: 0.015 % 1 times / day
            route: topical
            experiment_type: multiple
            dose_type: Recommended
            co-adm with
              data_source:
              https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
              unhealthy, 61 years
              Erythema 1 pts%
              Disc. AE
              0.05 % 1 times / day multiple, topical
              Recommended
              dose: 0.05 % 1 times / day
              route: topical
              experiment_type: multiple
              dose_type: Recommended
              co-adm with
                data_source:
                https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
                unhealthy
                Skin exfoliation 1 pts%
                Disc. AE
                0.05 % 1 times / day multiple, topical
                Recommended
                dose: 0.05 % 1 times / day
                route: topical
                experiment_type: multiple
                dose_type: Recommended
                co-adm with
                  data_source:
                  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
                  unhealthy
                  Lymphangitis 1 pts%
                  Disc. AE
                  0.25 % 1 times / day multiple, topical
                  Highest studied dose
                  dose: 0.25 % 1 times / day
                  route: topical
                  experiment_type: multiple
                  dose_type: Highest studied dose
                  co-adm with
                    data_source:
                    https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf
                    unhealthy
                    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

                    PubMed

                    PubMed

                    TitleDatePubMed
                    Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate.
                    2006 Dec 1
                    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
                    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