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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:

Property	Value	Reference
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

Approvals:

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

FDA Adverse Event Reporting System (Female)

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
Blood creatinine increased	34.18	33.86	29	2682	87815	63398496

FDA Adverse Event Reporting System (Male)

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
Pneumonia	38.22	22.76	140	5713	362487	34588591
Febrile neutropenia	37.08	22.76	75	5778	136774	34814304
Drug ineffective	35.76	22.76	16	5837	456735	34494343
Pneumocystis jirovecii pneumonia	33.10	22.76	27	5826	19683	34931395
Blood triglycerides increased	31.67	22.76	23	5830	14136	34936942
Renal cell carcinoma	29.01	22.76	15	5838	5033	34946045
Osteonecrosis of jaw	26.91	22.76	23	5830	17866	34933212
Lymphocyte count decreased	26.00	22.76	25	5828	22597	34928481
Extravasation	24.86	22.76	10	5843	1880	34949198
Metastatic renal cell carcinoma	24.02	22.76	10	5843	2051	34949027
Anaemia	23.56	22.76	89	5764	233246	34717832

FDA Adverse Event Reporting System (Geriatric)

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
Mucosal inflammation	53.10	25.22	45	6078	75535	79662730
Thrombocytopenia	50.11	25.22	80	6043	265179	79473086
Pneumonia	49.51	25.22	136	5987	660110	79078155
Death	45.75	25.22	120	6003	566394	79171871
Renal cell carcinoma	43.30	25.22	17	6106	6561	79731704
Pneumocystis jirovecii pneumonia	42.24	25.22	28	6095	32480	79705785
Blood bilirubin increased	39.62	25.22	36	6087	66196	79672069
Lymphocyte count decreased	39.17	25.22	31	6092	47258	79691007
Blood creatinine increased	36.70	25.22	52	6071	155005	79583260
Anaemia	34.57	25.22	93	6030	444922	79293343
Hypophosphataemia	32.98	25.22	20	6103	19893	79718372
Hypokalaemia	32.17	25.22	47	6076	143993	79594272
Drug ineffective	30.78	25.22	23	6100	1080890	78657375
Neutrophil count decreased	30.78	25.22	37	6086	93922	79644343
Proteinuria	30.61	25.22	23	6100	32479	79705786
Blood triglycerides increased	29.47	25.22	19	6104	21021	79717244
Platelet count decreased	29.15	25.22	53	6070	194611	79543654
Metastatic renal cell carcinoma	26.35	25.22	9	6114	2346	79735919
Epistaxis	25.78	25.22	37	6086	111478	79626787

FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

Source	Code	Description
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 | Suggest Off label Use Form| |View source of the data|

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

Orange Book patent data (new drug applications)

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.

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

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

External reference:

ID	Source
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
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
DB00877	DRUGBANK_ID
7104	INN_ID
D020123	MESH_DESCRIPTOR_UI
5284616	PUBCHEM_CID

Pharmaceutical products:

None