clofarabine Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definitionDrug idCAS RN
arabinofuranosyl derivatives 691 123318-82-1

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • ivozall
  • clofarabine
  • clofarex
  • clolar
  • evoltra
Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5’-triphosphate metabolite. Clofarabine has affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. Clofarabine inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5’-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro.
  • Molecular weight: 303.68
  • Formula: C10H11ClFN5O3
  • CLOGP: -0.46
  • LIPINSKI: 0
  • HAC: 8
  • HDO: 3
  • TPSA: 119.31
  • ALOGS: -1.79
  • ROTB: 2
  • Status: OFP
    • Legend:
    OFP - off patent
    OFM - off market
    ONP - on patent

Drug dosage:

None

ADMET properties:

PropertyValueReference
BDDCS (Biopharmaceutical Drug Disposition Classification System) 3 Benet LZ, Broccatelli F, Oprea TI
S (Water solubility) 1 mg/mL Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine) 55 % Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose) 4.23 µM/kg/day Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
BA (Bioavailability) 50 % Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H
Vd (Volume of distribution) 1.75 L/kg Lombardo F, Berellini G, Obach RS
CL (Clearance) 7.70 mL/min/kg Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma) 0.53 % Lombardo F, Berellini G, Obach RS
t_half (Half-life) 4 hours Lombardo F, Berellini G, Obach RS

Approvals:

DateAgencyCompanyOrphan
Nov. 14, 2019 EMA ORPHELIA PHARMA SAS
Dec. 28, 2004 FDA GENZYME

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
Febrile neutropenia 238.11 33.15 128 3775 94499 46587660
Bone marrow failure 156.87 33.15 67 3836 29602 46652557
Multiple organ dysfunction syndrome 124.22 33.15 68 3835 51642 46630517
Capillary leak syndrome 122.32 33.15 29 3874 1868 46680291
Acute lymphocytic leukaemia 101.78 33.15 27 3876 2746 46679413
Mucosal inflammation 81.94 33.15 47 3856 38929 46643230
Septic shock 81.40 33.15 54 3849 57839 46624320
Acute myeloid leukaemia 74.70 33.15 33 3870 15745 46666414
Neutropenia 69.61 33.15 72 3831 143132 46539027
Acute myeloid leukaemia recurrent 67.84 33.15 17 3886 1379 46680780
Haematotoxicity 66.01 33.15 24 3879 6909 46675250
Palmar-plantar erythrodysaesthesia syndrome 63.57 33.15 32 3871 20419 46661740
Pyrexia 60.74 33.15 106 3797 348696 46333463
Staphylococcal bacteraemia 58.21 33.15 20 3883 4884 46677275
Pancytopenia 54.87 33.15 50 3853 85008 46597151
Bronchopulmonary aspergillosis 53.43 33.15 21 3882 7475 46674684
Hyperbilirubinaemia 49.93 33.15 22 3881 10416 46671743
Blood bilirubin increased 48.27 33.15 32 3871 34152 46648007
Transaminases increased 46.65 33.15 29 3874 27732 46654427
Enterobacter bacteraemia 44.93 33.15 9 3894 261 46681898
Respiratory failure 44.78 33.15 47 3856 94769 46587390
Staphylococcal sepsis 43.02 33.15 18 3885 7514 46674645
Graft versus host disease 41.89 33.15 17 3886 6571 46675588
Blood culture positive 40.65 33.15 15 3888 4497 46677662
Sepsis 38.63 33.15 52 3851 135962 46546197
Neutropenic sepsis 37.45 33.15 19 3884 12305 46669854
Toxic erythema of chemotherapy 37.39 33.15 6 3897 46 46682113
Human herpesvirus 6 infection 37.12 33.15 12 3891 2427 46679732
Leukaemia recurrent 35.27 33.15 10 3893 1299 46680860
Thrombocytopenia 33.83 33.15 47 3856 126534 46555625

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
Febrile neutropenia 223.70 28.00 169 5088 106524 29840697
Multiple organ dysfunction syndrome 122.58 28.00 96 5161 63391 29883830
Haematotoxicity 120.26 28.00 44 5213 6126 29941095
Capillary leak syndrome 118.53 28.00 32 5225 1640 29945581
Blood bilirubin increased 113.66 28.00 74 5183 36562 29910659
Sepsis 110.81 28.00 132 5125 146263 29800958
Palmar-plantar erythrodysaesthesia syndrome 94.58 28.00 48 5209 14822 29932399
Oedema 87.19 28.00 67 5190 42926 29904295
Skin toxicity 81.67 28.00 28 5229 3221 29944000
Neutropenia 81.24 28.00 106 5151 128434 29818787
Acute lymphocytic leukaemia 79.27 28.00 27 5230 3045 29944176
Bone marrow failure 77.55 28.00 54 5203 29731 29917490
Mucosal inflammation 76.40 28.00 54 5203 30440 29916781
Aplasia 75.73 28.00 28 5229 4009 29943212
Aspartate aminotransferase increased 72.03 28.00 71 5186 63351 29883870
Acute myeloid leukaemia recurrent 66.23 28.00 20 5237 1532 29945689
Alanine aminotransferase increased 66.14 28.00 73 5184 74203 29873018
Acute myeloid leukaemia 64.82 28.00 40 5217 17966 29929255
Hepatotoxicity 64.54 28.00 40 5217 18105 29929116
Cystitis haemorrhagic 64.14 28.00 26 5231 4761 29942460
Pancytopenia 62.98 28.00 76 5181 84976 29862245
Respiratory failure 51.43 28.00 75 5182 100567 29846654
Pneumonia fungal 47.66 28.00 22 5235 5511 29941710
Streptococcal sepsis 47.57 28.00 15 5242 1327 29945894
Adenovirus infection 46.48 28.00 20 5237 4248 29942973
Acute lymphocytic leukaemia recurrent 44.56 28.00 17 5240 2650 29944571
Neutropenic colitis 43.79 28.00 16 5241 2214 29945007
Acute graft versus host disease in skin 42.19 28.00 19 5238 4497 29942724
Transaminases increased 39.88 28.00 33 5224 23424 29923797
Nephropathy toxic 39.20 28.00 24 5233 10615 29936606
Enterococcal bacteraemia 38.71 28.00 13 5244 1403 29945818
Venoocclusive liver disease 38.13 28.00 20 5237 6593 29940628
Bacterial sepsis 37.54 28.00 18 5239 4908 29942313
Hyperbilirubinaemia 35.59 28.00 27 5230 16915 29930306
Neutropenic sepsis 35.19 28.00 23 5234 11386 29935835
Staphylococcal infection 34.55 28.00 34 5223 30190 29917031
Pulmonary haemorrhage 34.12 28.00 21 5236 9371 29937850
Fungal infection 31.53 28.00 23 5234 13577 29933644
Bronchopulmonary aspergillosis 31.30 28.00 22 5235 12262 29934959
Tumour lysis syndrome 30.35 28.00 22 5235 12863 29934358
Blood culture positive 28.71 28.00 15 5242 4904 29942317

Pharmacologic Action:

SourceCodeDescription
ATC L01BB06 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
ANTIMETABOLITES
Purine analogues
FDA MoA N0000000233 Nucleic Acid Synthesis Inhibitors
FDA EPC N0000175595 Nucleoside Metabolic Inhibitor
MeSH PA D000963 Antimetabolites
MeSH PA D000964 Antimetabolites, Antineoplastic
MeSH PA D000970 Antineoplastic Agents
MeSH PA D009676 Noxae
CHEBI has role CHEBI:35221 antimetabolite
CHEBI has role CHEBI:35610 cytostatic

Drug Use (View source of the data)

DiseaseRelationSNOMED_IDDOID
Acute lymphoid leukemia indication 91857003 DOID:9952
Mycosis contraindication 3218000 DOID:1564
Hyperbilirubinemia contraindication 14783006 DOID:2741
Viral disease contraindication 34014006 DOID:934
Dehydration contraindication 34095006
Renal failure syndrome contraindication 42399005 DOID:1074
Low blood pressure contraindication 45007003
Bacterial infectious disease contraindication 87628006
Capillary leak syndrome contraindication 87730004 DOID:14400
Liver function tests abnormal contraindication 166603001
Disease of liver contraindication 235856003 DOID:409
Sepsis syndrome contraindication 238150007
Anemia contraindication 271737000 DOID:2355
Pregnancy, function contraindication 289908002
Thrombocytopenic disorder contraindication 302215000 DOID:1588
Neutropenic disorder contraindication 303011007 DOID:1227
Bone marrow depression contraindication 307762000
Breastfeeding (mother) contraindication 413712001
Chemotherapy-Induced Hyperuricemia contraindication

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 11.77 acidic
pKa2 12.4 acidic
pKa3 3.11 Basic
pKa4 2.3 Basic

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
DNA polymerase alpha catalytic subunit Enzyme INHIBITOR WOMBAT-PK CHEMBL
Ribonucleoside-diphosphate reductase subunit M2 Enzyme INHIBITOR IC50 8.30 IUPHAR CHEMBL
Ribonucleoside-diphosphate reductase large subunit Enzyme INHIBITOR IC50 8.30 IUPHAR CHEMBL
Uridine-cytidine kinase 2 Kinase WOMBAT-PK
Uridine-cytidine kinase 1 Kinase WOMBAT-PK
Ribose-phosphate pyrophosphokinase 1 Kinase WOMBAT-PK

External reference:

IDSource
4024904 VUID
N0000171589 NUI
D03546 KEGG_DRUG
4024904 VANDF
C0092777 UMLSCUI
CHEBI:681569 CHEBI
CFB PDB_CHEM_ID
CHEMBL1750 ChEMBL_ID
DB00631 DRUGBANK_ID
D000077866 MESH_DESCRIPTOR_UI
119182 PUBCHEM_CID
6802 IUPHAR_LIGAND_ID
8422 INN_ID
762RDY0Y2H UNII
44151 RXNORM
19116 MMSL
257236 MMSL
64071 MMSL
d05423 MMSL
008803 NDDF
413873006 SNOMEDCT_US
417601005 SNOMEDCT_US

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
Clolar HUMAN PRESCRIPTION DRUG LABEL 1 0024-5860 INJECTION 1 mg INTRAVENOUS NDA 29 sections
Clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 0955-1746 INJECTION 1 mg INTRAVENOUS NDA AUTHORIZED GENERIC 29 sections
Clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 43598-309 INJECTION 1 mg INTRAVENOUS ANDA 23 sections
CLOFARABINE HUMAN PRESCRIPTION DRUG LABEL 1 49315-003 INJECTION 1 mg INTRAVENOUS ANDA 1 sections
CLOFARABINE HUMAN PRESCRIPTION DRUG LABEL 1 50742-512 INJECTION, SOLUTION 1 mg INTRAVENOUS ANDA 23 sections
Clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 60505-6166 INJECTION 1 mg INTRAVENOUS ANDA 26 sections
CLOFARABINE Human Prescription Drug Label 1 63323-572 INJECTION 1 mg INTRAVENOUS ANDA 24 sections
clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 67457-546 INJECTION 1 mg INTRAVENOUS ANDA 26 sections
Clofarabine Human Prescription Drug Label 1 68083-386 INJECTION 1 mg INTRAVENOUS ANDA 26 sections
Clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 70121-1236 INJECTION 1 mg INTRAVENOUS ANDA 24 sections
Clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 71288-128 INJECTION 1 mg INTRAVENOUS ANDA 25 sections
CLOFARABINE HUMAN PRESCRIPTION DRUG LABEL 1 72266-108 INJECTION 1 mg INTRAVENOUS ANDA 26 sections