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Identification
NameClofarabine
Accession NumberDB00631  (APRD00878, DB07554)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Clofarabine is a purine nucleoside antimetabolite that is being studied in the treatment of cancer. It is marketed in the U.S. and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra.

Clofarabine is used in paediatrics to treat a type of leukaemia called relapsed or refractory acute lymphoblastic leukaemia (ALL), only after at least two other types of treatment have failed. It is not known if the drug extends life expectancy. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out.

Structure
Thumb
Synonyms
SynonymLanguageCode
(2R,3R,4S,5R)-5-(6-amino-2-Chloropurin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-olNot AvailableNot Available
2-chloro-9-(2-Deoxy-2-fluoro-beta-D-arabinofuranosyl)adenineNot AvailableNot Available
2-chloro-9-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)adenineNot AvailableNot Available
CAFdANot AvailableNot Available
CL-F-Ara-aNot AvailableNot Available
ClofarabinGermanINN
ClofarabinaSpanishINN
ClofarabineFrenchINN
ClofarabinumLatinINN
ClofarexNot AvailableIS
ClolarNot AvailableIS
SaltsNot Available
Brand names
NameCompany
ClofazicRaffo
ClolarGenzyme
EvoltraGenzyme
Brand mixturesNot Available
Categories
CAS number123318-82-1
WeightAverage: 303.677
Monoisotopic: 303.053445155
Chemical FormulaC10H11ClFN5O3
InChI KeyWDDPHFBMKLOVOX-AYQXTPAHSA-N
InChI
InChI=1S/C10H11ClFN5O3/c11-10-15-7(13)5-8(16-10)17(2-14-5)9-4(12)6(19)3(1-18)20-9/h2-4,6,9,18-19H,1H2,(H2,13,15,16)/t3-,4+,6-,9-/m1/s1
IUPAC Name
(2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol
SMILES
[H][C@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C=NC2=C(N)N=C(Cl)N=C12
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassCarbohydrates and Carbohydrate Conjugates
SubclassGlycosyl Compounds
Direct parentPurine 2'-deoxyribonucleosides and Analogues
Alternative parentsPentoses; Purines and Purine Derivatives; Halopyrimidines; Aminopyrimidines and Derivatives; N-substituted Imidazoles; Aryl Chlorides; Primary Aromatic Amines; Tetrahydrofurans; Oxolanes; Fluorohydrins; Secondary Alcohols; Primary Alcohols; Polyamines; Ethers; Organofluorides; Organochlorides; Alkyl Fluorides
Substituentspentose monosaccharide; purine; imidazopyrimidine; aminopyrimidine; halopyrimidine; aryl halide; primary aromatic amine; aryl chloride; pyrimidine; monosaccharide; n-substituted imidazole; tetrahydrofuran; imidazole; oxolane; azole; secondary alcohol; halohydrin; fluorohydrin; primary alcohol; ether; polyamine; organochloride; organofluoride; amine; organohalogen; primary amine; alcohol; organonitrogen compound; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the purine 2'-deoxyribonucleosides and analogues. These are compounds consisting of a purine linked to a ribose which lacks an hydroxyl group at position 2.
Pharmacology
IndicationFor the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use.
PharmacodynamicsClofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells.
Mechanism of actionClofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. 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.
AbsorptionNot Available
Volume of distribution
  • 172 L/m2
Protein binding47% bound to plasma proteins, predominantly to albumin.
Metabolism

Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine.

SubstrateEnzymesProduct
Clofarabine
clofarabind-5'-monophosphateDetails
Route of eliminationBased on 24-hour urine collections in the pediatric studies, 49 - 60% of the dose is excreted in the urine unchanged.
Half lifeThe terminal half-life is estimated to be 5.2 hours.
Clearance
  • 28.8 L/h/m2 [Pediatric patients (2 – 19 years old) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) receiving 52 mg/m2 dose]
ToxicityThere were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9827
Caco-2 permeable - 0.7369
P-glycoprotein substrate Non-substrate 0.8001
P-glycoprotein inhibitor I Non-inhibitor 0.9382
P-glycoprotein inhibitor II Non-inhibitor 0.8279
Renal organic cation transporter Non-inhibitor 0.9144
CYP450 2C9 substrate Non-substrate 0.9031
CYP450 2D6 substrate Non-substrate 0.8291
CYP450 3A4 substrate Non-substrate 0.5681
CYP450 1A2 substrate Non-inhibitor 0.817
CYP450 2C9 substrate Non-inhibitor 0.8462
CYP450 2D6 substrate Non-inhibitor 0.8849
CYP450 2C19 substrate Non-inhibitor 0.8391
CYP450 3A4 substrate Non-inhibitor 0.8499
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9002
Ames test Non AMES toxic 0.7338
Carcinogenicity Non-carcinogens 0.7723
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.2651 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9643
hERG inhibition (predictor II) Non-inhibitor 0.8304
Pharmacoeconomics
Manufacturers
  • Genzyme corp
Packagers
Dosage forms
FormRouteStrength
Injection, solutionIntravenous drip
Prices
Unit descriptionCostUnit
Clolar 20 mg/20 ml vial135.0USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States56611361998-07-142018-07-14
Canada21027822003-09-162012-05-07
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP0Not Available
Predicted Properties
PropertyValueSource
Water Solubility4.89ALOGPS
logP0.32ALOGPS
logP-0.29ChemAxon
logS-1.8ALOGPS
pKa (Strongest Acidic)12.71ChemAxon
pKa (Strongest Basic)1.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area119.31 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity67 m3·mol-1ChemAxon
Polarizability26.06 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  2. Harned TM, Gaynon PS: Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag. 2008 Apr;4(2):327-36. Pubmed
  3. Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. Pubmed
  4. Larson ML, Venugopal P: Clofarabine: a new treatment option for patients with acute myeloid leukemia. Expert Opin Pharmacother. 2009 Jun;10(8):1353-7. Pubmed
  5. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed
External Links
ResourceLink
PubChem Compound119182
PubChem Substance46504968
ChemSpider106472
ChEBI681569
ChEMBLCHEMBL1750
Therapeutic Targets DatabaseDAP000849
PharmGKBPA164754863
HETCFB
RxListhttp://www.rxlist.com/cgi/generic3/clofarabine.htm
Drugs.comhttp://www.drugs.com/cdi/clofarabine.html
WikipediaClofarabine
ATC CodesL01BB06
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(281 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
LeflunomideImmunosuppressants such as clofarabine may enhance the adverse/toxic effect of leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Consider eliminating the use of a leflunomide loading dose in patients who are receiving other immunosuppressants in order to reduce the risk for serious adverse events such as hematologic toxicity. Also, patients receiving both leflunomide and another immunosuppressive medication should be monitored for bone marrow suppression at least monthly throughout the duration of concurrent therapy.
NatalizumabImmunosuppressants such as clofarabine may enhance the adverse/toxic effect of natalizumab. Specifically, the risk of concurrent infection may be increased. Patients receiving natalizumab should not use concurrent immunosuppressants, and patients receiving chronic corticosteroids prior to natalizumab should be tapered off of steroids prior to starting natalizumab.
PimecrolimusPimecrolimus may enhance the adverse/toxic effect of immunosuppressants such as clofarabine. Avoid use of pimecrolimus cream in patients receiving immunosuppressants.
RoflumilastRoflumilast may enhance the immunosuppressive effect of Immunosuppressants. The Canadian roflumilast product monograph recommends avoiding concurrent use of roflumilast with any immunosuppressant medications due to the antiinflammatory/immune altering effects of roflumilast and the lack of relevant clinical experience with such use. Of note, this recommendation to avoid concurrent use does not apply to either inhaled corticosteroids (which have much more limited systemic immune-suppressing actions) or short-term systemic corticosteroid use. U.S. prescribing information does not contain this warning; but it appears prudent to avoid this combination when possible.
TacrolimusTacrolimus (topical) may enhance the adverse/toxic effect of immunosuppressants such as clofarabine. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions
  • Echinacea should be used with caution, if at all, in patients receiving therapeutic immunosuppressants. Monitor for reduced efficacy of the immunosuppressant during concomitant use.

Targets

1. DNA polymerase alpha catalytic subunit

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
DNA polymerase alpha catalytic subunit P09884 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  4. Clofarabine. Drugs R D. 2004;5(4):213-7. Pubmed
  5. Musto P, Ferrara F: Clofarabine: in search of combinations for the treatment of patients with high-risk acute myeloid leukemia. Cancer. 2008 Oct 15;113(8):1995-8. Pubmed
  6. Harned TM, Gaynon PS: Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag. 2008 Apr;4(2):327-36. Pubmed
  7. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. Pubmed
  8. Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. Pubmed
  9. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed

2. Ribonucleoside-diphosphate reductase large subunit

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Ribonucleoside-diphosphate reductase large subunit P23921 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  4. Clofarabine. Drugs R D. 2004;5(4):213-7. Pubmed
  5. Musto P, Ferrara F: Clofarabine: in search of combinations for the treatment of patients with high-risk acute myeloid leukemia. Cancer. 2008 Oct 15;113(8):1995-8. Pubmed
  6. Harned TM, Gaynon PS: Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag. 2008 Apr;4(2):327-36. Pubmed
  7. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. Pubmed
  8. Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. Pubmed
  9. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed

3. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: other/unknown

Components

Name UniProt ID Details

References:

  1. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  2. Harned TM, Gaynon PS: Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag. 2008 Apr;4(2):327-36. Pubmed

Enzymes

1. Deoxycytidine kinase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Deoxycytidine kinase P27707 Details

References:

  1. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  2. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed
  3. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. Pubmed

Transporters

1. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. de Wolf C, Jansen R, Yamaguchi H, de Haas M, van de Wetering K, Wijnholds J, Beijnen J, Borst P: Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides. Mol Cancer Ther. 2008 Sep;7(9):3092-102. Epub 2008 Sep 2. Pubmed

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11