aprepitant Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
neurokinin NK1 (substance P) receptor antagonist	230	170729-80-3

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: emend aprepitant L-754030	Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Molecular weight: 534.44 Formula: C23H21F7N4O3 CLOGP: 4.60 LIPINSKI: 1 HAC: 7 HDO: 2 TPSA: 75.19 ALOGS: -4.44 ROTB: 8 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

emend
aprepitant
L-754030

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions.

Molecular weight: 534.44
Formula: C23H21F7N4O3
CLOGP: 4.60
LIPINSKI: 1
HAC: 7
HDO: 2
TPSA: 75.19
ALOGS: -4.44
ROTB: 8

Status: OFP

Legend:
OFP - off patent
OFM - off market
ONP - on patent

Drug dosage:

Dose	Unit	Route
165	mg	O
150	mg	P

ADMET properties:

Property	Value	Reference
BDDCS (Biopharmaceutical Drug Disposition Classification System)	2	Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine)	0 %	Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose)	3.34 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
BA (Bioavailability)	62.50 %	Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H
Vd (Volume of distribution)	0.94 L/kg	Lombardo F, Berellini G, Obach RS
CL (Clearance)	1 mL/min/kg	Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma)	0.05 %	Lombardo F, Berellini G, Obach RS
t_half (Half-life)	13 hours	Lombardo F, Berellini G, Obach RS

Approvals:

Date	Agency	Company	Orphan
March 27, 2003	FDA	MERCK

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
Febrile neutropenia	354.49	17.15	288	17073	94339	46574362
Nausea	209.20	17.15	642	16719	686812	45981889
Erythema	161.13	17.15	230	17131	142590	46526111
Mucosal inflammation	159.17	17.15	125	17236	38851	46629850
Neutropenia	157.72	17.15	228	17133	142976	46525725
Encephalopathy	148.66	17.15	113	17248	33476	46635225
Drug ineffective	101.36	17.15	64	17297	677774	45990927
Febrile bone marrow aplasia	95.46	17.15	48	17313	6814	46661887
Flushing	94.08	17.15	118	17243	64496	46604205
Atelectasis	87.05	17.15	65	17296	18725	46649976
Computerised tomogram thorax abnormal	84.90	17.15	28	17333	1333	46667368
Pyrexia	80.41	17.15	298	17063	348504	46320197
Hypoxia	66.56	17.15	89	17272	51749	46616952
Hepatocellular injury	61.66	17.15	65	17296	29457	46639244
Vomiting	61.19	17.15	330	17031	452464	46216237
Hyponatraemia	60.40	17.15	123	17238	101209	46567492
Bone marrow failure	59.63	17.15	64	17297	29605	46639096
Decreased appetite	59.00	17.15	182	17179	193654	46475047
Palmar-plantar erythrodysaesthesia syndrome	55.63	17.15	52	17309	20399	46648302
Vascular pain	55.10	17.15	17	17344	651	46668050
Dyspnoea	54.97	17.15	353	17008	515195	46153506
Infusion site streaking	51.51	17.15	14	17347	339	46668362
Diarrhoea	50.63	17.15	368	16993	559234	46109467
Constipation	49.77	17.15	160	17201	173937	46494764
Neutrophil count decreased	48.90	17.15	70	17291	43356	46625345
Sense of oppression	47.73	17.15	17	17344	1022	46667679
Fall	46.36	17.15	33	17328	329064	46339637
Aplasia	43.90	17.15	23	17338	3553	46665148
Respiratory syncytial virus infection	42.62	17.15	25	17336	4810	46663891
Inappropriate antidiuretic hormone secretion	42.53	17.15	38	17323	14064	46654637
Gastrointestinal disorder	41.17	17.15	77	17284	59499	46609202
Hypersensitivity	39.23	17.15	134	17227	150187	46518514
Alveolitis	39.18	17.15	19	17342	2494	46666207
Oral pain	38.81	17.15	47	17314	24750	46643951
Chemotherapy	36.44	17.15	15	17346	1337	46667364
Anaphylactic shock	36.00	17.15	41	17320	20233	46648468
Tonsillar haemorrhage	34.20	17.15	9	17352	192	46668509
Cerebellar syndrome	33.43	17.15	19	17342	3446	46665255
Abdominal pain	33.20	17.15	171	17190	229860	46438841
Interstitial lung disease	32.72	17.15	66	17295	53883	46614818
Feeling hot	32.65	17.15	54	17307	37874	46630827
Chest discomfort	32.42	17.15	90	17271	90179	46578522
Neuropathy peripheral	32.03	17.15	90	17271	90803	46577898
Intestinal strangulation	29.99	17.15	7	17354	89	46668612
Depression	29.76	17.15	13	17348	170091	46498610
Joint swelling	28.57	17.15	13	17348	166060	46502641
Hypomagnesaemia	28.28	17.15	38	17323	22172	46646529
Drug intolerance	27.75	17.15	10	17351	147039	46521662
Injection site pain	26.69	17.15	4	17357	107148	46561553
Weight increased	26.58	17.15	14	17347	164459	46504242
Toxicity to various agents	26.32	17.15	24	17337	211742	46456959
Anorectal disorder	26.14	17.15	12	17349	1392	46667309
Colony stimulating factor therapy	25.79	17.15	8	17353	312	46668389
Intercepted product administration error	25.65	17.15	6	17355	77	46668624
Sputum abnormal	24.77	17.15	8	17353	356	46668345
Oropharyngeal discomfort	24.45	17.15	15	17346	3130	46665571
Gastrointestinal scarring	24.17	17.15	7	17354	215	46668486
Thrombocytopenic purpura	24.12	17.15	11	17350	1257	46667444
Leukopenia	23.41	17.15	67	17294	68276	46600425
Hypokalaemia	23.40	17.15	79	17282	87945	46580756
Gait disturbance	22.55	17.15	13	17348	145250	46523451
Periorbital cellulitis	22.28	17.15	8	17353	492	46668209
Laryngeal discomfort	22.20	17.15	7	17354	288	46668413
Antinuclear antibody	22.14	17.15	8	17353	501	46668200
Pain	22.01	17.15	97	17264	476851	46191850
Body temperature abnormal	21.88	17.15	10	17351	1148	46667553
Dysgeusia	21.59	17.15	47	17314	40444	46628257
Myocardial infarction	21.39	17.15	5	17356	97523	46571178
Tumour pain	21.32	17.15	10	17351	1219	46667482
Anaphylactic reaction	21.12	17.15	55	17306	53057	46615644
Hypermagnesaemia	20.75	17.15	9	17352	913	46667788
Infusion site vesicles	20.57	17.15	7	17354	367	46668334
Subacute cutaneous lupus erythematosus	19.83	17.15	11	17350	1904	46666797
Phlebitis	19.70	17.15	17	17344	6009	46662692
Hallucination, tactile	19.57	17.15	6	17355	225	46668476
Administration site oedema	18.93	17.15	4	17357	31	46668670
Paraesthesia	18.81	17.15	90	17271	117347	46551354
Bronchitis	18.68	17.15	8	17353	105971	46562730
Abdominal operation	18.68	17.15	7	17354	486	46668215
Dehydration	18.58	17.15	112	17249	159428	46509273
Toxic encephalopathy	18.02	17.15	15	17346	5047	46663654
White blood cell count decreased	17.97	17.15	86	17275	112145	46556556
Hypophagia	17.93	17.15	36	17325	29270	46639431
Musculoskeletal stiffness	17.92	17.15	7	17354	97986	46570715
Exposure during pregnancy	17.79	17.15	9	17352	108203	46560498

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
Febrile neutropenia	156.35	18.90	196	11050	106497	29834735
Hiccups	105.03	18.90	57	11189	9377	29931855
Erythema	91.21	18.90	128	11118	77323	29863909
Nausea	86.89	18.90	276	10970	296681	29644551
Neutropenia	81.80	18.90	161	11085	128379	29812853
Hypersensitivity	80.10	18.90	100	11146	53928	29887304
Neutrophil count decreased	71.75	18.90	84	11162	42370	29898862
Drug ineffective	64.15	18.90	24	11222	340363	29600869
Vomiting	60.18	18.90	200	11046	219618	29721614
Thrombocytopenia	57.07	18.90	145	11101	136899	29804333
Fixed eruption	52.81	18.90	19	11227	1165	29940067
Intestinal ischaemia	51.08	18.90	32	11214	6865	29934367
Decreased appetite	50.77	18.90	147	11099	149763	29791469
Diarrhoea	47.85	18.90	249	10997	333854	29607378
Encephalopathy	46.71	18.90	59	11187	32146	29909086
Hepatocellular injury	45.70	18.90	52	11194	25419	29915813
Mouth ulceration	42.93	18.90	34	11212	10575	29930657
Stomatitis	42.89	18.90	61	11185	37218	29904014
Testicular germ cell cancer metastatic	42.58	18.90	9	11237	69	29941163
Aplasia	41.09	18.90	23	11223	4014	29937218
Toxicity to various agents	37.72	18.90	10	11236	177173	29764059
Sense of oppression	34.53	18.90	11	11235	464	29940768
Stoma site pain	33.83	18.90	12	11234	706	29940526
Emotional disorder	33.67	18.90	22	11224	5072	29936160
Change of bowel habit	33.25	18.90	13	11233	1004	29940228
Toxic encephalopathy	33.17	18.90	21	11225	4588	29936644
Seminoma	32.53	18.90	9	11237	231	29941001
Mucosal inflammation	32.31	18.90	48	11198	30446	29910786
Oral pain	31.32	18.90	27	11219	9442	29931790
Neuropathy peripheral	30.76	18.90	76	11170	70399	29870833
Febrile bone marrow aplasia	30.74	18.90	25	11221	8072	29933160
Alopecia	30.65	18.90	37	11209	19238	29921994
Bone marrow failure	30.29	18.90	46	11200	29739	29911493
White blood cell count decreased	29.98	18.90	84	11162	83863	29857369
Paraesthesia	28.53	18.90	63	11183	54264	29886968
Flushing	27.83	18.90	44	11202	29448	29911784
Anaphylactic shock	27.55	18.90	30	11216	13963	29927269
Leukopenia	27.12	18.90	63	11183	56096	29885136
Enteritis	26.25	18.90	21	11225	6624	29934608
Large intestine perforation	25.68	18.90	22	11224	7629	29933603
Anaphylactic reaction	25.37	18.90	41	11205	27941	29913291
Platelet count increased	25.08	18.90	23	11223	8719	29932513
Septic shock	25.05	18.90	66	11180	63541	29877691
Dehydration	24.90	18.90	102	11144	123437	29817795
Interstitial lung disease	24.26	18.90	63	11183	60134	29881098
Chemotherapeutic drug level increased	23.95	18.90	7	11239	220	29941012
Jaundice	23.42	18.90	43	11203	32443	29908789
Constipation	23.37	18.90	94	11152	112812	29828420
Acute kidney injury	23.32	18.90	179	11067	273663	29667569
Platelet count decreased	23.29	18.90	90	11156	106039	29835193
Pyrexia	22.63	18.90	188	11058	294301	29646931
Incorrect drug administration rate	21.98	18.90	10	11236	1126	29940106
Peritonitis	21.71	18.90	33	11213	21342	29919890
Hyperammonaemic encephalopathy	20.12	18.90	11	11235	1833	29939399
Necrotising ulcerative gingivostomatitis	19.80	18.90	5	11241	89	29941143
Cardiac failure congestive	19.45	18.90	4	11242	84403	29856829

Pharmacologic Action:

Source	Code	Description
ATC	A04AD12	ALIMENTARY TRACT AND METABOLISM ANTIEMETICS AND ANTINAUSEANTS ANTIEMETICS AND ANTINAUSEANTS Other antiemetics
FDA MoA	N0000010262	Neurokinin 1 Antagonists
FDA EPC	N0000175786	Substance P/Neurokinin-1 Receptor Antagonist
MeSH PA	D000932	Antiemetics
MeSH PA	D002491	Central Nervous System Agents
MeSH PA	D005765	Gastrointestinal Agents
MeSH PA	D064729	Neurokinin-1 Receptor Antagonists
MeSH PA	D018377	Neurotransmitter Agents
MeSH PA	D018373	Peripheral Nervous System Agents
FDA MoA	N0000182141	Cytochrome P450 3A4 Inhibitors
FDA MoA	N0000185506	Cytochrome P450 3A4 Inducers
FDA MoA	N0000185507	Cytochrome P450 2C9 Inducers
CHEBI has role	CHEBI:35469	thymoanaleptics
CHEBI has role	CHEBI:49110	peripheral nervous system agent
CHEBI has role	CHEBI:50919	antiemetico
CHEBI has role	CHEBI:55350	neurokinin-1 receptor antagonists
CHEBI has role	CHEBI:55351	substance p receptor antagonists

Drug Use (View source of the data)

Disease	Relation	SNOMED_ID
Chemotherapy-induced nausea and vomiting	indication	236084000
Prevention of Post-Operative Nausea and Vomiting	indication
Hepatic failure	contraindication	59927004

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	8.8	acidic
pKa2	13.0	acidic
pKa3	3.22	Basic
pKa4	2.56	Basic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Substance-P receptor	GPCR	P25103	NK1R_HUMAN	ANTAGONIST	Ki	10.70	CHEMBL	CHEMBL
Cytochrome P450 3A4	Enzyme	P08684	CP3A4_HUMAN				WOMBAT-PK
Neuromedin-K receptor	GPCR	P29371	NK3R_HUMAN		Ki	6.34	CHEMBL
Substance-P receptor	Unclassified		NK1R_MERUN		IC50	10.05	CHEMBL

External reference:

ID	Source
1NF15YR6UY	UNII
D02968	KEGG_DRUG
C1176306	UMLSCUI
CHEBI:499361	CHEBI
CHEMBL1471	ChEMBL_ID
CHEMBL1201782	ChEMBL_ID
DB00673	DRUGBANK_ID
D000077608	MESH_DESCRIPTOR_UI
135413536	PUBCHEM_CID
8050	INN_ID
3490	IUPHAR_LIGAND_ID
357280	RXNORM
17180	MMSL
247683	MMSL
46392	MMSL
d04855	MMSL
009926	NDDF
398690007	SNOMEDCT_US
409205009	SNOMEDCT_US
4021391	VANDF

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
EMEND	HUMAN PRESCRIPTION DRUG LABEL	1	0006-0461	CAPSULE	80 mg	ORAL	NDA	31 sections
EMEND	HUMAN PRESCRIPTION DRUG LABEL	1	0006-0462	CAPSULE	125 mg	ORAL	NDA	31 sections
EMEND	HUMAN PRESCRIPTION DRUG LABEL	1	0006-0464	CAPSULE	40 mg	ORAL	NDA	31 sections
EMEND	HUMAN PRESCRIPTION DRUG LABEL	1	0006-3066	POWDER, FOR SUSPENSION	125 mg	ORAL	NDA	31 sections
Aprepitant	HUMAN PRESCRIPTION DRUG LABEL	1	0781-2321	CAPSULE	40 mg	ORAL	ANDA	26 sections
Aprepitant	HUMAN PRESCRIPTION DRUG LABEL	1	0781-2322	CAPSULE	80 mg	ORAL	ANDA	26 sections
Aprepitant	HUMAN PRESCRIPTION DRUG LABEL	1	0781-2323	CAPSULE	125 mg	ORAL	ANDA	26 sections
APREPITANT	HUMAN PRESCRIPTION DRUG LABEL	1	13668-591	CAPSULE	40 mg	ORAL	ANDA	24 sections
APREPITANT	HUMAN PRESCRIPTION DRUG LABEL	1	13668-592	CAPSULE	80 mg	ORAL	ANDA	24 sections
APREPITANT	HUMAN PRESCRIPTION DRUG LABEL	1	13668-593	CAPSULE	125 mg	ORAL	ANDA	24 sections
EMEND	HUMAN PRESCRIPTION DRUG LABEL	1	42254-160	CAPSULE	40 mg	ORAL	NDA	26 sections
CINVANTI	HUMAN PRESCRIPTION DRUG LABEL	1	47426-201	INJECTION, EMULSION	130 mg	INTRAVENOUS	NDA	28 sections
EMEND	HUMAN PRESCRIPTION DRUG LABEL	1	54868-5231	CAPSULE	80 mg	ORAL	NDA	26 sections
Aprepitant	HUMAN PRESCRIPTION DRUG LABEL	1	68462-583	CAPSULE	40 mg	ORAL	ANDA	25 sections
Aprepitant	HUMAN PRESCRIPTION DRUG LABEL	1	68462-584	CAPSULE	80 mg	ORAL	ANDA	25 sections
Aprepitant	HUMAN PRESCRIPTION DRUG LABEL	1	68462-585	CAPSULE	125 mg	ORAL	ANDA	25 sections