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

Stem definition	Drug id	CAS RN
immunosuppressants, rapamycin derivatives	4161	162635-04-3

Description:

Molecule	Description
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

Molecule

Description

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:

Dose	Unit	Route
3.57	mg	P

ADMET properties:

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Property	Value	Reference
CL (Clearance)	7.70 mL/min/kg	Lombardo F, Berellini G, Obach RS
EoM (Fraction excreted unchanged in urine)	4.60 %	Benet LZ, Broccatelli F, Oprea TI
Vd (Volume of distribution)	3 L/kg	Lombardo F, Berellini G, Obach RS
BDDCS (Biopharmaceutical Drug Disposition Classification System)	2	Bocci G, Oprea TI, Benet LZ
t_half (Half-life)	18 hours	Lombardo F, Berellini G, Obach RS
MRTD (Maximum Recommended Therapeutic Daily Dose)	0.15 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
S (Water solubility)	0.02 mg/mL	Bocci G, Oprea TI, Benet LZ

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Approvals:

Date	Agency	Company	Orphan
May 30, 2007	FDA	PF PRISM CV
Nov. 19, 2007	EMA	Pfizer Limited

FDA Adverse Event Reporting System (Female)

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MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Disease progression	250.78	33.86	116	2595	122642	63363669
Dehydration	65.16	33.86	56	2655	173298	63313013
Hyperglycaemia	59.39	33.86	31	2680	41836	63444475
Death	49.91	33.86	70	2641	374311	63112000
Mucosal inflammation	45.34	33.86	27	2684	46901	63439410
Stomatitis	44.47	33.86	41	2670	138684	63347627
Hypokalaemia	41.93	33.86	35	2676	103769	63382542
Hypophosphataemia	40.38	33.86	16	2695	11410	63474901
Hypertriglyceridaemia	37.80	33.86	13	2698	6246	63480065
Pneumonitis	35.94	33.86	21	2690	35201	63451110

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FDA Adverse Event Reporting System (Male)

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MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Disease progression	472.40	22.76	266	5587	107811	34843267
Stomatitis	113.89	22.76	77	5776	42437	34908641
Interstitial lung disease	94.61	22.76	82	5771	65200	34885878
Pneumonitis	85.09	22.76	59	5794	33819	34917259
Neoplasm progression	84.19	22.76	51	5802	23249	34927829
Pleural effusion	79.06	22.76	82	5771	81464	34869614
Dehydration	52.92	22.76	85	5768	129884	34821194
Mucosal inflammation	45.05	22.76	43	5810	38579	34912499
Thrombocytopenia	44.02	22.76	87	5766	156160	34794918
Hypertriglyceridaemia	42.60	22.76	23	5830	8425	34942653

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FDA Adverse Event Reporting System (Geriatric)

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MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Disease progression	542.64	25.22	269	5854	184093	79554172
Stomatitis	150.41	25.22	109	6014	146648	79591617
Dehydration	100.81	25.22	109	6014	248078	79490187
Neoplasm progression	93.78	25.22	55	6068	51627	79686638
Febrile neutropenia	91.25	25.22	100	6023	230899	79507366
Pleural effusion	71.86	25.22	71	6052	145191	79593074
Interstitial lung disease	71.01	25.22	63	6060	112537	79625728
Pneumonitis	70.99	25.22	49	6074	60811	79677454
Hyperglycaemia	60.23	25.22	47	6076	70288	79667977
Hypertriglyceridaemia	53.82	25.22	24	6099	12716	79725549

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FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

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Source	Code	Description
ATC	L01EG01	ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS ANTINEOPLASTIC AGENTS PROTEIN KINASE INHIBITORS Mammalian target of rapamycin (mTOR) 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 EPC	N0000175625	mTOR Inhibitor Immunosuppressant
FDA MoA	N0000175076	Protein Kinase Inhibitors

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Drug Use | Suggest Off label Use Form| |View source of the data|

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Disease	Relation	SNOMED_ID	DOID
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

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🐶 Veterinary Drug Use

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🐶 Veterinary products

None

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	10.5	acidic
pKa2	13.82	acidic

Orange Book patent data (new drug applications)

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Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Patent number	Patent expiration date	Patent 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.

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Orange Book exclusivity data (new drug applications)

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Bioactivity Summary:

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Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Peptidyl-prolyl cis-trans isomerase FKBP1A	Enzyme	P62942	FKB1A_HUMAN	INHIBITOR			CHEMBL	CHEMBL
Multidrug resistance protein 1	Transporter	P08183	MDR1_HUMAN				WOMBAT-PK
Serine/threonine-protein kinase mTOR	Kinase	P42345	MTOR_HUMAN		IC50	5.75	CHEMBL
Peptidyl-prolyl cis-trans isomerase FKBP3	Enzyme	Q00688	FKBP3_HUMAN				WOMBAT-PK

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External reference:

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ID	Source
A4I	PDB_CHEM_ID
007885	NDDF
012233	NDDF
110527	MMSL
116109004	SNOMEDCT_US
210889	MMSL
23908	MMSL
287829	MMSL
35302	RXNORM
387014003	SNOMEDCT_US

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Pharmaceutical products:

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