temsirolimus 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:

None

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	429.11	44.34	110	770	16985	2340220
Renal cell carcinoma	183.38	44.34	32	848	725	2356480
Hyperglycaemia	119.06	44.34	31	849	4854	2352351
Metastatic renal cell carcinoma	104.62	44.34	17	863	244	2356961
Hypokalaemia	103.38	44.34	33	847	10621	2346584
Dehydration	93.41	44.34	37	843	22258	2334947
Dyspnoea	91.36	44.34	54	826	78679	2278526
Mucosal inflammation	79.90	44.34	23	857	5201	2352004
Pneumonia	76.49	44.34	41	839	49255	2307950
Blood creatinine increased	75.55	44.34	26	854	10507	2346698
Hypophosphataemia	74.95	44.34	16	864	1054	2356151
Anaemia	74.51	44.34	36	844	34756	2322449
Pleural effusion	72.95	44.34	26	854	11642	2345563
Hypertension	69.90	44.34	32	848	27329	2329876
Death	69.40	44.34	46	834	81422	2275783
Pneumonitis	67.20	44.34	19	861	4020	2353185
Fatigue	65.29	44.34	45	835	84828	2272377
Nausea	58.32	44.34	47	833	112142	2245063
Stomatitis	58.25	44.34	21	859	9689	2347516
Febrile neutropenia	55.91	44.34	21	859	10861	2346344
Hypertriglyceridaemia	54.87	44.34	12	868	884	2356321
Diarrhoea	54.25	44.34	40	840	83524	2273681
Blood bilirubin increased	53.54	44.34	17	863	5328	2351877
Vomiting	52.68	44.34	37	843	71565	2285640
Pyrexia	52.13	44.34	33	847	53675	2303530
Platelet count decreased	51.61	44.34	22	858	15791	2341414
Neoplasm progression	51.56	44.34	16	864	4652	2352553
Respiratory failure	51.48	44.34	21	859	13507	2343698
Abdominal pain	48.73	44.34	27	853	34347	2322858

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	805.19	42.56	238	1684	17025	1727834
Renal cell carcinoma	329.15	42.56	72	1850	1436	1743423
Interstitial lung disease	215.44	42.56	77	1845	9619	1735240
Metastatic renal cell carcinoma	189.24	42.56	39	1883	572	1744287
Pneumonia	181.92	42.56	110	1812	46072	1698787
Pleural effusion	169.32	42.56	67	1855	11043	1733816
Pneumonitis	167.14	42.56	51	1871	3864	1740995
Dyspnoea	152.62	42.56	103	1819	51956	1692903
Thrombocytopenia	148.12	42.56	74	1848	21175	1723684
Dehydration	133.39	42.56	65	1857	17593	1727266
Neoplasm progression	124.34	42.56	39	1883	3228	1741631
Anaemia	117.56	42.56	71	1851	29386	1715473
Stomatitis	101.43	42.56	38	1884	5366	1739493
Pyrexia	99.23	42.56	76	1846	46324	1698535
Blood creatinine increased	95.25	42.56	48	1874	13898	1730961
General physical health deterioration	95.04	42.56	47	1875	13071	1731788
Nausea	94.74	42.56	77	1845	51119	1693740
Mucosal inflammation	91.86	42.56	33	1889	4136	1740723
Renal failure	89.49	42.56	52	1870	19965	1724894
Condition aggravated	89.45	42.56	53	1869	21097	1723762
Febrile neutropenia	87.06	42.56	42	1880	11058	1733801
Hypersensitivity	86.41	42.56	41	1881	10403	1734456
Acute kidney injury	76.19	42.56	58	1864	34886	1709973
Pneumocystis jirovecii pneumonia	75.70	42.56	25	1897	2431	1742428
Hyponatraemia	73.40	42.56	35	1887	8965	1735894
Vomiting	69.35	42.56	57	1865	38258	1706601
Fatigue	68.74	42.56	64	1858	50717	1694142
Hyperglycaemia	67.60	42.56	28	1894	5137	1739722
Rash	64.70	42.56	55	1867	38638	1706221
Platelet count decreased	63.54	42.56	39	1883	16484	1728375
Renal cancer	63.04	42.56	18	1904	1073	1743786
Decreased appetite	61.81	42.56	44	1878	23827	1721032
Blood triglycerides increased	58.81	42.56	21	1901	2579	1742280
Diarrhoea	58.13	42.56	60	1862	53792	1691067
Mantle cell lymphoma	56.62	42.56	13	1909	320	1744539
Neoplasm malignant	55.00	42.56	23	1899	4316	1740543
Epistaxis	54.88	42.56	28	1894	8278	1736581
Ascites	52.55	42.56	24	1898	5562	1739297
Infusion related reaction	48.76	42.56	24	1898	6569	1738290
Hypertriglyceridaemia	48.30	42.56	15	1907	1194	1743665
Respiratory failure	47.62	42.56	31	1891	14474	1730385
Flushing	46.86	42.56	23	1899	6256	1738603
Death	46.30	42.56	68	1854	87375	1657484
Blood cholesterol increased	45.03	42.56	18	1904	3008	1741851
Blood bilirubin increased	44.12	42.56	22	1900	6188	1738671
Asthenia	43.52	42.56	42	1880	34628	1710231

Pharmacologic Action:

Source	Code	Description
ATC	L01XE09	ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS ANTINEOPLASTIC AGENTS OTHER ANTINEOPLASTIC AGENTS Protein kinase inhibitors
FDA EPC	N0000175605	Kinase Inhibitor
FDA MoA	N0000175076	Protein Kinase Inhibitors

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

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
Peptidyl-prolyl cis-trans isomerase FKBP3	Enzyme	Q00688	FKBP3_HUMAN				WOMBAT-PK
Multidrug resistance protein 1	Transporter	P08183	MDR1_HUMAN				WOMBAT-PK
Serine/threonine-protein kinase mTOR	Kinase	P42345	MTOR_HUMAN		IC50	5.75	CHEMBL

External reference:

ID	Source
4026239	VUID
N0000179796	NUI
C1707080	UMLSCUI
D06068	KEGG_DRUG
624KN6GM2T	UNII
8212	INN_ID
287829	MMSL
427299005	SNOMEDCT_US
23908	MMSL
d06836	MMSL
657797	RXNORM
4026239	VANDF
427153004	SNOMEDCT_US
012233	NDDF
DB06287	DRUGBANK_ID
CHEBI:79699	CHEBI
CHEMBL1201182	ChEMBL_ID
6918289	PUBCHEM_CID
5892	IUPHAR_LIGAND_ID
C401859	MESH_SUPPLEMENTAL_RECORD_UI
DB00877	DRUGBANK_ID

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Torisel	HUMAN PRESCRIPTION DRUG LABEL	1	0008-1179	KIT	25 mg	None	NDA	19 sections
Temsirolimus	HUMAN PRESCRIPTION DRUG LABEL	1	16729-223	KIT	25 mg	None	ANDA	18 sections
Temsirolimus	HUMAN PRESCRIPTION DRUG LABEL	1	68083-202	KIT	25 mg	None	ANDA	18 sections
Temsirolimus	HUMAN PRESCRIPTION DRUG LABEL	1	72611-785	KIT	25 mg	None	ANDA	18 sections