temsirolimus ๐Ÿถ Veterinary Use | 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:

DoseUnitRoute
3.57 mg P

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 ยตM/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 248.36 29.02 113 2484 95753 50506774
Hyperglycaemia 58.11 29.02 31 2566 36374 50566153
Dehydration 54.70 29.02 52 2545 152397 50450130
Death 46.13 29.02 69 2528 325310 50277217
Hypophosphataemia 42.28 29.02 16 2581 8398 50594129
Mucosal inflammation 42.09 29.02 26 2571 40116 50562411
Hypokalaemia 41.37 29.02 35 2562 87957 50514570
Stomatitis 40.99 29.02 37 2560 101307 50501220
Hypertriglyceridaemia 37.12 29.02 13 2584 5478 50597049
Pneumonitis 35.81 29.02 21 2576 29489 50573038
Blood creatinine increased 33.15 29.02 29 2568 76131 50526396
Febrile neutropenia 30.63 29.02 31 2566 97636 50504891

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 500.72 24.01 264 5440 81652 29487171
Interstitial lung disease 93.32 24.01 82 5622 57636 29511187
Neoplasm progression 88.13 24.01 51 5653 18561 29550262
Stomatitis 85.85 24.01 65 5639 37048 29531775
Pneumonitis 85.25 24.01 58 5646 27986 29540837
Pleural effusion 69.21 24.01 77 5627 71831 29496992
Dehydration 50.51 24.01 84 5620 114664 29454159
Thrombocytopenia 44.40 24.01 87 5617 134736 29434087
Mucosal inflammation 43.36 24.01 41 5663 31554 29537269
Hypertriglyceridaemia 42.19 24.01 23 5681 7452 29561371
Pneumocystis jirovecii pneumonia 33.57 24.01 27 5677 16752 29552071
Drug ineffective 32.20 24.01 15 5689 363155 29205668
Pneumonia 31.25 24.01 133 5571 320039 29248784
Febrile neutropenia 29.40 24.01 66 5638 112174 29456649
Renal cell carcinoma 28.03 24.01 15 5689 4681 29564142
Lymphocyte count decreased 26.41 24.01 25 5679 19246 29549577
Blood triglycerides increased 26.41 24.01 21 5683 12813 29556010
Osteonecrosis of jaw 25.70 24.01 23 5681 16487 29552336
Extravasation 24.67 24.01 10 5694 1662 29567161

FDA Adverse Event Reporting System (Geriatric)

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 554.70 25.30 265 5600 141415 64351452
Stomatitis 125.26 25.30 93 5772 109512 64383355
Neoplasm progression 94.33 25.30 54 5811 40910 64451957
Dehydration 90.98 25.30 105 5760 216658 64276209
Febrile neutropenia 77.18 25.30 90 5775 187567 64305300
Interstitial lung disease 69.53 25.30 63 5802 97669 64395198
Pneumonitis 69.52 25.30 48 5817 50317 64442550
Pleural effusion 61.04 25.30 66 5799 126493 64366374
Hyperglycaemia 59.15 25.30 47 5818 60921 64431946
Hypertriglyceridaemia 52.89 25.30 24 5841 11181 64481686
Thrombocytopenia 48.80 25.30 79 5786 223722 64269145
Mucosal inflammation 47.75 25.30 42 5823 62542 64430325
Pneumocystis jirovecii pneumonia 42.07 25.30 28 5837 27606 64465261
Renal cell carcinoma 41.75 25.30 17 5848 6087 64486780
Pneumonia 41.48 25.30 128 5737 559448 63933419
Death 41.07 25.30 116 5749 482589 64010278
Blood bilirubin increased 38.74 25.30 36 5829 57517 64435350
Lymphocyte count decreased 38.65 25.30 31 5834 40668 64452199
Hypophosphataemia 35.45 25.30 20 5845 14700 64478167
Blood creatinine increased 33.81 25.30 51 5814 135731 64357136
Hypokalaemia 32.09 25.30 47 5818 121856 64371011
Proteinuria 30.41 25.30 23 5842 27700 64465167
Drug ineffective 29.87 25.30 20 5845 840227 63652640
Anaemia 29.25 25.30 88 5777 378592 64114275
Neutrophil count decreased 28.32 25.30 35 5830 77161 64415706
Blood triglycerides increased 26.05 25.30 18 5847 18848 64474019
Platelet count decreased 25.93 25.30 51 5814 167660 64325207
Metastatic renal cell carcinoma 25.48 25.30 9 5856 2187 64490680

FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

SourceCodeDescription
ATC L01EG01 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
PROTEIN KINASE INHIBITORS
Mammalian target of rapamycin (mTOR) kinase inhibitors
FDA MoA N0000175076 Protein Kinase Inhibitors
FDA PE N0000175550 Decreased Immunologic Activity
MeSH PA D000970 Antineoplastic Agents
MeSH PA D004791 Enzyme Inhibitors
MeSH PA D007155 Immunologic Factors
MeSH PA D007166 Immunosuppressive Agents
MeSH PA D000091203 MTOR Inhibitors
MeSH PA D047428 Protein Kinase Inhibitors
CHEBI has role CHEBI:35610 antineoplastic agents
CHEBI has role CHEBI:35705 immunosuppressive agents
CHEBI has role CHEBI:36047 antibacterial drugs
CHEBI has role CHEBI:68481 mTOR inhibitors
CHEBI has role CHEBI:149553 anticoronaviral drug
CHEBI has role CHEBI:176497 geroprotectors
FDA EPC N0000175605 Kinase Inhibitor
FDA MoA N0000175624 mTOR Inhibitors
FDA EPC N0000175625 mTOR Inhibitor Immunosuppressant
MeSH PA D000900 Anti-Bacterial Agents
MeSH PA D000890 Anti-Infective Agents
MeSH PA D000903 Antibiotics, Antineoplastic
MeSH PA D000935 Antifungal Agents

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




๐Ÿถ Veterinary Drug Use

None

๐Ÿถ Veterinary products

None

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
Multidrug resistance protein 1 Transporter WOMBAT-PK
Serine/threonine-protein kinase mTOR Kinase IC50 5.75 CHEMBL
Peptidyl-prolyl cis-trans isomerase FKBP3 Enzyme WOMBAT-PK

External reference:

IDSource
4026239 VUID
N0000179796 NUI
D06068 KEGG_DRUG
4021176 VANDF
4026239 VANDF
C1707080 UMLSCUI
CHEBI:79699 CHEBI
CHEBI:9168 CHEBI
A4I PDB_CHEM_ID
CHEMBL1201182 ChEMBL_ID
DB06287 DRUGBANK_ID
C401859 MESH_SUPPLEMENTAL_RECORD_UI
5892 IUPHAR_LIGAND_ID
8212 INN_ID
624KN6GM2T UNII
6918289 PUBCHEM_CID
DB00877 DRUGBANK_ID
35302 RXNORM
110527 MMSL
210889 MMSL
23908 MMSL
287829 MMSL
8303 MMSL
d04453 MMSL
d06836 MMSL
007885 NDDF
012233 NDDF
116109004 SNOMEDCT_US
387014003 SNOMEDCT_US
427153004 SNOMEDCT_US
427299005 SNOMEDCT_US
5284616 PUBCHEM_CID
C0072980 UMLSCUI
D020123 MESH_DESCRIPTOR_UI
7104 INN_ID

Pharmaceutical products:

None