clofarabine ๐Ÿถ Veterinary Use | 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 5โ€™-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5โ€™-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 5โ€™-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: 0.34
  • 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 ยตM/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 221.01 34.57 112 3073 97555 50504384
Bone marrow failure 116.69 34.57 49 3136 27575 50574364
Capillary leak syndrome 93.04 34.57 22 3163 1868 50600071
Multiple organ dysfunction syndrome 85.95 34.57 48 3137 50289 50551650
Mucosal inflammation 78.83 34.57 42 3143 40100 50561839
Haematotoxicity 73.55 34.57 25 3160 7870 50594069
Staphylococcal bacteraemia 68.11 34.57 21 3164 4856 50597083
Septic shock 57.74 34.57 39 3146 57136 50544803
Palmar-plantar erythrodysaesthesia syndrome 57.01 34.57 27 3158 20071 50581868
Blood bilirubin increased 53.14 34.57 30 3155 32008 50569931
Pyrexia 51.18 34.57 88 3097 380115 50221824
Pancytopenia 50.53 34.57 42 3143 83988 50517951
Hyperbilirubinaemia 47.23 34.57 19 3166 9551 50592388
Transaminases increased 45.99 34.57 26 3159 27798 50574141
Blood culture positive 45.50 34.57 15 3170 4293 50597646
Leukaemia recurrent 43.41 34.57 11 3174 1243 50600696
Neutropenia 41.92 34.57 49 3136 147916 50454023
Staphylococcal sepsis 41.88 34.57 16 3169 7020 50594919
Graft versus host disease 36.62 34.57 14 3171 6152 50595787
Enterobacter bacteraemia 35.76 34.57 7 3178 241 50601698
Alanine aminotransferase increased 35.08 34.57 35 3150 88324 50513615
Aspartate aminotransferase increased 34.91 34.57 33 3152 77965 50523974

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 208.13 29.37 157 4421 112083 29457866
Haematotoxicity 118.40 29.37 43 4535 6656 29563293
Blood bilirubin increased 117.07 29.37 70 4508 33823 29536126
Capillary leak syndrome 99.96 29.37 28 4550 1871 29568078
Multiple organ dysfunction syndrome 98.53 29.37 80 4498 63036 29506913
Palmar-plantar erythrodysaesthesia syndrome 94.61 29.37 46 4532 14713 29555236
Oedema 93.69 29.37 65 4513 40418 29529531
Sepsis 84.71 29.37 107 4471 142575 29427374
Skin toxicity 77.18 29.37 27 4551 3744 29566205
Aplasia 75.21 29.37 27 4551 4036 29565913
Mucosal inflammation 73.69 29.37 51 4527 31544 29538405
Hepatotoxicity 69.78 29.37 40 4538 17827 29552122
Aspartate aminotransferase increased 69.40 29.37 64 4514 59661 29510288
Alanine aminotransferase increased 63.68 29.37 66 4512 70878 29499071
Neutropenia 58.65 29.37 86 4492 131625 29438324
Cystitis haemorrhagic 53.15 29.37 22 4556 4820 29565129
Bone marrow failure 49.63 29.37 38 4540 27411 29542538
Pancytopenia 48.60 29.37 62 4516 83106 29486843
Pneumonia fungal 46.22 29.37 21 4557 5756 29564193
Venoocclusive liver disease 45.62 29.37 22 4556 6895 29563054
Streptococcal sepsis 45.37 29.37 14 4564 1309 29568640
Adenovirus infection 41.47 29.37 18 4560 4429 29565520
Transaminases increased 40.14 29.37 31 4547 22631 29547318
Hyperbilirubinaemia 36.89 29.37 25 4553 14909 29555040
Acute lymphocytic leukaemia recurrent 36.56 29.37 14 4564 2502 29567447
Enterococcal bacteraemia 35.33 29.37 12 4566 1521 29568428
Nephropathy toxic 33.94 29.37 21 4557 10735 29559214
Tumour lysis syndrome 33.72 29.37 23 4555 13861 29556088
Staphylococcal infection 33.25 29.37 31 4547 29209 29540740
Venoocclusive disease 32.90 29.37 13 4565 2526 29567423
Pulmonary haemorrhage 31.55 29.37 19 4559 9251 29560698
Blood culture positive 31.52 29.37 15 4563 4562 29565387
Acute graft versus host disease in skin 31.25 29.37 15 4563 4649 29565300
Bacterial sepsis 31.13 29.37 15 4563 4688 29565261
Neutropenic colitis 30.03 29.37 12 4566 2399 29567550

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
Febrile neutropenia 344.61 28.34 227 6745 187430 64304330
Haematotoxicity 178.76 28.34 63 6909 12833 64478927
Blood bilirubin increased 162.58 28.34 92 6880 57461 64434299
Multiple organ dysfunction syndrome 162.34 28.34 113 6859 101300 64390460
Capillary leak syndrome 158.80 28.34 42 6930 3255 64488505
Palmar-plantar erythrodysaesthesia syndrome 132.83 28.34 64 6908 28755 64463005
Mucosal inflammation 127.26 28.34 81 6891 62503 64429257
Bone marrow failure 115.09 28.34 69 6903 47883 64443877
Aplasia 108.02 28.34 37 6935 6916 64484844
Oedema 103.49 28.34 83 6889 91852 64399908
Skin toxicity 94.31 28.34 33 6939 6569 64485191
Aspartate aminotransferase increased 90.16 28.34 86 6886 119702 64372058
Alanine aminotransferase increased 88.33 28.34 91 6881 138940 64352820
Sepsis 88.00 28.34 116 6856 230225 64261535
Neutropenia 84.40 28.34 116 6856 239508 64252252
Cystitis haemorrhagic 73.94 28.34 29 6943 7927 64483833
Transaminases increased 71.93 28.34 50 6922 44544 64447216
Pancytopenia 70.46 28.34 82 6890 143227 64348533
Hepatotoxicity 69.64 28.34 47 6925 39915 64451845
Hyperbilirubinaemia 65.52 28.34 36 6936 21169 64470591
Pyrexia 61.02 28.34 164 6808 558480 63933280
Pneumonia fungal 60.79 28.34 26 6946 8851 64482909
Blood culture positive 60.41 28.34 25 6947 7843 64483917
Venoocclusive liver disease 57.78 28.34 26 6946 9989 64481771
Fusarium infection 56.94 28.34 16 6956 1553 64490207
Toxic erythema of chemotherapy 55.95 28.34 11 6961 221 64491539
Adenovirus infection 55.53 28.34 23 6949 7232 64484528
Staphylococcal bacteraemia 53.81 28.34 25 6947 10330 64481430
Acute lymphocytic leukaemia recurrent 53.21 28.34 19 6953 4007 64487753
Acute myeloid leukaemia recurrent 51.90 28.34 17 6955 2767 64488993
Staphylococcal infection 51.18 28.34 43 6929 50635 64441125
Respiratory failure 50.68 28.34 74 6898 161109 64330651
Venoocclusive disease 49.64 28.34 18 6954 3967 64487793
Septic shock 49.57 28.34 59 6913 105378 64386382
Acute graft versus host disease in skin 43.41 28.34 19 6953 6836 64484924
Aspergillus infection 43 28.34 25 6947 16354 64475406
Graft versus host disease 41.42 28.34 23 6949 13790 64477970
Leukaemia recurrent 41.04 28.34 14 6958 2580 64489180
Fatigue 39.30 28.34 16 6956 748714 63743046
Bacterial sepsis 38.74 28.34 18 6954 7439 64484321
Tumour lysis syndrome 36.59 28.34 24 6948 19416 64472344
Enterococcal infection 35.96 28.34 21 6951 13845 64477915
Bronchopulmonary aspergillosis 34.56 28.34 23 6949 19062 64472698
Acute lymphocytic leukaemia 33.93 28.34 14 6958 4357 64487403
Nephropathy toxic 33.88 28.34 22 6950 17492 64474268
Enterococcal bacteraemia 33.78 28.34 12 6960 2493 64489267
Graft versus host disease in skin 31.21 28.34 14 6958 5333 64486427
Neutropenic colitis 29.99 28.34 13 6959 4568 64487192
Acute graft versus host disease 29.65 28.34 16 6956 9068 64482692

FDA Adverse Event Reporting System (Pediatric)

None

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 antineoplastic agents

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




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 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
Ribonucleoside-diphosphate reductase large subunit Enzyme INHIBITOR IC50 8.30 IUPHAR CHEMBL
DNA polymerase alpha catalytic subunit Enzyme INHIBITOR WOMBAT-PK CHEMBL
Ribonucleoside-diphosphate reductase subunit M2 Enzyme INHIBITOR IC50 8.30 IUPHAR CHEMBL
Uridine-cytidine kinase 1 Kinase WOMBAT-PK
cGMP-dependent 3',5'-cyclic phosphodiesterase Enzyme IC50 5.51 CHEMBL
Uridine-cytidine kinase 2 Kinase WOMBAT-PK
Ribose-phosphate pyrophosphokinase 1 Kinase WOMBAT-PK

External reference:

IDSource
4024904 VUID
N0000171589 NUI
D03546 KEGG_DRUG
44151 RXNORM
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
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 16729-431 INJECTION 1 mg INTRAVENOUS ANDA 27 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 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