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 229.76 33.76 115 3165 105430 56183357
Bone marrow failure 126.06 33.76 51 3229 28235 56260552
Capillary leak syndrome 93.86 33.76 22 3258 1944 56286843
Acute lymphocytic leukaemia 91.52 33.76 23 3257 2721 56286066
Multiple organ dysfunction syndrome 87.29 33.76 48 3232 52722 56236065
Mucosal inflammation 79.33 33.76 42 3238 42768 56246019
Haematotoxicity 73.97 33.76 25 3255 8358 56280429
Staphylococcal bacteraemia 68.34 33.76 21 3259 5188 56283599
Septic shock 58.26 33.76 39 3241 60796 56227991
Palmar-plantar erythrodysaesthesia syndrome 57.78 33.76 27 3253 21038 56267749
Blood bilirubin increased 54.17 33.76 30 3250 33324 56255463
Acute myeloid leukaemia 53.61 33.76 24 3256 16948 56271839
Pyrexia 52.53 33.76 90 3190 418683 55870104
Pancytopenia 51.37 33.76 42 3238 88673 56200114
Leukaemia recurrent 48.63 33.76 12 3268 1316 56287471
Hyperbilirubinaemia 47.41 33.76 19 3261 10216 56278571
Transaminases increased 47.05 33.76 26 3254 28744 56260043
Blood culture positive 46.51 33.76 15 3265 4331 56284456
Staphylococcal sepsis 42.40 33.76 16 3264 7333 56281454
Neutropenia 42.33 33.76 49 3231 158118 56130669
Acute myeloid leukaemia recurrent 37.32 33.76 10 3270 1518 56287269
Sepsis 36.86 33.76 43 3237 139797 56148990
Graft versus host disease 36.37 33.76 14 3266 6767 56282020
Enterobacter bacteraemia 35.81 33.76 7 3273 259 56288528
Alanine aminotransferase increased 35.63 33.76 35 3245 93627 56195160
Aspartate aminotransferase increased 35.47 33.76 33 3247 82569 56206218
Respiratory failure 35.20 33.76 35 3245 95027 56193760
Thrombocytopenia 34.43 33.76 41 3239 136183 56152604
Venoocclusive liver disease 34.37 33.76 12 3268 4409 56284378

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 211.49 28.24 161 4537 121688 31570958
Haematotoxicity 117.56 28.24 43 4655 7094 31685552
Blood bilirubin increased 117.54 28.24 70 4628 35066 31657580
Capillary leak syndrome 99.55 28.24 28 4670 1985 31690661
Multiple organ dysfunction syndrome 96.12 28.24 80 4618 68123 31624523
Palmar-plantar erythrodysaesthesia syndrome 94.41 28.24 46 4652 15437 31677209
Oedema 93.29 28.24 65 4633 42496 31650150
Sepsis 84.63 28.24 108 4590 151821 31540825
Acute lymphocytic leukaemia 80.26 28.24 27 4671 3479 31689167
Skin toxicity 75.74 28.24 27 4671 4132 31688514
Aplasia 75.46 28.24 27 4671 4176 31688470
Mucosal inflammation 71.73 28.24 51 4647 34376 31658270
Hepatotoxicity 71.53 28.24 41 4657 19085 31673561
Aspartate aminotransferase increased 69.09 28.24 64 4634 62655 31629991
Alanine aminotransferase increased 63.26 28.24 66 4632 74590 31618056
Neutropenia 60.20 28.24 88 4610 140276 31552370
Cystitis haemorrhagic 52.19 28.24 22 4676 5267 31687379
Acute lymphocytic leukaemia recurrent 51.80 28.24 19 4679 3151 31689495
Bone marrow failure 50.41 28.24 38 4660 27970 31664676
Pancytopenia 48.33 28.24 62 4636 87254 31605392
Streptococcal sepsis 45.72 28.24 14 4684 1333 31691313
Pneumonia fungal 45.26 28.24 21 4677 6308 31686338
Venoocclusive liver disease 45.08 28.24 22 4676 7390 31685256
Adenovirus infection 41.07 28.24 18 4680 4736 31687910
Acute myeloid leukaemia 39.64 28.24 28 4670 18644 31674002
Transaminases increased 39.37 28.24 31 4667 24310 31668336
Enterococcal bacteraemia 38.62 28.24 13 4685 1675 31690971
Hyperbilirubinaemia 36.67 28.24 25 4673 15725 31676921
Nephropathy toxic 33.73 28.24 21 4677 11332 31681314
Staphylococcal infection 33.17 28.24 31 4667 30601 31662045
Venoocclusive disease 32.80 28.24 13 4685 2659 31689987
Tumour lysis syndrome 32.48 28.24 23 4675 15362 31677284
Blood culture positive 32.08 28.24 15 4683 4583 31688063
Pulmonary haemorrhage 31.67 28.24 19 4679 9596 31683050
Bacterial sepsis 31.38 28.24 15 4683 4813 31687833
Acute graft versus host disease in skin 31.37 28.24 15 4683 4817 31687829
Graft versus host disease in liver 30.73 28.24 10 4688 1160 31691486
Neutropenic colitis 29.26 28.24 12 4686 2680 31689966
Respiratory failure 28.96 28.24 53 4645 101396 31591250

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 359.19 28.92 234 6893 204084 70717233
Haematotoxicity 179.64 28.92 63 7064 13611 70907706
Blood bilirubin increased 165.41 28.92 92 7035 59809 70861508
Multiple organ dysfunction syndrome 162.87 28.92 113 7014 108402 70812915
Capillary leak syndrome 159.80 28.92 42 7085 3420 70917897
Palmar-plantar erythrodysaesthesia syndrome 134.33 28.92 64 7063 30183 70891134
Acute lymphocytic leukaemia 131.62 28.92 40 7087 5505 70915812
Mucosal inflammation 126.68 28.92 81 7046 67769 70853548
Bone marrow failure 123.69 28.92 71 7056 48939 70872378
Aplasia 109.14 28.92 37 7090 7214 70914103
Oedema 100.11 28.92 83 7044 103498 70817819
Sepsis 93.93 28.92 119 7008 244426 70676891
Skin toxicity 93.87 28.92 33 7094 7165 70914152
Aspartate aminotransferase increased 91.24 28.92 86 7041 126892 70794425
Alanine aminotransferase increased 89.39 28.92 91 7036 147389 70773928
Neutropenia 87.66 28.92 118 7009 257038 70664279
Acute lymphocytic leukaemia recurrent 77.65 28.92 26 7101 4878 70916439
Cystitis haemorrhagic 73.83 28.92 29 7098 8564 70912753
Transaminases increased 72.83 28.92 50 7077 46968 70874349
Pancytopenia 71.79 28.92 82 7045 151025 70770292
Hepatotoxicity 71.04 28.92 48 7079 43938 70877379
Acute myeloid leukaemia 67.96 28.92 41 7086 30899 70890418
Hyperbilirubinaemia 65.88 28.92 36 7091 22532 70898785
Venoocclusive liver disease 64.45 28.92 28 7099 10650 70910667
Blood culture positive 62 28.92 25 7102 7901 70913416
Pyrexia 61.99 28.92 166 6961 606786 70314531
Pneumonia fungal 59.75 28.92 26 7101 9927 70911390
Fusarium infection 56.53 28.92 16 7111 1716 70919601
Toxic erythema of chemotherapy 55.85 28.92 11 7116 241 70921076
Adenovirus infection 55.63 28.92 23 7104 7745 70913572
Acute myeloid leukaemia recurrent 55.62 28.92 18 7109 3036 70918281
Staphylococcal bacteraemia 53.94 28.92 25 7102 11057 70910260
Respiratory failure 52.22 28.92 74 7053 168661 70752656
Staphylococcal infection 51.95 28.92 43 7084 53361 70867956
Septic shock 51.73 28.92 60 7067 112198 70809119
Venoocclusive disease 50.00 28.92 18 7109 4182 70917135
Leukaemia recurrent 49.09 28.92 16 7111 2759 70918558
Aspergillus infection 45.33 28.92 26 7101 17842 70903475
Acute graft versus host disease in skin 44.00 28.92 19 7108 7118 70914199
Graft versus host disease 41.19 28.92 23 7104 15000 70906317
Fatigue 40.84 28.92 16 7111 824303 70097014
Bacterial sepsis 39.56 28.92 18 7109 7629 70913688
Enterococcal bacteraemia 37.46 28.92 13 7114 2713 70918604
Enterococcal infection 36.41 28.92 21 7106 14561 70906756
Tumour lysis syndrome 36.12 28.92 24 7103 21336 70899981
Nephropathy toxic 34.24 28.92 22 7105 18492 70902825
Bronchopulmonary aspergillosis 34.08 28.92 23 7104 20979 70900338
Graft versus host disease in skin 31.50 28.92 14 7113 5616 70915701
Acute graft versus host disease 29.98 28.92 16 7111 9546 70911771
Neutropenic colitis 29.53 28.92 13 7114 5101 70916216
Acute lymphocytic leukaemia refractory 29.33 28.92 6 7121 160 70921157

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

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 30 sections
Clolar HUMAN PRESCRIPTION DRUG LABEL 1 0024-5860 INJECTION 1 mg INTRAVENOUS NDA 30 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 24 sections
Clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 43598-309 INJECTION 1 mg INTRAVENOUS ANDA 24 sections
CLOFARABINE HUMAN PRESCRIPTION DRUG LABEL 1 49315-003 INJECTION 1 mg INTRAVENOUS ANDA 1 sections
CLOFARABINE HUMAN PRESCRIPTION DRUG LABEL 1 49315-003 INJECTION 1 mg INTRAVENOUS ANDA 1 sections
CLOFARABINE Human Prescription Drug Label 1 55150-326 INJECTION 1 mg INTRAVENOUS ANDA 26 sections
Clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 60505-6166 INJECTION 1 mg INTRAVENOUS ANDA 27 sections
Clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 60505-6166 INJECTION 1 mg INTRAVENOUS ANDA 27 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 27 sections
clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 67457-546 INJECTION 1 mg INTRAVENOUS ANDA 27 sections
Clofarabine Human Prescription Drug Label 1 68083-386 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 25 sections
Clofarabine HUMAN PRESCRIPTION DRUG LABEL 1 70121-1236 INJECTION 1 mg INTRAVENOUS ANDA 25 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
CLOFARABINE HUMAN PRESCRIPTION DRUG LABEL 1 72266-108 INJECTION 1 mg INTRAVENOUS ANDA 26 sections