nitisinone 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | PK/Tox | Related Drugs | BioActivity |

Stem definitionDrug idCAS RN
1944 104206-65-7

Description:

MoleculeDescription

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:

DoseUnitRoute
20 mg O

ADMET properties:

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

Predicted pharmacokinetic/toxicological properties (PK-AZ):

PropertyDescriptionValueUnitConfidenceSimilarity
kinase-safety-class ACVR2A,ACVR2B,ACVRL1,AURKA,AXL,BRAF,BTK,CAMK2B,CAMK2D,CDK5,CDK9,DDR1,DYRK1B,EIF2AK3,EPHB4,ERBB2,GRK2,GSK3B,ITK,JAK2,JAK3,MAP2K6,MAP3K21,MAP3K7,MAPK10,MAPK7,MAPK9,MAPKAPK2,MARK4,MET,MTOR,NTRK2,PDK1,PDK2,PDK4,PDPK1,PIK3CB,PIK3CD,PIK3CG,PIM2,PLK1,PRKDC,SIK2,STK33,SYK,TEK,TTK,ZAP70 48
kinase-selectivity-class AXL,CDK9,DYRK1B,EIF2AK3,GRK2,MAP2K6,MAPK7,PDK4,STK33,TEK,TTK,UHMK1 12
pfas-class PFAS structural alert (1 = True, 0 = False) 1
pld-class Phospholipidosis risk class (1 = positive, 0 = negative) 0 High 1

Approvals:

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

FDA Adverse Event Reporting System (Female)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Amino acid level increased 316.34 111.09 35 286 422 90627704
Succinylacetone increased 173.62 111.09 15 306 0 90628126
Liver transplant 168.47 111.09 24 297 2293 90625833
Alpha 1 foetoprotein increased 155.97 111.09 17 304 171 90627955
Hepatocellular carcinoma 151.42 111.09 22 299 2406 90625720

FDA Adverse Event Reporting System (Male)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Amino acid level increased 465.69 73.00 56 391 457 42620431
Liver transplant 237.49 73.00 38 409 2653 42618235
Lenticular opacities 156.08 73.00 20 427 273 42620615
Succinylacetone increased 146.74 73.00 14 433 0 42620888
Alpha 1 foetoprotein increased 121.81 73.00 18 429 724 42620164
Hepatocellular carcinoma 117.62 73.00 25 422 8169 42612719
Cataract 89.33 73.00 26 421 30578 42590310

FDA Adverse Event Reporting System (Geriatric)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Amino acid level increased 738.21 87.45 84 582 752 110587881
Liver transplant 388.27 87.45 58 608 4531 110584102
Lenticular opacities 276.04 87.45 34 632 601 110588032
Alpha 1 foetoprotein increased 239.20 87.45 31 635 833 110587800
Hepatocellular carcinoma 208.62 87.45 38 628 9842 110578791
Succinylacetone increased 176.52 87.45 16 650 0 110588633
Cataract 170.73 87.45 47 619 79438 110509195

FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

SourceCodeDescription
ATC A16AX04 ALIMENTARY TRACT AND METABOLISM
OTHER ALIMENTARY TRACT AND METABOLISM PRODUCTS
OTHER ALIMENTARY TRACT AND METABOLISM PRODUCTS
Various alimentary tract and metabolism products
MeSH PA D004791 Enzyme Inhibitors
FDA MoA N0000175808 Hydroxyphenylpyruvate Dioxygenase Inhibitors
FDA EPC N0000175809 4-Hydroxyphenyl-Pyruvate Dioxygenase Inhibitor
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
CHEBI has role CHEBI:38317 EC 1.13.11.27 (4-hydroxyphenylpyruvate dioxygenase) inhibitor

Related Drugs by ATC class:

A16AX Various alimentary tract and metabolism products 23 drugs
anethole trithionedoxecitinedoxribtimineeliglustatfosdenopteringivosiranglycerol phenylbutyratelonafarniblumasiranmigalastatmiglustatnedosiran show all 23 →

Drug Use | Suggest Off label Use Form| |View source of the data|

DiseaseRelationSNOMED_IDDOID
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




🐶 Veterinary Drug Use

None

🐶 Veterinary products

None

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 3.5 acidic

Orange Book patent data (new drug applications)

Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRoutePatent numberPatent expiration datePatent use
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
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
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

Orange Book exclusivity data (new drug applications)

Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRouteExclusivity dateDescription
2MG HARLIKU CYCLE N209449 June 10, 2025 RX TABLET ORAL June 10, 2032 REDUCTION OF URINE HOMOGENTISIC ACID (HGA) IN ADULT PATIENTS WITH ALKAPTONURIA (AKU)

Bioactivity Summary:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])		Mechanism
action		Bioact sourceMoA source
4-hydroxyphenylpyruvate dioxygenase Enzyme INHIBITOR IC50 7.40 WOMBAT-PK CHEMBL
4-hydroxyphenylpyruvate dioxygenase Enzyme IC50 7.40 CHEMBL
4-hydroxyphenylpyruvate dioxygenase Enzyme IC50 7.40 CHEMBL

External reference:

IDSource
4021290 VUID
N0000148727 NUI
D05177 KEGG_DRUG
4021290 VANDF
C0173083 UMLSCUI
CHEBI:50378 CHEBI
CHEMBL1337 ChEMBL_ID
DB00348 DRUGBANK_ID
C077073 MESH_SUPPLEMENTAL_RECORD_UI
115355 PUBCHEM_CID
6834 IUPHAR_LIGAND_ID
7720 INN_ID
K5BN214699 UNII
326381 RXNORM
16303 MMSL
251189 MMSL
42739 MMSL
d04789 MMSL
009172 NDDF
009558 NDDF
385996000 SNOMEDCT_US
385997009 SNOMEDCT_US
K5BN214699 INXIGHT DRUGS

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
Nitisinone Human Prescription Drug Label 1 0254-3020 CAPSULE 2 mg ORAL ANDA 25 sections
Nitisinone Human Prescription Drug Label 1 0254-3021 CAPSULE 5 mg ORAL ANDA 25 sections
Nitisinone Human Prescription Drug Label 1 0254-3022 CAPSULE 10 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 63629-2234 CAPSULE 2 mg ORAL ANDA 26 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 63629-2235 CAPSULE 5 mg ORAL ANDA 26 sections
Orfadin HUMAN PRESCRIPTION DRUG LABEL 1 66658-102 CAPSULE 2 mg ORAL NDA 27 sections
Orfadin HUMAN PRESCRIPTION DRUG LABEL 1 66658-105 CAPSULE 5 mg ORAL NDA 27 sections
Orfadin HUMAN PRESCRIPTION DRUG LABEL 1 66658-110 CAPSULE 10 mg ORAL NDA 27 sections
Orfadin HUMAN PRESCRIPTION DRUG LABEL 1 66658-120 CAPSULE 20 mg ORAL NDA 27 sections
ORFADIN HUMAN PRESCRIPTION DRUG LABEL 1 66658-204 SUSPENSION 4 mg ORAL NDA 27 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 70505-202 CAPSULE 2 mg ORAL ANDA 26 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 70505-205 CAPSULE 5 mg ORAL ANDA 26 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 70505-210 CAPSULE 10 mg ORAL ANDA 26 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 70505-220 CAPSULE 20 mg ORAL ANDA 26 sections
NITYR HUMAN PRESCRIPTION DRUG LABEL 1 70709-000 TABLET 10 mg ORAL NDA 26 sections
NITYR HUMAN PRESCRIPTION DRUG LABEL 1 70709-002 TABLET 2 mg ORAL NDA 26 sections
NITYR HUMAN PRESCRIPTION DRUG LABEL 1 70709-005 TABLET 5 mg ORAL NDA 26 sections
HARLIKU HUMAN PRESCRIPTION DRUG LABEL 1 70709-112 TABLET 2 mg ORAL NDA 23 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 71863-119 CAPSULE 2 mg ORAL ANDA 17 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 71863-119 CAPSULE 2 mg ORAL ANDA 17 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 71863-120 CAPSULE 5 mg ORAL ANDA 17 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 71863-120 CAPSULE 5 mg ORAL ANDA 17 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 71863-121 CAPSULE 10 mg ORAL ANDA 17 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 71863-121 CAPSULE 10 mg ORAL ANDA 17 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 71863-122 CAPSULE 20 mg ORAL ANDA 17 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 71863-122 CAPSULE 20 mg ORAL ANDA 17 sections