temsirolimus Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definitionDrug idCAS RN
immunosuppressants, rapamycin derivatives 4161 162635-04-3

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • temsirolimus
  • torisel
  • temsorolimus
  • CCI-779
  • CCI 779
Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.
  • Molecular weight: 1030.30
  • Formula: C56H87NO16
  • CLOGP: 7.46
  • LIPINSKI: 3
  • HAC: 17
  • HDO: 4
  • TPSA: 241.96
  • ALOGS: -5.64
  • ROTB: 11

  • Status: OFP

  • Legend:
    OFP - off patent
    OFM - off market
    ONP - on patent

Drug dosage:

None

ADMET properties:

PropertyValueReference
BDDCS (Biopharmaceutical Drug Disposition Classification System) 1 Benet LZ, Broccatelli F, Oprea TI
S (Water solubility) 0.01 mg/mL Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine) 4.60 % Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose) 0.15 ┬ÁM/kg/day Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
Vd (Volume of distribution) 3 L/kg Lombardo F, Berellini G, Obach RS
CL (Clearance) 7.70 mL/min/kg Lombardo F, Berellini G, Obach RS
t_half (Half-life) 18 hours Lombardo F, Berellini G, Obach RS

Approvals:

DateAgencyCompanyOrphan
Nov. 19, 2007 EMA Pfizer Limited
May 30, 2007 FDA PF PRISM CV

FDA Adverse Event Reporting System (Female)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Disease progression 429.11 44.34 110 770 16985 2340220
Renal cell carcinoma 183.38 44.34 32 848 725 2356480
Hyperglycaemia 119.06 44.34 31 849 4854 2352351
Metastatic renal cell carcinoma 104.62 44.34 17 863 244 2356961
Hypokalaemia 103.38 44.34 33 847 10621 2346584
Dehydration 93.41 44.34 37 843 22258 2334947
Dyspnoea 91.36 44.34 54 826 78679 2278526
Mucosal inflammation 79.90 44.34 23 857 5201 2352004
Pneumonia 76.49 44.34 41 839 49255 2307950
Blood creatinine increased 75.55 44.34 26 854 10507 2346698
Hypophosphataemia 74.95 44.34 16 864 1054 2356151
Anaemia 74.51 44.34 36 844 34756 2322449
Pleural effusion 72.95 44.34 26 854 11642 2345563
Hypertension 69.90 44.34 32 848 27329 2329876
Death 69.40 44.34 46 834 81422 2275783
Pneumonitis 67.20 44.34 19 861 4020 2353185
Fatigue 65.29 44.34 45 835 84828 2272377
Nausea 58.32 44.34 47 833 112142 2245063
Stomatitis 58.25 44.34 21 859 9689 2347516
Febrile neutropenia 55.91 44.34 21 859 10861 2346344
Hypertriglyceridaemia 54.87 44.34 12 868 884 2356321
Diarrhoea 54.25 44.34 40 840 83524 2273681
Blood bilirubin increased 53.54 44.34 17 863 5328 2351877
Vomiting 52.68 44.34 37 843 71565 2285640
Pyrexia 52.13 44.34 33 847 53675 2303530
Platelet count decreased 51.61 44.34 22 858 15791 2341414
Neoplasm progression 51.56 44.34 16 864 4652 2352553
Respiratory failure 51.48 44.34 21 859 13507 2343698
Abdominal pain 48.73 44.34 27 853 34347 2322858

FDA Adverse Event Reporting System (Male)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Disease progression 805.19 42.56 238 1684 17025 1727834
Renal cell carcinoma 329.15 42.56 72 1850 1436 1743423
Interstitial lung disease 215.44 42.56 77 1845 9619 1735240
Metastatic renal cell carcinoma 189.24 42.56 39 1883 572 1744287
Pneumonia 181.92 42.56 110 1812 46072 1698787
Pleural effusion 169.32 42.56 67 1855 11043 1733816
Pneumonitis 167.14 42.56 51 1871 3864 1740995
Dyspnoea 152.62 42.56 103 1819 51956 1692903
Thrombocytopenia 148.12 42.56 74 1848 21175 1723684
Dehydration 133.39 42.56 65 1857 17593 1727266
Neoplasm progression 124.34 42.56 39 1883 3228 1741631
Anaemia 117.56 42.56 71 1851 29386 1715473
Stomatitis 101.43 42.56 38 1884 5366 1739493
Pyrexia 99.23 42.56 76 1846 46324 1698535
Blood creatinine increased 95.25 42.56 48 1874 13898 1730961
General physical health deterioration 95.04 42.56 47 1875 13071 1731788
Nausea 94.74 42.56 77 1845 51119 1693740
Mucosal inflammation 91.86 42.56 33 1889 4136 1740723
Renal failure 89.49 42.56 52 1870 19965 1724894
Condition aggravated 89.45 42.56 53 1869 21097 1723762
Febrile neutropenia 87.06 42.56 42 1880 11058 1733801
Hypersensitivity 86.41 42.56 41 1881 10403 1734456
Acute kidney injury 76.19 42.56 58 1864 34886 1709973
Pneumocystis jirovecii pneumonia 75.70 42.56 25 1897 2431 1742428
Hyponatraemia 73.40 42.56 35 1887 8965 1735894
Vomiting 69.35 42.56 57 1865 38258 1706601
Fatigue 68.74 42.56 64 1858 50717 1694142
Hyperglycaemia 67.60 42.56 28 1894 5137 1739722
Rash 64.70 42.56 55 1867 38638 1706221
Platelet count decreased 63.54 42.56 39 1883 16484 1728375
Renal cancer 63.04 42.56 18 1904 1073 1743786
Decreased appetite 61.81 42.56 44 1878 23827 1721032
Blood triglycerides increased 58.81 42.56 21 1901 2579 1742280
Diarrhoea 58.13 42.56 60 1862 53792 1691067
Mantle cell lymphoma 56.62 42.56 13 1909 320 1744539
Neoplasm malignant 55.00 42.56 23 1899 4316 1740543
Epistaxis 54.88 42.56 28 1894 8278 1736581
Ascites 52.55 42.56 24 1898 5562 1739297
Infusion related reaction 48.76 42.56 24 1898 6569 1738290
Hypertriglyceridaemia 48.30 42.56 15 1907 1194 1743665
Respiratory failure 47.62 42.56 31 1891 14474 1730385
Flushing 46.86 42.56 23 1899 6256 1738603
Death 46.30 42.56 68 1854 87375 1657484
Blood cholesterol increased 45.03 42.56 18 1904 3008 1741851
Blood bilirubin increased 44.12 42.56 22 1900 6188 1738671
Asthenia 43.52 42.56 42 1880 34628 1710231

Pharmacologic Action:

SourceCodeDescription
ATC L01XE09 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
OTHER ANTINEOPLASTIC AGENTS
Protein kinase inhibitors
FDA EPC N0000175605 Kinase Inhibitor
FDA MoA N0000175076 Protein Kinase Inhibitors

Drug Use (View source of the data)

DiseaseRelationSNOMED_IDDOID
Mantle cell lymphoma indication 443487006
Renal cell carcinoma indication 702391001 DOID:4450
Hyperbilirubinemia contraindication 14783006 DOID:2741
Gastrointestinal perforation contraindication 51875005
Hyperlipidemia contraindication 55822004 DOID:1168
Acute infectious disease contraindication 63171007
Interstitial pneumonia contraindication 64667001
Diabetes mellitus contraindication 73211009 DOID:9351
Hyperglycemia contraindication 80394007 DOID:4195
Kidney disease contraindication 90708001 DOID:557
Secondary malignant neoplasm of cerebrum contraindication 94248000
Perioperative care contraindication 133897009
Cerebrovascular accident contraindication 230690007
Disease of liver contraindication 235856003 DOID:409
Impaired wound healing contraindication 271618001
Pregnancy, function contraindication 289908002
Surgical procedure contraindication 387713003
Breastfeeding (mother) contraindication 413712001
Malignant neoplasm of brain contraindication 428061005 DOID:1319

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 10.5 acidic
pKa2 13.82 acidic

Orange Book patent data (new drug applications)

Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRoutePatent numberPatent expiration datePatent use
25MG/ML (25MG/ML) TORISEL PF PRISM CV N022088 May 30, 2007 RX SOLUTION INTRAVENOUS 8791097 May 10, 2032 METHOD OF TREATING METASTATIC PAPILLARY RENAL CELL CARCINOMA WITH TEMSIROLIMUS.
25MG/ML (25MG/ML) TORISEL PF PRISM CV N022088 May 30, 2007 RX SOLUTION INTRAVENOUS 8791097 May 10, 2032 METHOD OF TREATING PAPILLARY RENAL CELL CARCINOMA WITH TEMSIROLIMUS, IN THE ABSENCE OF INTERFERON ALPHA.

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])
Mechanism
action
Bioact sourceMoA source
Peptidyl-prolyl cis-trans isomerase FKBP1A Enzyme INHIBITOR CHEMBL CHEMBL
Peptidyl-prolyl cis-trans isomerase FKBP3 Enzyme WOMBAT-PK
Multidrug resistance protein 1 Transporter WOMBAT-PK
Serine/threonine-protein kinase mTOR Kinase IC50 5.75 CHEMBL

External reference:

IDSource
4026239 VUID
N0000179796 NUI
C1707080 UMLSCUI
D06068 KEGG_DRUG
624KN6GM2T UNII
8212 INN_ID
287829 MMSL
427299005 SNOMEDCT_US
23908 MMSL
d06836 MMSL
657797 RXNORM
4026239 VANDF
427153004 SNOMEDCT_US
012233 NDDF
DB06287 DRUGBANK_ID
CHEBI:79699 CHEBI
CHEMBL1201182 ChEMBL_ID
6918289 PUBCHEM_CID
5892 IUPHAR_LIGAND_ID
C401859 MESH_SUPPLEMENTAL_RECORD_UI
DB00877 DRUGBANK_ID

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
Torisel HUMAN PRESCRIPTION DRUG LABEL 1 0008-1179 KIT 25 mg None NDA 19 sections
Temsirolimus HUMAN PRESCRIPTION DRUG LABEL 1 16729-223 KIT 25 mg None ANDA 18 sections
Temsirolimus HUMAN PRESCRIPTION DRUG LABEL 1 68083-202 KIT 25 mg None ANDA 18 sections
Temsirolimus HUMAN PRESCRIPTION DRUG LABEL 1 72611-785 KIT 25 mg None ANDA 18 sections