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

Stem definition	Drug id	CAS RN
	5231	120685-11-2

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: midostaurin CGP 41251 PKC 412 rydapt	Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFR-alfa/beta, VEGFR2, as well as members of the serine/threonine kinase PKC (protein kinase C) family. Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells. Molecular weight: 570.65 Formula: C35H30N4O4 CLOGP: 5.53 LIPINSKI: 2 HAC: 8 HDO: 1 TPSA: 77.73 ALOGS: -4.56 ROTB: 3 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

midostaurin
CGP 41251
PKC 412
rydapt

Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFR-alfa/beta, VEGFR2, as well as members of the serine/threonine kinase PKC (protein kinase C) family. Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.

Molecular weight: 570.65
Formula: C35H30N4O4
CLOGP: 5.53
LIPINSKI: 2
HAC: 8
HDO: 1
TPSA: 77.73
ALOGS: -4.56
ROTB: 3

Status: OFP

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

Drug dosage:

Dose	Unit	Route
0.10	g	O

ADMET properties:

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Property	Value	Reference
BDDCS (Biopharmaceutical Drug Disposition Classification System)	2	Bocci G, Oprea TI, Benet LZ
S (Water solubility)	0.00 mg/mL	Bocci G, Oprea TI, Benet LZ

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Approvals:

Date	Agency	Company	Orphan
April 28, 2017	FDA	NOVARTIS PHARMS CORP
Sept. 18, 2017	EMA	Novartis Europharm Ltd

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
Acute myeloid leukaemia recurrent	178.25	34.17	33	2129	1590	63485270
Febrile neutropenia	152.39	34.17	76	2086	118373	63368487
Minimal residual disease	66.23	34.17	10	2152	134	63486726
Death	61.01	34.17	69	2093	374312	63112548
Thrombocytopenia	60.28	34.17	46	2116	151111	63335749
Neutropenic colitis	59.53	34.17	15	2147	3080	63483780
Cytopenia	47.41	34.17	17	2145	11584	63475276
Abdominal wall wound	47.00	34.17	7	2155	85	63486775
Sepsis	47.00	34.17	40	2122	153083	63333777
Myeloblast percentage decreased	43.39	34.17	6	2156	41	63486819

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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
Acute myeloid leukaemia recurrent	262.17	34.02	54	2473	2116	34952288
Febrile neutropenia	135.86	34.02	97	2430	136752	34817652
Bone marrow failure	123.62	34.02	54	2473	29199	34925205
Skin toxicity	95.53	34.02	28	2499	4756	34949648
Pancytopenia	73.06	34.02	58	2469	95099	34859305
Tryptase increased	66.67	34.02	12	2515	225	34954179
Neutropenic colitis	60.99	34.02	18	2509	3126	34951278
Lymphadenopathy	58.05	34.02	32	2495	28431	34925973
Thrombocytopenia	46.98	34.02	57	2470	156190	34798214
Septic shock	43.04	34.02	38	2489	71796	34882608

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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
Acute myeloid leukaemia recurrent	396.74	31.96	78	4151	3305	79736854
Febrile neutropenia	271.23	31.96	162	4067	230837	79509322
Bone marrow failure	141.51	31.96	64	4165	51043	79689116
Neutropenic colitis	131.71	31.96	35	4194	5672	79734487
Thrombocytopenia	103.24	31.96	96	4133	265163	79474996
Pancytopenia	101.64	31.96	78	4151	165667	79574492
Skin toxicity	88.76	31.96	28	4201	8286	79731873
Neutropenia	78.57	31.96	86	4143	287624	79452535
Tryptase increased	70.09	31.96	14	4215	639	79739520
Sepsis	67.45	31.96	77	4152	269351	79470808

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FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

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Source	Code	Description
ATC	L01EX10	ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS ANTINEOPLASTIC AGENTS PROTEIN KINASE INHIBITORS Other protein kinase inhibitors
CHEBI has role	CHEBI:35610	antineoplastic agents
CHEBI has role	CHEBI:37700	protein kinase C inhibitors
FDA EPC	N0000175605	Kinase Inhibitor
FDA MoA	N0000020000	Receptor Tyrosine Kinase Inhibitors
MeSH PA	D000970	Antineoplastic Agents
MeSH PA	D004791	Enzyme Inhibitors
MeSH PA	D047428	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
Acute myeloid leukemia, disease	indication	91861009
Mast cell leukemia	indication	110002002
Aggressive systemic mastocytosis	indication	716655008	DOID:4798

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🐶 Veterinary Drug Use

None

🐶 Veterinary products

None

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	9.7	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	RYDAPT	NOVARTIS	N207997	April 28, 2017	RX	CAPSULE	ORAL	7973031	Oct. 9, 2028	TREATMENT OF ADULT PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (AML) WHO ARE FLT3 MUTATION-POSITIVE, IN COMBINATION WITH STANDARD CYTARABINE AND DAUNORUBICIN INDUCTION AND CYTARABINE CONSOLIDATION CHEMOTHERAPY
25MG	RYDAPT	NOVARTIS	N207997	April 28, 2017	RX	CAPSULE	ORAL	8575146	Dec. 2, 2030	TREATMENT OF ADULT PATIENTS WITH AGGRESSIVE SYSTEMIC MASTOCYTOSIS (ASM), SYSTEMIC MASTOCYTOSIS WITH ASSOCIATED HEMATOLOGICAL NEOPLASM (SM-AHN), OR MAST CELL LEUKEMIA (MCL)

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Orange Book exclusivity data (new drug applications)

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Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Exclusivity date	Description
25MG	RYDAPT	NOVARTIS	N207997	April 28, 2017	RX	CAPSULE	ORAL	April 28, 2024	TREATMENT OF ADULT PATIENTS WITH AGGRESSIVE SYSTEMIC MASTOCYTOSIS (ASM), SYSTEMIC MASTOCYTOSIS WITH ASSOCIATED HEMATOLOGICAL NEOPLASM (SM-AHN), OR MAST CELL LEUKEMIA (MCL)
25MG	RYDAPT	NOVARTIS	N207997	April 28, 2017	RX	CAPSULE	ORAL	April 28, 2024	TREATMENT OF ADULT PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (AML) THAT IS FLT3 MUTATION-POSITIVE AS DETECTED BY AN FDA APPROVED TEST, IN COMBINATION WITH STANDARD CYTARABINE AND DAUNORUBICIN INDUCTION AND CYTARABINE CONSOLIDATION

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Bioactivity Summary:

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Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Receptor-type tyrosine-protein kinase FLT3	Kinase	P36888	FLT3_HUMAN	INHIBITOR	Kd	7.96	IUPHAR	DRUG LABEL
Serine/threonine-protein kinase pim-1	Kinase	P11309	PIM1_HUMAN		Kd	6.25	CHEMBL
Ribosomal protein S6 kinase alpha-3	Kinase	P51812	KS6A3_HUMAN		Kd	6.13	CHEMBL
Tyrosine-protein kinase JAK3	Kinase	P52333	JAK3_HUMAN		Kd	7.92	CHEMBL
Platelet-derived growth factor receptor beta	Kinase	P09619	PGFRB_HUMAN		Kd	6.96	CHEMBL
Tyrosine-protein kinase ABL1	Kinase	P00519	ABL1_HUMAN		Kd	6.10	CHEMBL
Mast/stem cell growth factor receptor Kit	Kinase	P10721	KIT_HUMAN		Kd	8.11	CHEMBL
Epidermal growth factor receptor	Kinase	P00533	EGFR_HUMAN		Kd	8.06	CHEMBL
Aspartyl/asparaginyl beta-hydroxylase	Enzyme	Q12797	ASPH_HUMAN		IC50	5.22	CHEMBL
Proto-oncogene tyrosine-protein kinase Src	Kinase	P12931	SRC_HUMAN		Kd	5.92	CHEMBL

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External reference:

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ID	Source
2K2	PDB_CHEM_ID
017198	NDDF
1919083	RXNORM
256612	MMSL
32671	MMSL
4036652	VANDF
5702	IUPHAR_LIGAND_ID
763613005	SNOMEDCT_US
763614004	SNOMEDCT_US
7677	INN_ID

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Pharmaceutical products:

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Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
RYDAPT	HUMAN PRESCRIPTION DRUG LABEL	1	0078-0698	CAPSULE, LIQUID FILLED	25 mg	ORAL	NDA	28 sections
RYDAPT	HUMAN PRESCRIPTION DRUG LABEL	1	0078-0698	CAPSULE, LIQUID FILLED	25 mg	ORAL	NDA	28 sections
RYDAPT	HUMAN PRESCRIPTION DRUG LABEL	1	0078-0698	CAPSULE, LIQUID FILLED	25 mg	ORAL	NDA	28 sections

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