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

Stem definition	Drug id	CAS RN
	1944	104206-65-7

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: nitisinone nitisone orfadin NTBC	Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 (HT-1), nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Molecular weight: 329.23 Formula: C14H10F3NO5 CLOGP: 1.38 LIPINSKI: 0 HAC: 6 HDO: 0 TPSA: 94.35 ALOGS: -4.61 ROTB: 4 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

nitisinone
nitisone
orfadin
NTBC

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 (HT-1), nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity.

Molecular weight: 329.23
Formula: C14H10F3NO5
CLOGP: 1.38
LIPINSKI: 0
HAC: 6
HDO: 0
TPSA: 94.35
ALOGS: -4.61
ROTB: 4

Status: OFP

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

Drug dosage:

Dose	Unit	Route
20	mg	O

ADMET properties:

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Property	Value	Reference
BA (Bioavailability)	90 %	Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H
MRTD (Maximum Recommended Therapeutic Daily Dose)	6.07 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD

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Approvals:

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Date	Agency	Company	Orphan
Feb. 21, 2005	EMA	Swedish Orphan Biovitrum International AB
Jan. 18, 2002	FDA	SWEDISH ORPHAN

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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
Amino acid level increased	291.44	121.38	33	268	363	63488358
Liver transplant	161.81	121.38	24	277	2267	63486454
Succinylacetone increased	157.96	121.38	14	287	0	63488721
Alpha 1 foetoprotein increased	150.51	121.38	17	284	177	63488544
Hepatocellular carcinoma	147.28	121.38	22	279	2172	63486549

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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
Amino acid level increased	422.56	90.15	51	349	391	34956140
Liver transplant	222.17	90.15	36	364	2498	34954033
Lenticular opacities	156.70	90.15	20	380	241	34956290
Succinylacetone increased	124.72	90.15	12	388	0	34956531
Alpha 1 foetoprotein increased	121.15	90.15	18	382	689	34955842
Hepatocellular carcinoma	106.32	90.15	23	377	7486	34949045
Cataract	91.19	90.15	26	374	26160	34930371

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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
Amino acid level increased	670.69	91.13	78	541	650	79743119
Liver transplant	360.88	91.13	56	563	4367	79739402
Lenticular opacities	271.33	91.13	34	585	533	79743236
Alpha 1 foetoprotein increased	233.47	91.13	31	588	777	79742992
Hepatocellular carcinoma	189.86	91.13	36	583	8985	79734784
Cataract	170.52	91.13	47	572	62073	79681696
Succinylacetone increased	150.89	91.13	14	605	0	79743769

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FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

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Source	Code	Description
ATC	A16AX04	ALIMENTARY TRACT AND METABOLISM OTHER ALIMENTARY TRACT AND METABOLISM PRODUCTS OTHER ALIMENTARY TRACT AND METABOLISM PRODUCTS Various alimentary tract and metabolism products
CHEBI has role	CHEBI:38317	HPPD inhibitors
FDA EPC	N0000175809	4-Hydroxyphenyl-Pyruvate Dioxygenase Inhibitor
FDA MoA	N0000175808	Hydroxyphenylpyruvate Dioxygenase Inhibitors
FDA MoA	N0000185504	Cytochrome P450 2C9 Inhibitors
FDA MoA	N0000190110	Organic Anion Transporter 1 Inhibitors
FDA MoA	N0000190111	Organic Anion Transporter 3 Inhibitors
FDA MoA	N0000193955	Cytochrome P450 2E1 Inducers
MeSH PA	D004791	Enzyme 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
Homogentisate 1,2dioxygenase deficiency	indication	360378009
Tyrosinemia type I	indication	410056006
Hypophosphatemia	contraindication	4996001
Pain in eye	contraindication	41652007
Hypertyrosinemia	contraindication	56595005
Red eye	contraindication	75705005
Leukopenia	contraindication	84828003	DOID:615
Kidney disease	contraindication	90708001	DOID:557
Thrombocytopenic disorder	contraindication	302215000	DOID:1588
Photophobia	contraindication	409668002

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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	3.5	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
10MG	NITYR	CYCLE	N209449	July 26, 2017	RX	TABLET	ORAL	10328029	Jan. 5, 2035	TREATMENT OF HEREDITARY TYROSINEMIA TYPE 1 (HT-1) IN COMBINATION WITH DIETARY RESTRICTION OF TYROSINE AND PHENYLALANINE
2MG	NITYR	CYCLE	N209449	July 26, 2017	RX	TABLET	ORAL	10328029	Jan. 5, 2035	TREATMENT OF HEREDITARY TYROSINEMIA TYPE 1 (HT-1) IN COMBINATION WITH DIETARY RESTRICTION OF TYROSINE AND PHENYLALANINE
4MG/ML	ORFADIN	SWEDISH ORPHAN	N206356	April 22, 2016	RX	SUSPENSION	ORAL	9301932	Feb. 28, 2033	TREATMENT OF HEREDITARY TYROSINEMIA TYPE 1 (HT-1) IN COMBINATION WITH DIETARY RESTRICTION OF TYROSINE AND PHENYLALANINE
5MG	NITYR	CYCLE	N209449	July 26, 2017	RX	TABLET	ORAL	10328029	Jan. 5, 2035	TREATMENT OF HEREDITARY TYROSINEMIA TYPE 1 (HT-1) IN COMBINATION WITH DIETARY RESTRICTION OF TYROSINE AND PHENYLALANINE

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Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

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Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
4-hydroxyphenylpyruvate dioxygenase	Enzyme	P32754	HPPD_HUMAN	INHIBITOR	IC50	7.40	WOMBAT-PK	CHEMBL
4-hydroxyphenylpyruvate dioxygenase	Enzyme		HPPD_PIG		IC50	7.40	CHEMBL
4-hydroxyphenylpyruvate dioxygenase	Unclassified		HPPD_RAT		IC50	7.40	CHEMBL

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External reference:

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ID	Source
009172	NDDF
009558	NDDF
115355	PUBCHEM_CID
16303	MMSL
251189	MMSL
326381	RXNORM
385996000	SNOMEDCT_US
385997009	SNOMEDCT_US
4021290	VUID
4021290	VANDF

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Pharmaceutical products:

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Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	0254-3020	CAPSULE	2 mg	ORAL	ANDA	26 sections
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	0254-3021	CAPSULE	5 mg	ORAL	ANDA	26 sections
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	0254-3022	CAPSULE	10 mg	ORAL	ANDA	26 sections
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	13668-629	CAPSULE	2 mg	oral	ANDA	25 sections
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	13668-630	CAPSULE	5 mg	oral	ANDA	25 sections
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	13668-631	CAPSULE	10 mg	ORAL	ANDA	25 sections
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	13668-632	CAPSULE	20 mg	oral	ANDA	25 sections
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	63629-2233	CAPSULE	10 mg	ORAL	ANDA	26 sections
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	63629-2233	CAPSULE	10 mg	ORAL	ANDA	26 sections
Nitisinone	HUMAN PRESCRIPTION DRUG LABEL	1	63629-2234	CAPSULE	2 mg	ORAL	ANDA	26 sections

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