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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{Infobox drug |
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| verifiedrevid = 460042726 |
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| Watchedfields = changed |
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| drug_name = |
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| verifiedrevid = 398778727 |
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| INN = |
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| IUPAC_name = 5-(6-amino-2-chloro-purin-9-yl) -4-fluoro-2- (hydroxymethyl)oxolan-3-ol |
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| type = <!-- empty --> |
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| image = Clofarabine.svg |
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| image = Clofarabine.svg |
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| width = |
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| alt = |
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| caption = |
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<!--Clinical data--> |
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<!-- Clinical data --> |
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| tradename = |
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| pronounce = |
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| tradename = Clolar, Evoltra |
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| Drugs.com = {{drugs.com|monograph|clofarabine}} |
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| Drugs.com = {{drugs.com|monograph|clofarabine}} |
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| MedlinePlus = a607012 |
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| MedlinePlus = a607012 |
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| DailyMedID = Clofarabine |
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| pregnancy_category = |
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| legal_status = |
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| licence_EU = yes |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| routes_of_administration = |
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| pregnancy_AU_comment = |
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| pregnancy_US = <!-- A / B / C / D / X / N --> |
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| pregnancy_US_comment = |
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| pregnancy_category= |
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| dependency_liability = |
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| addiction_liability = |
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| routes_of_administration = Intravenous |
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| class = |
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| ATCvet = |
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| ATC_prefix = L01 |
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| ATC_suffix = BB06 |
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| ATC_supplemental = |
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<!--Pharmacokinetic data--> |
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<!-- Legal status --> |
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| bioavailability = |
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| legal_AU = S4 |
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| protein_bound = |
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| legal_AU_comment = |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| metabolism = |
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| legal_BR_comment = |
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| elimination_half-life = |
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| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_CA_comment = |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> |
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| legal_UK_comment = |
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| legal_US = Rx-only |
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| legal_US_comment = <ref>{{cite web | title=Clolar- clofarabine injection | website=DailyMed | date=31 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=55d3c78b-dca5-436b-97b5-73d166217415 | access-date=27 September 2020}}</ref> |
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| legal_EU = Rx-only |
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| legal_EU_comment = <ref name="Evoltra EPAR">{{cite web | title=Evoltra EPAR | website=] (EMA) | date=6 March 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/evoltra | access-date=27 September 2020}}</ref> |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = Rx-only |
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<!--Identifiers--> |
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<!-- Pharmacokinetic data --> |
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| bioavailability = |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| protein_bound = |
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| metabolism = |
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| metabolites = |
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| onset = |
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| elimination_half-life = |
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| duration_of_action = |
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| excretion = |
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<!-- Identifiers --> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 123318-82-1 |
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| CAS_number = 123318-82-1 |
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| ATC_prefix = L01 |
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| CAS_supplemental = |
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| ATC_suffix = BB06 |
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| ATC_supplemental = |
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| PubChem = 119182 |
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| PubChem = 119182 |
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| IUPHAR_ligand = 6802 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB00631 |
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| DrugBank = DB00631 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 762RDY0Y2H |
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| UNII = 762RDY0Y2H |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D03546 |
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| KEGG = D03546 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 681569 |
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| ChEBI = 681569 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 1750 |
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| ChEMBL = 1750 |
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| NIAID_ChemDB = |
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| PDB_ligand = |
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| synonyms = |
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<!--Chemical data--> |
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<!-- Chemical and physical data --> |
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| IUPAC_name = 5-(6-amino-2-chloro-purin-9-yl) -4-fluoro-2- (hydroxymethyl)oxolan-3-ol |
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| C=10 | H=11 | Cl=1 | F=1 | N=5 | O=3 |
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| C=10 | H=11 | Cl=1 | F=1 | N=5 | O=3 |
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| molecular_weight = 303.677 g/mol |
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| smiles = Clc1nc(c2ncn(c2n1)3O((O)3F)CO)N |
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| SMILES = Clc1nc(c2ncn(c2n1)3O((O)3F)CO)N |
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| InChI = 1/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 |
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| InChIKey = WDDPHFBMKLOVOX-AYQXTPAHBH |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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 |
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| StdInChI = 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 |
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| StdInChI_comment = |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = WDDPHFBMKLOVOX-AYQXTPAHSA-N |
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| StdInChIKey = WDDPHFBMKLOVOX-AYQXTPAHSA-N |
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| density = |
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| density_notes = |
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| solubility = |
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}} |
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}} |
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'''Clofarabine''' is a ] ] ] marketed in the ] and ] as '''Clolar'''. In ] and ]/] the product is marketed under the name '''Evoltra'''. It is FDA-approved for treating a type of ] called relapsed or refractory ] (ALL) in children, after at least two other types of treatment have failed. It is not known if it extends life expectancy. Some investigations of effectiveness in cases of ] (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy, if any, for managing other cancers. |
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'''Clofarabine''' is a ] ] ] marketed in the United States and Canada as '''Clolar'''. In Europe and Australia/New Zealand the product is marketed under the name '''Evoltra'''. It is FDA-approved for treating relapsed or refractory ] (ALL) in children after at least two other types of treatment have failed. Some investigations of effectiveness in cases of ] (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy for managing other cancers. |
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==Approval== |
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Clolar was ] (FDA) approved 28 December 2004. (Under accelerated approval regulations requiring further clinical studies.) |
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==Side effects== |
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==Side effects== |
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* ] (TLS). Clofarabine quickly kills leukaemia cells in the blood. The body may react to this. Signs include hyperkalemia, hyperuricemia, and hyperphosphatemia. TLS is very serious and can lead to death if it is not treated right away. |
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* ] (TLS). Clofarabine quickly kills leukaemia cells in the blood. The body may react to this. Signs include hyperkalemia, hyperuricemia, and hyperphosphatemia. TLS is very serious and can lead to death if it is not treated right away. |
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* Systemic Inflammatory Response Syndrome (SIRS): Symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs. |
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* Systemic inflammatory response syndrome (SIRS): symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs. |
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*Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enough ], ], and ]. Serious side effects that can happen because of bone marrow suppression include severe infection (]), bleeding, and ]. |
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*Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enough ], ], and ]. Serious side effects that can happen because of bone marrow suppression include severe infection (]), bleeding, and ]. |
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*Effects on ] and ]. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby. |
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*Effects on ] and ]. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby. |
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*] and ]. Clofarabine can cause ]ing and ] which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased ]. |
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*] and ]. Clofarabine can cause ] and ] which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased ]. |
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*Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and ]), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count, ], and infection. Clofarabine can also cause ] and can affect the ] and ]. |
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*Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and ]), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count, ], and infection). Clofarabine can also cause ] and can affect the ] and ]. |
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==Contraindications== |
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==Contraindications== |
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==Delivery== |
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==Delivery== |
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*By ]. |
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*By ]. |
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*Dosage is a 2 hour infusion (52 mg/m²) every day for five days. The cycle is repeated every 2 to 6 weeks. |
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*Dosage is a 2-hour infusion (52 mg/m<sup>2</sup>) every day for five days. The cycle is repeated every 2 to 6 weeks. |
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*Regular blood tests to monitor his or her blood cells, kidney function, and liver function. |
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*Regular blood tests to monitor his or her blood cells, kidney function, and liver function. |
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==Biology== |
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==Results of clinical trials== |
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Efficacy and safety were demonstrated in a single multi-center trial that enrolled 40 patients aged 2-19. The patients were suffering with relapsed or refractory acute lymphoblastic leukaemia (ALL) (An additional 9 patients suffering with ] (AML) had similar ] but are not included in the figure below.) Most patients had received 2 to 4 prior regimens and 15/49 (31%) had undergone at least one ]. The median age was 12 years. Clofarabine was given at a dose of 52 mg/m<sup>2</sup>, intravenously, over 2 hours daily x 5 repeated every 2 to 6 weeks following recovery or return to baseline organ function. The study endpoints were the rate of complete response (CR) and the rate of complete response without platelet recovery (CRp). The former was defined as no evidence of circulating ]s or extramedullary disease, an M1 ], and recovery of peripheral platelet and absolute ] counts; the latter was defined as meeting all criteria for CR except for platelet count recovery. Response rates were determined by an Independent Response Review Panel (IRRP). |
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Clofarabine is a second-generation purine nucleoside analog designed to overcome biological limitations observed with ara-A and fludarabine. A 2´(S)-fluorine in clofarabine significantly increased the stability of the glycosidic bond in acidic solution and toward phosphorolytic cleavage as compared to fludarabine.<ref name=" Parker 2003">{{cite journal |vauthors=Parker WB, Allan PW, Hassan AE, Secrist JA 3rd, Sorscher EJ, Waud WR | title =Antitumor activity of 2-fluoror-2'deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase | journal = Cancer Gene Ther | volume = 10 | issue = 1 | pages = 23–29 | date=Jan 2003 | pmid = 12489025 | doi = 10.1038/sj.cgt.7700520 | s2cid =35923404 | doi-access = free }}</ref> A chlorine substitution at the 2-position of the adenine base avoids production of a 2-fluoroadenine analog, a precursor to the toxic 2-fluoro-adenosine-5´-triphosphate and prevents deamination of the base as compared to ara-A.<ref name=" Bonate 2006">{{cite journal |vauthors=Bonate PL, Arthaud L, Cantrell WR Jr, Stephenson K, Secrist JA 3rd, Weitman S | title = Discovery and development of clofarabine: a nucleoside analogue for treating cancer | journal = Nat Rev Drug Discov | volume = 5 | issue = 10 | pages = 855–63 | date=Feb 2014 | pmid = 17016426 | doi = 10.1038/nrd2055 | s2cid = 21361350 }}</ref> |
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Six patients (12%) achieved a CR and 4 patients (8%) achieved a CRp, and 5 patients (10%) achieved a PR. Of the 15 responding patients, 6 had post-clofarabine bone marrow transplantation. Hence, response durations could not be determined. In the patients who were not transplanted, the response durations for CR were 43, 50, 82, 93+, and 160+ days; for CRp the response duration was 32 days. |
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Clofarabine can be administered intravenously or given orally. Clofarabine enters cells via hENT1, hENT2, and hCNT2, where upon it is phosphorylated by deoxycytidine kinase to generate clofarabine-5´-monophosphate. The rate-limiting step in clofarabine metabolism is clofarabine-5´-diphosphosphate. Clofarabine-5´-triphosphate is the active-metabolite, and it inhibits ], resulting in a decrease cellular dNTP concentrations, which promotes greater incorporation of clofarabine-5´-triphosphate during DNA synthesis. Embedded clofarabine-5´-monophosphate in the DNA promotes polymerase arrest at the replication fork, triggering DNA repair mechanisms that without repair lead to DNA strand breaks in vitro and cytochrome c-mediated apoptosis in vitro. Studies using cell lines have shown that clofarabine-5´-triphosphate can also be incorporated into RNA.<ref name=" Shelton 2016">{{cite journal |vauthors=Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF | title = Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs | journal = Chem Rev | volume = 116 | issue = 23 | pages = 14379–14455 |date=Dec 2016 | pmid = 27960273 | doi = 10.1021/acs.chemrev.6b00209 | pmc = 7717319 }}</ref> |
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The principal clofarabine toxicities were nausea, vomiting, hematologic toxicity, ], ], infections and renal toxicity. Clofarabine can produce ]/] (SIRS), manifested by the rapid development of ], tachycardia, ], shock, and multi-organ failure. Cardiac toxicity was characterized as ] ]; tachycardia may also occur. |
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Mechanisms of resistance and turnover have been reported. Clofarabine-resistance arises from decreased deoxycytidine kinase activity in vitro.<ref name=" Lotfi 1999">{{cite journal |vauthors=Lotfi K, Månsson E, Spasokoukotskaja T, Pettersson B, Liliemark J, Peterson C, Eriksson S, Albertioni F | title = Biochemical pharmacology and resistance to 2-chloro-2'-arabino-fluoro-2'deoxyadenosine, a novel analogue of cladribine in human leukemic cells | journal = Clin Cancer Res | volume = 5 | issue = 9 | pages = 2438–44 | date=1999 | pmid = 10499616 }}</ref> ABC transporter ABCG2 promotes export of clofarabine-5´-monophosphate and thus limits the cytotoxic effects of this analog in vivo.<ref name=" Nagai 2011">{{cite journal |vauthors=Nagai S, Takenaka K, Nachagari D, Rose C, Domoney K, Sun D, Sparreboom A, Schuetz JD | title = Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity | journal = Cancer Res | volume = 75 | issue = 1 | pages = 1781–91 | date= Mar 2011 | pmid = 21245102 | doi = 10.1158/0008-5472.CAN-10-1919 | pmc=3531552}}</ref> Biochemically, clofarabine-5’-triphosphate was shown to be substrate for SAMHD1, thus potentially limiting the amount of active compound in cells.<ref name=" Arnold 2015">{{cite journal |vauthors=Arnold LH, Kunzelmann S, Webb MR, Taylor IA | title = A continuous enzyme-coupled assay for triphosphohydrolase activity of HIV-1 restriction factor SAMHD1 | journal = Antimicrob Agents Chemother | volume = 59 | issue = 1 | pages = 186–92 | date=Jan 2015 | pmid = 25331707| doi = 10.1128/AAC.03903-14 | pmc=4291348}}</ref> |
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==Approval== |
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Clolar was ] (FDA) Approved 28 December 2004. (Under accelerated approval regulations requiring further clinical studies.) |
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==References== |
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{{reflist}} |
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== External links == |
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* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/clofarabine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Clofarabine }} |
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==External links== |
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{{Chemotherapeutic agents}} |
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{{Chemotherapeutic agents}} |
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{{Portal bar | Medicine}} |
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