nitisinone 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 µM/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 278.88 136.18 31 229 239 46685563
Succinylacetone increased 155.76 136.18 14 246 0 46685802

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 402.34 80.88 48 286 343 29951801
Liver transplant 177.43 80.88 30 304 2772 29949372
Lenticular opacities 160.02 80.88 20 314 208 29951936
Succinylacetone increased 125.07 80.88 12 322 0 29952144
Alpha 1 foetoprotein increased 83.42 80.88 13 321 702 29951442

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
FDA MoA N0000175808 Hydroxyphenylpyruvate Dioxygenase Inhibitors
FDA EPC N0000175809 4-Hydroxyphenyl-Pyruvate Dioxygenase Inhibitor
MeSH PA D004791 Enzyme Inhibitors
FDA MoA N0000185504 Cytochrome P450 2C9 Inhibitors
CHEBI has role CHEBI:38317 hppd inhibitors

Drug Use (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

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)

None

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

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
6834 IUPHAR_LIGAND_ID
7720 INN_ID
K5BN214699 UNII
115355 PUBCHEM_CID
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 63629-2234 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
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