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)	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 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	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 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	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 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	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:

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 (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
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