clofarabine 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | PK/Tox | Related Drugs | 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: 0.34
  • 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 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

Predicted pharmacokinetic/toxicological properties (PK-AZ):

PropertyDescriptionValueUnitConfidenceSimilarity
azlogd74 LogD at pH 7.4 0.385 High 1
caco2-efflux Caco-2 efflux ratio (BA/AB) 54.828 High 1
caco2-intrinsic-papp Caco-2 intrinsic apparent permeability 2.805 10^-6 cm/s High 1
dh-clint Dog hepatocyte intrinsic clearance 1.400 uL/min/10^6 cells High 1
dppb Dog plasma protein binding (% unbound) 79.920 % High 1
fcs-ppb Fetal calf serum protein binding (% unbound) 88.190 % High 1
herg hERG pIC50 3.859 pIC50 High 1
hh-clint Human hepatocyte intrinsic clearance 0.918 uL/min/10^6 cells High 1
hlm-clint Human liver microsomal intrinsic clearance 2.992 uL/min/mg protein High 1
hppb Human plasma protein binding (% unbound) 77.930 % High 1
kinase-safety-class ACVR2B,AURKA,AXL,BRAF,CAMK2B,CAMK2D,CDK1,CDK5,CDK9,CLK2,CLK4,DYRK1B,EIF2AK3,ERBB2,FLT3,GRK2,IRAK1,IRAK4,ITK,MAP3K21,MAPK7,NTRK1,NTRK2,PDK1,PDK2,PDK4,PIK3CD,PRKDC,SIK2,SIK3 30
kinase-selectivity-class CDK2,CDK3 2
mdck-mdr1-bcrp-efflux MDCK-MDR1-BCRP efflux ratio 5.272 High 1
mdck-mdr1-efflux MDCK-MDR1 efflux ratio 10.965 High 1
mh-clint Mouse hepatocyte intrinsic clearance 4.198 High 1
mppb Mouse plasma protein binding (% unbound) 80.760 High 1
nih-mdck-mdr1-efflux NIH MDCK-MDR1 efflux ratio 6.194 High 1
pfas-class PFAS structural alert (1 = True, 0 = False) 0
pld-class Phospholipidosis risk class (1 = positive, 0 = negative) 0 High 1
pppb Pig plasma protein binding (% unbound) 84.090 % High 1
rat-kpuu-brain Rat brain Kpuu 0.021 % High 1
rh-clint Rat hepatocyte intrinsic clearance 1.807 uL/min/10^6 cells High 1
rh-fuinc Rat hepatocyte fraction unbound in incubation 94.840 % High 1
rppb Rat plasma protein binding (% unbound) 74.520 % High 1
solubility-dd Solubility at pH 7.4 in DMSO 924.698 uM High 1

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 190.11 42.20 92 2528 158257 90467570
Bone marrow failure 126.92 42.20 44 2576 32177 90593650
Mucosal inflammation 95.53 42.20 42 2578 57583 90568244
Capillary leak syndrome 90.59 42.20 20 2600 2747 90623080
Multiple organ dysfunction syndrome 82.57 42.20 40 2580 68296 90557531
Haematotoxicity 77.10 42.20 24 2596 12511 90613316
Septic shock 69.12 42.20 38 2582 84122 90541705
Staphylococcal bacteraemia 61.89 42.20 18 2602 7451 90618376
Pyrexia 61.86 42.20 85 2535 660400 89965427
Blood bilirubin increased 60.30 42.20 28 2592 43442 90582385
Graft versus host disease 56.04 42.20 17 2603 8127 90617700
Palmar-plantar erythrodysaesthesia syndrome 51.53 42.20 22 2598 28001 90597826
Staphylococcal sepsis 49.56 42.20 16 2604 9367 90616460
Leukaemia recurrent 44.69 42.20 10 2610 1457 90624370
Pancytopenia 42.66 42.20 32 2588 120231 90505596

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 158.82 33.27 137 4062 185566 42431570
Blood bilirubin increased 121.01 33.27 66 4133 42186 42574950
Haematotoxicity 120.33 33.27 44 4155 10941 42606195
Oedema 100.62 33.27 63 4136 51938 42565198
Mucosal inflammation 98.51 33.27 61 4138 49313 42567823
Capillary leak syndrome 88.85 33.27 25 4174 2682 42614454
Palmar-plantar erythrodysaesthesia syndrome 87.51 33.27 42 4157 20540 42596596
Graft versus host disease in liver 81.44 33.27 21 4178 1618 42615518
Cytomegalovirus infection reactivation 80.43 33.27 33 4166 11145 42605991
Skin toxicity 74.55 33.27 27 4172 6522 42610614
Aplasia 74.52 33.27 25 4174 4818 42612318
Graft versus host disease in gastrointestinal tract 73.05 33.27 25 4174 5118 42612018
Multiple organ dysfunction syndrome 71.46 33.27 66 4133 96969 42520167
Aspartate aminotransferase increased 63.71 33.27 56 4143 77107 42540029
Hepatotoxicity 62.93 33.27 36 4163 25131 42592005
Alanine aminotransferase increased 62.89 33.27 59 4140 88347 42528789
Adenovirus infection 59.03 33.27 23 4176 6786 42610350
Epstein-Barr virus infection reactivation 54.44 33.27 17 4182 2610 42614526
Cystitis haemorrhagic 53.94 33.27 22 4177 7307 42609829
Graft versus host disease in skin 53.80 33.27 20 4179 5192 42611944
Hypogammaglobulinaemia 52.75 33.27 25 4174 11866 42605270
Sepsis 46.87 33.27 76 4123 199258 42417878
Streptococcal sepsis 46.41 33.27 14 4185 1914 42615222
Venoocclusive liver disease 43.69 33.27 21 4178 10281 42606855
Acute graft versus host disease in skin 43.66 33.27 19 4180 7405 42609731
Acute graft versus host disease 41.81 33.27 19 4180 8196 42608940
Bacterial sepsis 39.46 33.27 17 4182 6465 42610671
Pancytopenia 39.33 33.27 53 4146 117690 42499446
Staphylococcal infection 38.62 33.27 31 4168 37612 42579524
Nephropathy toxic 36.58 33.27 22 4177 16816 42600320
Neutropenia 36.35 33.27 68 4131 199363 42417773
Pneumonia fungal 33.87 33.27 17 4182 9129 42608007

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 331.43 34.55 213 6165 316554 110266367
Blood bilirubin increased 180.93 34.55 88 6290 75884 110507037
Haematotoxicity 179.34 34.55 61 6317 21021 110561900
Mucosal inflammation 178.22 34.55 94 6284 96047 110486874
Capillary leak syndrome 153.50 34.55 39 6339 4869 110578052
Multiple organ dysfunction syndrome 145.72 34.55 97 6281 151613 110431308
Palmar-plantar erythrodysaesthesia syndrome 130.17 34.55 58 6320 40967 110541954
Bone marrow failure 125.73 34.55 63 6315 57785 110525136
Aplasia 108.98 34.55 33 6345 7840 110575081
Skin toxicity 95.90 34.55 33 6345 11750 110571171
Alanine aminotransferase increased 92.68 34.55 80 6298 183693 110399228
Cytomegalovirus infection reactivation 92.15 34.55 36 6342 18297 110564624
Aspartate aminotransferase increased 89.64 34.55 74 6304 159862 110423059
Oedema 83.51 34.55 80 6298 209896 110373025
Adenovirus infection 82.56 34.55 29 6349 10965 110571956
Pyrexia 82.53 34.55 168 6210 898097 109684824
Sepsis 76.22 34.55 94 6284 327252 110255669
Cystitis haemorrhagic 75.89 34.55 28 6350 12181 110570740
Fusarium infection 71.97 34.55 19 6359 2752 110580169
Pancytopenia 70.65 34.55 73 6305 209540 110373381
Venoocclusive liver disease 69.91 34.55 28 6350 15179 110567742
Neutropenia 69.22 34.55 96 6282 374524 110208397
Hepatotoxicity 66.76 34.55 43 6335 63357 110519564
Transaminases increased 64.31 34.55 42 6336 63348 110519573
Graft versus host disease 60.93 34.55 27 6351 18779 110564142
Pneumonia fungal 57.04 34.55 24 6354 14730 110568191
Septic shock 56.94 34.55 57 6321 157471 110425450
Toxic erythema of chemotherapy 56.55 34.55 11 6367 401 110582520
Acute lymphocytic leukaemia recurrent 54.14 34.55 18 6360 5769 110577152
Acute graft versus host disease in skin 53.65 34.55 21 6357 10719 110572202
Staphylococcal infection 53.62 34.55 39 6339 69905 110513016
Hyperbilirubinaemia 51.16 34.55 28 6350 30643 110552278
Bacterial sepsis 50.72 34.55 20 6358 10406 110572515
Blood culture positive 50.00 34.55 19 6359 8957 110573964
Graft versus host disease in skin 47.89 34.55 18 6360 8236 110574685
Staphylococcal bacteraemia 47.84 34.55 22 6356 16666 110566255
Graft versus host disease in liver 45.86 34.55 13 6365 2452 110580469
Venoocclusive disease 44.82 34.55 16 6362 6334 110576587
Respiratory failure 43.97 34.55 58 6320 215274 110367647
Enterococcal infection 43.67 34.55 22 6356 20344 110562577
Graft versus host disease in gastrointestinal tract 42.91 34.55 17 6361 8951 110573970
Nephropathy toxic 40.15 34.55 23 6355 27455 110555466
Leukaemia recurrent 38.55 34.55 12 6366 3119 110579802
Fatigue 37.21 34.55 12 6366 1215946 109366975
Acute graft versus host disease 36.98 34.55 17 6361 12864 110570057
Acute myeloid leukaemia recurrent 36.46 34.55 13 6365 5126 110577795
Aspergillus infection 36.25 34.55 21 6357 25595 110557326

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
MeSH PA D000963 Antimetabolites
MeSH PA D000964 Antimetabolites, Antineoplastic
MeSH PA D000970 Antineoplastic Agents
FDA EPC N0000175595 Nucleoside Metabolic Inhibitor
CHEBI has role CHEBI:35221 antimetabolite
CHEBI has role CHEBI:35610 antineoplastic agent

Related Drugs by ATC class:

L01BB Purine analogues 5 drugs
cladribinefludarabine phosphatemercaptopurinenelarabinethioguanine

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




🐶 Veterinary Drug Use

None

🐶 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
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
4024904 VANDF

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
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 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 63323-572 INJECTION 1 mg INTRAVENOUS ANDA 24 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 71288-128 INJECTION 1 mg INTRAVENOUS ANDA 26 sections
CLOFARABINE HUMAN PRESCRIPTION DRUG LABEL 1 72266-108 INJECTION 1 mg INTRAVENOUS ANDA 26 sections