nitisinone ๐Ÿถ Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | 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 ยตM/kg/day Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
BA (Bioavailability) 90 % Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H

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 283.03 117.79 32 246 296 50604550
Succinylacetone increased 155.93 117.79 14 264 0 50604846
Alpha 1 foetoprotein increased 130.59 117.79 15 263 156 50604690
Liver transplant 129.61 117.79 20 258 2112 50602734
Hepatocellular carcinoma 123.34 117.79 19 259 1980 50602866

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 399.19 79.71 48 328 315 29573836
Liver transplant 200.24 79.71 33 343 2283 29571868
Lenticular opacities 159.85 79.71 20 356 181 29573970
Succinylacetone increased 123.47 79.71 12 364 0 29574151
Alpha 1 foetoprotein increased 90.78 79.71 14 362 617 29573534
Hepatocellular carcinoma 88.82 79.71 20 356 7018 29567133
Cataract 88.01 79.71 25 351 22353 29551798

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 644.11 80.67 75 511 530 64497616
Liver transplant 312.43 80.67 50 536 4042 64494104
Lenticular opacities 274.35 80.67 34 552 410 64497736
Alpha 1 foetoprotein increased 181.07 80.67 25 561 715 64497431
Cataract 162.89 80.67 45 541 51217 64446929
Hepatocellular carcinoma 162.19 80.67 32 554 8371 64489775
Succinylacetone increased 148.69 80.67 14 572 0 64498146

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 HPPD inhibitors

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

DiseaseRelationSNOMED_IDDOID
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




๐Ÿถ Veterinary Drug Use

None

๐Ÿถ 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 PHARMS LTD 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 PHARMS LTD 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 PHARMS LTD 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)

None

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 Unclassified 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

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
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 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
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
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 66658-102 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 66658-105 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 66658-110 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 66658-120 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 27 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 70505-205 CAPSULE 5 mg ORAL ANDA 27 sections
Nitisinone HUMAN PRESCRIPTION DRUG LABEL 1 70505-210 CAPSULE 10 mg ORAL ANDA 27 sections
NITYR HUMAN PRESCRIPTION DRUG LABEL 1 70709-000 TABLET 10 mg ORAL NDA 27 sections
NITYR HUMAN PRESCRIPTION DRUG LABEL 1 70709-002 TABLET 2 mg ORAL NDA 27 sections
NITYR HUMAN PRESCRIPTION DRUG LABEL 1 70709-005 TABLET 5 mg ORAL NDA 27 sections