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nitisinone 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | PK/Tox | Related Drugs | BioActivity |
| Stem definition | Drug id | CAS RN |
|---|---|---|
| 1944 | 104206-65-7 |
Description:
| Molecule | Description |
|---|---|
|
Synonyms:
|
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.
Legend: OFP - off patent OFM - off market ONP - on patent |
Drug dosage:
| Dose | Unit | Route |
|---|---|---|
| 20 | mg | O |
ADMET properties:
| Property | Value | Reference |
|---|---|---|
| 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):
| Property | Description | Value | Unit | Confidence | Similarity |
|---|---|---|---|---|---|
| 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:
| Date | Agency | Company | Orphan |
|---|---|---|---|
| Feb. 21, 2005 | EMA | Swedish Orphan Biovitrum International AB | |
| Jan. 18, 2002 | FDA | SWEDISH ORPHAN |
FDA Adverse Event Reporting System (Female)
| 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 | 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 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 | 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 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 | 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:
| 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 |
| 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
Drug Use | Suggest Off label Use Form| |View source of the data|
| 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 |
🐶 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)
| Formulation strength | Trade name | Applicant | Application number | Approval date | Type | Dose form | Route | Patent number | Patent expiration date | Patent 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 strength | Trade name | Applicant | Application number | Approval date | Type | Dose form | Route | Exclusivity date | Description |
|---|---|---|---|---|---|---|---|---|---|
| 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:
| Target | Class | Pharos | UniProt | Action | Type | Activity value (-log[M]) | Mechanism action | Bioact source | MoA 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:
| ID | Source |
|---|---|
| 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:
| Product | Category | Ingredients | NDC | Form | Quantity | Route | Marketing | Label |
|---|---|---|---|---|---|---|---|---|
| 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 |