Identification

Summary

Temsirolimus is a antineoplastic agent used in the treatment of renal cell carcinoma (RCC) that works by inhibiting mTOR.

Brand Names
Torisel
Generic Name
Temsirolimus
DrugBank Accession Number
DB06287
Background

Temsirolimus is a derivative of sirolimus used in the treatment of renal cell carcinoma (RCC). It was developed by Wyeth Pharmaceuticals under the trade name Torisel. Temsirolimus was approved by the FDA in late May 2007 as well as the European Medicines Agency (EMEA) on November 2007.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 1030.2871
Monoisotopic: 1029.602485741
Chemical Formula
C56H87NO16
Synonyms
  • Temsirolimus
External IDs
  • CCI 779
  • CCI-779
  • WAY-CCI 779

Pharmacology

Indication

For the treatment of renal cell carcinoma (RCC). Also investigated for use/treatment in breast cancer, lymphoma (unspecified), rheumatoid arthritis, and multiple myeloma.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Not Available

Mechanism of action

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.

TargetActionsOrganism
ASerine/threonine-protein kinase mTOR
inhibitor
Humans
Absorption

Infused intravenous over 30 - 60 minutes. Cmax is typically observed at the end of infusion

Volume of distribution

172 L in whole blood of cancer patients; both temsirolimus and sirolimus are extensive distributed partitioned into formed blood elements

Protein binding

87% bound to plasma proteins in vitro at a concentration of 100 ng/ml

Metabolism

Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in in vitro temsirolimus metabolism studies include hydroxylation, reduction and demethylation.

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Route of elimination

Excreted predominantly in feces (76%), 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection.

Half-life

Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively.

Clearance

16.2 L/h (22%)

Adverse Effects
Adverseeffects
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Toxicity

Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus greater than 25 mg.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Temsirolimus can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Temsirolimus can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Temsirolimus.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Temsirolimus.
AbirateroneThe metabolism of Temsirolimus can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Temsirolimus can be decreased when combined with Acalabrutinib.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Temsirolimus.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Temsirolimus.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Temsirolimus.
AcetaminophenThe metabolism of Temsirolimus can be increased when combined with Acetaminophen.
Interactions
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of temsirolimus, which may increase its serum concentration.
  • Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of temsirolimus and may reduce its serum concentration.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ToriselSolution25 mg / mLIntravenousPfizer Canada Ulc2008-01-11Not applicableCanada flag
ToriselSolution25 mg/1mLIntravenousWyeth Pharmaceuticals Llc, a Subsidiary of Pfizer Inc.2007-07-01Not applicableUS flag
ToriselInjection, solution, concentrate30 mgIntravenousPfizer Europe Ma Eeig2016-09-08Not applicableEU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Gd-temsirolimusSolution25 mg / mLIntravenousGenmed A Division Of Pfizer Canada UlcNot applicableNot applicableCanada flag
TemsirolimusKit25 mg/1mLIntravenousGland Pharma Limited2019-08-26Not applicableUS flag
TemsirolimusKit25 mg/1mLIntravenousFresenius Kabi USA, LLC2020-11-20Not applicableUS flag
TemsirolimusKit25 mg/1mLIntravenousAccord Healthcare Limited2018-08-13Not applicableUS flag
TemsirolimusKit25 mg/1mLIntravenousAlmaject, Inc.2020-05-08Not applicableUS flag

Categories

ATC Codes
L01XE09 — Temsirolimus
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Macrolide lactams
Sub Class
Not Available
Direct Parent
Macrolide lactams
Alternative Parents
Alpha amino acid esters / Macrolides and analogues / Beta hydroxy acids and derivatives / Piperidines / Oxanes / Dicarboxylic acids and derivatives / Tertiary carboxylic acid amides / Secondary alcohols / Carboxylic acid esters / Cyclic ketones
show 11 more
Substituents
Alcohol / Aliphatic heteropolycyclic compound / Alpha-amino acid ester / Alpha-amino acid or derivatives / Azacycle / Beta-hydroxy acid / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Carboxylic acid ester
show 25 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
lactam, macrolide (CHEBI:79699)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
624KN6GM2T
CAS number
162635-04-3
InChI Key
CBPNZQVSJQDFBE-FUXHJELOSA-N
InChI
InChI=1S/C56H87NO16/c1-33-17-13-12-14-18-34(2)45(68-9)29-41-22-20-39(7)56(67,73-41)51(63)52(64)57-24-16-15-19-42(57)53(65)71-46(30-43(60)35(3)26-38(6)49(62)50(70-11)48(61)37(5)25-33)36(4)27-40-21-23-44(47(28-40)69-10)72-54(66)55(8,31-58)32-59/h12-14,17-18,26,33,35-37,39-42,44-47,49-50,58-59,62,67H,15-16,19-25,27-32H2,1-11H3/b14-12+,17-13+,34-18+,38-26+/t33-,35-,36-,37-,39-,40+,41+,42+,44-,45+,46+,47-,49-,50+,56-/m1/s1
IUPAC Name
(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0⁴,⁹]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate
SMILES
OCC(C)(CO)C(=O)O[C@@H]1CC[C@@H](C[C@@H](C)[C@]2([H])CC(=O)[C@H](C)\C=C(C)\[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(C)\[C@@H](OC)C[C@]3([H])CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC

References

Synthesis Reference

Kwang-Chung Lee, Ting-Huei Lee, Yen-Shih Tung, Chia-Chen Kao, Tzu-Ai Lee, "Process for preparation of temsirolimus." U.S. Patent US20100249415, issued September 30, 2010.

US20100249415
General References
  1. Boni J, Leister C, Burns J, Cincotta M, Hug B, Moore L: Pharmacokinetic profile of temsirolimus with concomitant administration of cytochrome p450-inducing medications. J Clin Pharmacol. 2007 Nov;47(11):1430-9. Epub 2007 Oct 3. [Article]
Human Metabolome Database
HMDB0015632
KEGG Drug
D06068
KEGG Compound
C15182
PubChem Compound
23724530
PubChem Substance
99443243
ChemSpider
21468899
BindingDB
50343413
RxNav
657797
ChEBI
79699
ChEMBL
CHEMBL1201182
Therapeutic Targets Database
DAP001222
PharmGKB
PA164746890
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Temsirolimus
FDA label
Download (402 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentNon-Hodgkin's Lymphoma (NHL)1
4Not Yet RecruitingTreatmentHemangioendothelioma of Liver1
3Active Not RecruitingTreatmentPRETEXT Stage 1 Hepatoblastoma / PRETEXT Stage 2 Hepatoblastoma / PRETEXT Stage 3 Hepatoblastoma / PRETEXT Stage 4 Hepatoblastoma1
3CompletedTreatmentMalignant Lymphomas1
3CompletedTreatmentMantle Cell Lymphoma (MCL)1
3CompletedTreatmentNeoplasms, Kidney / Renal Cell Adenocarcinoma1
3CompletedTreatmentRenal Cell Adenocarcinoma2
3Not Yet RecruitingTreatmentCritical Limb Ischemia (CLI) / Peripheral Arterial Disease (PAD)1
3RecruitingTreatmentBotryoid-Type Embryonal Rhabdomyosarcoma / Rhabdomyosarcoma, Alveolar / Rhabdomyosarcoma, Embryonal / Rhabdomyosarcomas / Sclerosing Rhabdomyosarcoma / Spindle Cell Rhabdomyosarcoma1
3TerminatedTreatmentNeoplasms, Breast / Neoplasms, Metastasis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Ben Venue Laboratories Inc.
  • Chunghwa Chemical Synthesis and Biotech Co. Ltd.
  • Pierre Fabre
  • Wyeth Pharmaceuticals
Dosage Forms
FormRouteStrength
KitIntravenous25 mg/1mL
Injection, solution, concentrateIntravenous30 mg
Injection, solution, concentrateIntravenous; Parenteral30 MG
SolutionIntravenous25 mg/1mL
SolutionIntravenous25 mg / mL
SolutionIntravenous30 mg
Injection, solutionIntravenous
Injection, solution, concentrateIntravenous25 mg/mL
Prices
Unit descriptionCostUnit
Torisel 25 mg kit1467.89USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2429020No2009-05-262021-11-13Canada flag
CA2187024No2004-08-102015-04-14Canada flag
US8791097Yes2014-07-292032-11-10US flag
US8455539Yes2013-06-042024-01-25US flag
US5362718Yes1994-11-082019-08-15US flag
US8722700Yes2014-05-132024-01-25US flag
US8026276Yes2011-09-272026-07-20US flag
USRE44768Yes2014-02-182019-08-15US flag
US8299116Yes2012-10-302024-01-25US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00235 mg/mLALOGPS
logP4.39ALOGPS
logP7.13ChemAxon
logS-5.6ALOGPS
pKa (Strongest Acidic)9.96ChemAxon
pKa (Strongest Basic)-2.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count14ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area241.96 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity277.07 m3·mol-1ChemAxon
Polarizability112.71 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.8908
Blood Brain Barrier-0.9494
Caco-2 permeable-0.664
P-glycoprotein substrateSubstrate0.8122
P-glycoprotein inhibitor IInhibitor0.8098
P-glycoprotein inhibitor IIInhibitor0.7467
Renal organic cation transporterNon-inhibitor0.7636
CYP450 2C9 substrateNon-substrate0.8699
CYP450 2D6 substrateNon-substrate0.8845
CYP450 3A4 substrateSubstrate0.7533
CYP450 1A2 substrateNon-inhibitor0.9126
CYP450 2C9 inhibitorNon-inhibitor0.8957
CYP450 2D6 inhibitorNon-inhibitor0.942
CYP450 2C19 inhibitorNon-inhibitor0.9155
CYP450 3A4 inhibitorNon-inhibitor0.9558
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9398
Ames testNon AMES toxic0.6087
CarcinogenicityNon-carcinogens0.9367
BiodegradationNot ready biodegradable0.9522
Rat acute toxicity2.8760 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9703
hERG inhibition (predictor II)Non-inhibitor0.7479
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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insights and accelerate drug research.
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Learn more
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Tfiiic-class transcription factor binding
Specific Function
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly...
Gene Name
MTOR
Uniprot ID
P42345
Uniprot Name
Serine/threonine-protein kinase mTOR
Molecular Weight
288889.05 Da
References
  1. Patard JJ, Pouessel D, Bensalah K, Culine S: Targeted therapy in renal cell carcinoma. World J Urol. 2008 Apr;26(2):135-40. doi: 10.1007/s00345-008-0237-4. Epub 2008 Feb 12. [Article]
  2. Radulovic S, Bjelogrlic SK: Sunitinib, sorafenib and mTOR inhibitors in renal cancer. J BUON. 2007 Sep;12 Suppl 1:S151-62. [Article]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created at March 19, 2008 16:22 / Updated at December 03, 2021 01:12