temsirolimus 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | PK/Tox | Related Drugs | 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) 2 Bocci G, Oprea TI, Benet LZ
S (Water solubility) 0.02 mg/mL Bocci G, Oprea TI, Benet LZ
EoM (Fraction excreted unchanged in urine) 4.60 % Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose) 0.15 µM/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
BA (Bioavailability) 15 %

Predicted pharmacokinetic/toxicological properties (PK-AZ):

PropertyDescriptionValueUnitConfidenceSimilarity
azlogd74 LogD at pH 7.4 4.237 High 1
caco2-efflux Caco-2 efflux ratio (BA/AB) 7.603 High 1
caco2-intrinsic-papp Caco-2 intrinsic apparent permeability 20.749 10^-6 cm/s High 1
dh-clint Dog hepatocyte intrinsic clearance 108.643 uL/min/10^6 cells High 1
dppb Dog plasma protein binding (% unbound) 0.770 % High 1
fcs-ppb Fetal calf serum protein binding (% unbound) 2.520 % High 1
herg hERG pIC50 4.621 pIC50 High 1
hh-clint Human hepatocyte intrinsic clearance 36.475 uL/min/10^6 cells High 1
hlm-clint Human liver microsomal intrinsic clearance 270.396 uL/min/mg protein High 1
hppb Human plasma protein binding (% unbound) 1.410 % High 1
kinase-safety-class ACVR2B,AXL,BRAF,BTK,CAMK2D,CDK5,CDK9,EIF2AK3,EPHB4,ERBB2,GRK2,ITK,MAPK10,MAPK7,NTRK2,PDK1,PDK2,PDK4,PRKDC,TEK 20
kinase-selectivity-class GRK2 1
mdck-mdr1-bcrp-efflux MDCK-MDR1-BCRP efflux ratio 40.926 High 0.90
mdck-mdr1-efflux MDCK-MDR1 efflux ratio 8.110 High 1
mh-clint Mouse hepatocyte intrinsic clearance 53.211 High 1
mppb Mouse plasma protein binding (% unbound) 0.640 High 1
nih-mdck-mdr1-efflux NIH MDCK-MDR1 efflux ratio 50.816 High 1
pfas-class PFAS structural alert (1 = True, 0 = False) 0
pld-class Phospholipidosis risk class (1 = positive, 0 = negative) 1 High 1
pppb Pig plasma protein binding (% unbound) 1.200 % High 1
rat-kpuu-brain Rat brain Kpuu 0.005 % High 0.89
rh-clint Rat hepatocyte intrinsic clearance 96.161 uL/min/10^6 cells High 1
rh-fuinc Rat hepatocyte fraction unbound in incubation 5.550 % High 1
rppb Rat plasma protein binding (% unbound) 1.530 % High 1
solubility-dd Solubility at pH 7.4 in DMSO 26.122 uM High 1

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 260.54 34.58 116 2661 156499 90469171
Dehydration 87.40 34.58 61 2716 194386 90431284
Hyperglycaemia 63.35 34.58 31 2746 50939 90574731
Death 58.91 34.58 71 2706 456480 90169190
Mucosal inflammation 48.52 34.58 27 2750 57598 90568072
Hypokalaemia 44.96 34.58 35 2742 131081 90494589
Hypophosphataemia 41.45 34.58 16 2761 14838 90610832
Metapneumovirus infection 39.60 34.58 9 2768 1326 90624344
Hypertriglyceridaemia 39.07 34.58 13 2764 7876 90617794
Blood creatinine increased 39.01 34.58 29 2748 101357 90524313
Pneumonitis 38.00 34.58 21 2756 44149 90581521
Neoplasm progression 37.86 34.58 21 2756 44465 90581205

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 442.44 24.48 264 5666 143392 42472013
Stomatitis 129.72 24.48 83 5847 50246 42565159
Interstitial lung disease 96.73 24.48 83 5847 78379 42537026
Pneumonitis 95.71 24.48 64 5866 41654 42573751
Neoplasm progression 87.73 24.48 53 5877 28947 42586458
Pleural effusion 77.92 24.48 81 5849 97085 42518320
Dehydration 57.79 24.48 84 5846 141683 42473722
Thrombocytopenia 44.50 24.48 88 5842 190191 42425214
Drug ineffective 43.22 24.48 17 5913 630180 41985225
Mucosal inflammation 42.85 24.48 43 5887 49331 42566074
Hypertriglyceridaemia 42.68 24.48 23 5907 10103 42605302
Pneumonia 40.91 24.48 140 5790 422009 42193396
Blood triglycerides increased 33.11 24.48 23 5907 15873 42599532
Pneumocystis jirovecii pneumonia 31.69 24.48 27 5903 25154 42590251
Febrile neutropenia 30.97 24.48 75 5855 185628 42429777
Renal cell carcinoma 30.37 24.48 15 5915 5502 42609903
Osteonecrosis of jaw 29.38 24.48 23 5907 19026 42596379
Lymphocyte count decreased 25.55 24.48 25 5905 27784 42587621
Metastatic renal cell carcinoma 25.29 24.48 10 5920 2164 42613241
Renal failure 24.96 24.48 59 5871 143667 42471738

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 544.89 26.56 268 6013 243766 110339252
Stomatitis 132.75 26.56 115 6166 270127 110312891
Dehydration 129.39 26.56 115 6166 279396 110303622
Neoplasm progression 108.80 26.56 59 6222 64536 110518482
Febrile neutropenia 90.06 26.56 100 6181 316667 110266351
Pneumonitis 84.08 26.56 53 6228 76478 110506540
Interstitial lung disease 77.94 26.56 64 6217 139270 110443748
Pleural effusion 77.90 26.56 71 6210 177638 110405380
Hyperglycaemia 64.89 26.56 47 6234 85043 110497975
Mucosal inflammation 55.50 26.56 45 6236 96096 110486922
Hypertriglyceridaemia 55.30 26.56 24 6257 16130 110566888
Death 55.23 26.56 122 6159 698747 109884271
Thrombocytopenia 53.16 26.56 81 6200 348804 110234214
Pneumonia 52.06 26.56 137 6144 876577 109706441
Renal cell carcinoma 46.05 26.56 17 6264 7513 110575505
Blood bilirubin increased 44.77 26.56 36 6245 75936 110507082
Pneumocystis jirovecii pneumonia 42.95 26.56 28 6253 42707 110540311
Blood creatinine increased 42.28 26.56 52 6229 182837 110400181
Lymphocyte count decreased 42.22 26.56 31 6250 57212 110525806
Anaemia 40.34 26.56 93 6188 546993 110036025
Hypokalaemia 34.53 26.56 47 6234 182401 110400617
Platelet count decreased 34.34 26.56 53 6228 230390 110352628
Metapneumovirus infection 32.92 26.56 10 6271 2434 110580584
Proteinuria 32.54 26.56 23 6258 39995 110543023
Blood triglycerides increased 32.50 26.56 19 6262 23907 110559111
Neutrophil count decreased 32.25 26.56 37 6244 120904 110462114
Epistaxis 31.63 26.56 38 6243 130334 110452684
Hypophosphataemia 29.15 26.56 20 6261 33162 110549856
Metastatic renal cell carcinoma 28.56 26.56 9 6272 2471 110580547
Pulmonary haemorrhage 27.59 26.56 15 6266 16441 110566577
Drug ineffective 27.10 26.56 28 6253 1520512 109062506

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 D000091203 MTOR Inhibitors
MeSH PA D000970 Antineoplastic Agents
MeSH PA D004791 Enzyme Inhibitors
MeSH PA D007155 Immunologic Factors
MeSH PA D007166 Immunosuppressive Agents
MeSH PA D047428 Protein Kinase Inhibitors
FDA EPC N0000175605 Kinase Inhibitor
FDA MoA N0000175624 mTOR Inhibitors
FDA EPC N0000175625 mTOR Inhibitor Immunosuppressant
CHEBI has role CHEBI:35610 antineoplastic agent
CHEBI has role CHEBI:35705 immunosuppressive agent
CHEBI has role CHEBI:36047 antibacterial drug
CHEBI has role CHEBI:68481 mTOR inhibitor
CHEBI has role CHEBI:76969 bacterial metabolite
CHEBI has role CHEBI:149553 anticoronaviral agent
CHEBI has role CHEBI:176497 geroprotector
MeSH PA D000890 Anti-Infective Agents
MeSH PA D000900 Anti-Bacterial Agents
MeSH PA D000903 Antibiotics, Antineoplastic
MeSH PA D000935 Antifungal Agents

Related Drugs by ATC class:

L01EG Mammalian target of rapamycin (mTOR) kinase inhibitors 3 drugs
everolimusridaforolimussirolimus

Drug Use | Suggest Off label Use Form| |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




🐶 Veterinary Drug Use

None

🐶 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
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
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
C0072980 UMLSCUI
CHEBI:79699 CHEBI
DB00877 DRUGBANK_ID
5284616 PUBCHEM_CID
7104 INN_ID
D020123 MESH_DESCRIPTOR_UI
CHEBI:9168 CHEBI
624KN6GM2T INXIGHT DRUGS

Pharmaceutical products:

None