CLOFARABINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C10H11ClFN5O3
Molecular Weight	303.677
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=NC(Cl)=NC2=C1N=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3F

InChI

InChIKey=WDDPHFBMKLOVOX-AYQXTPAHSA-N

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

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22840768
Curator's Comment: description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021673s024lbl.pdf

Clofarabine is a anti-cancer drug which was approved by FDA for the treatment of pediatric patients with relapsed or refractory acute lymphoblastic leukemia. After crossing the cell membrane the drug is rapidly metabolized by deoxycytidine kinase to diphosphate and triphosphate metabolites and these metabolites reversibly inhibit hRNR by binding to alpha subunit. Also the triphosphate is incorporated to DNA where it acts as a chain terminator.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 278 Target ID: CHEMBL2311221 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021673s024lbl.pdf	Binding Agent 1064
Ribonucleoside-diphosphate reductase RR1 14 Target ID: CHEMBL2095215 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021673s024lbl.pdf	Inhibitor 8297		17.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Relapsed or refractory acute lymphoblastic leukemia 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021673s024lbl.pdf	Primary		Approved 8429	CLOLAR Approved Use Clolar® (clofarabine) Injection is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. Launch Date 2004

C_max

Value	Dose	Co-administered	Analyte	Population
308 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28509593	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: CYTARABINE	CYTARABINE	CLOFARABINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1793 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28509593	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: CYTARABINE	CYTARABINE	CLOFARABINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
28 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29773602	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		CLOFARABINE blood	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
4.9 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28509593	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: CYTARABINE	CYTARABINE	CLOFARABINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.5 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29773602	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		CLOFARABINE blood	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
55 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 55 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 55 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	unhealthy, 42 years n = 4 Health Status: unhealthy Condition: acute leukemia Age Group: 42 years Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	Other AEs: Nausea, Diarrhea... Other AEs: Nausea (grade 1-2, 2 patients) Diarrhea (grade 1, 3 patients) Hepatotoxicity (grade 3, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/12637486
40 mg/m2 1 times / day multiple, intravenous MTD Dose: 40 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 40 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	unhealthy, 42 years n = 31 Health Status: unhealthy Condition: acute leukemia Age Group: 42 years Sex: M+F Population Size: 31 Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	Other AEs: Nausea, Fatigue... Other AEs: Nausea (grade 1-2, 3 patients) Fatigue (grade 3, 1 patient) Diarrhea (grade 1, 2 patients) Cramp (grade 1, 1 patient) Anorexia (grade 1, 1 patient) Mucositis (grade 1, 1 patient) Edema (grade 1, 1 patient) Hepatotoxicity (grade 3-4, 4 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/12637486
2 mg/m2 1 times / day multiple, intravenous MTD Dose: 2 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 2 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	unhealthy, 51 years n = 6 Health Status: unhealthy Condition: solid tumors Age Group: 51 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	DLT: Myelosuppression... Dose limiting toxicities: Myelosuppression (grade 3, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/12637486
6 mg 1 times / day multiple, oral Highest studied dose Dose: 6 mg, 1 times / day Route: oral Route: multiple Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24415560	unhealthy, 60-76 years n = 1 Health Status: unhealthy Condition: Acute Myeloid Leukemia Age Group: 60-76 years Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/24415560	Other AEs: Nausea, Hypoalbuminemia... Other AEs: Nausea (grade 1-2, 1 patient) Hypoalbuminemia (grade 1-2, 1 patient) Blood bilirubin decreased (grade 1-2, 1 patient) Lymphopenia (grade 3-4) Sources: https://pubmed.ncbi.nlm.nih.gov/24415560
70 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 70 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 70 mg/m2, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021673lbl.pdf	unhealthy, child n = 2 Health Status: unhealthy Condition: ALL Age Group: child Population Size: 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021673lbl.pdf	Other AEs: Hyperbilirubinemia, Vomiting... Other AEs: Hyperbilirubinemia (grade 4, 2 patients) Vomiting (grade 2-3, 2 patients) Maculopapular rash (grade 3, 2 patients) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021673lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP450 65

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP450 65	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-673_Clolar_biopharmr.PDF#page=18 Page: 18.0	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.pharmadoor.com.br/images/medicamentos/bulas/clolar_bula.pdf#page=30 Page: 30.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:681569	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:681569
MolPort	MolPort-005-941-711	https://www.molport.com/shop/molecule-link/MolPort-005-941-711
Selleck Chemicals	Clofarabine	http://www.selleckchem.com/products/Clofarabine.html
ZINC	ZINC000003798247	http://zinc15.docking.org/substances/ZINC000003798247
eMolecules	29256989	https://www.emolecules.com/cgi-bin/more?vid=29256989
eMolecules	30512527	https://www.emolecules.com/cgi-bin/more?vid=30512527

PubMed

Title	Date	PubMed
Nucleoside analogues in the treatment of haematological malignancies.	2001 Jun	11585009
Induction of complete remission using single agent clofarabine in a patient with primary refractory acute myeloblaste leukemia.	2003 Dec	14959859
Clofarabine. Bioenvision/ILEX.	2003 Dec	14763136
Gateways to clinical trials.	2003 Dec	14735233
Pharmacokinetics and pharmacodynamics of plasma clofarabine and cellular clofarabine triphosphate in patients with acute leukemias.	2003 Dec 15	14695132
Gateways to clinical trials.	2003 Jul-Aug	12949633
Gateways to clinical trials.	2003 Nov	14685303
Clofarabine.	2004	15230627
Prognostic factors and therapeutic options for relapsed or refractory acute myeloid leukemia.	2004 Aug	15339685
In vitro assessment of nucleoside analogs in multiple myeloma.	2004 Aug	15133625
Gateways to clinical trials.	2004 Jan-Feb	14988742
Purine nucleoside antimetabolites in development for the treatment of cancer.	2004 Jun	15242246
New nucleoside analogs in the treatment of hematological disorders.	2004 May-Jun	15481249
Clofarabine.	2005 May	15962525
The role of clofarabine in hematologic and solid malignancies--development of a next-generation nucleoside analog.	2005 May 15	15803490
New agents in the treatment of childhood leukemias and myelodysplastic syndromes.	2005 Nov	16221375
A comparison of the transportability, and its role in cytotoxicity, of clofarabine, cladribine, and fludarabine by recombinant human nucleoside transporters produced in three model expression systems.	2006 Jan	16234483
Gateways to clinical trials.	2006 Nov	17200730
Gateways to clinical trials.	2006 Oct	17136234
New directions in the treatment of mantle cell lymphoma: an overview.	2006 Oct	17101070
Discovery and development of clofarabine: a nucleoside analogue for treating cancer.	2006 Oct	17016426
Three new drugs for acute lymphoblastic leukemia: nelarabine, clofarabine, and forodesine.	2007 Dec	18086342
Clofarabine induced durable complete remission in heavily pretreated adolescents with relapsed and refractory leukemia.	2007 Sep	17805046
Treating refractory leukemias in childhood, role of clofarabine.	2008 Apr	18728851
Cytotoxic activities of nucleoside and nucleobase analog drugs in malignant mesothelioma: characterization of a novel nucleobase transport activity.	2008 May 15	18371936
Clofarabine combinations as acute myeloid leukemia salvage therapy.	2008 Oct 15	18756533
Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides.	2008 Sep	18765824
Enhancement of the in vivo antitumor activity of clofarabine by 1-beta-D-[4-thio-arabinofuranosyl]-cytosine.	2009 Jul	19002461

Patents

Sample Use Guides

In Vivo Use Guide

The recommended pediatric dose is 52 mg/m2 given as an intravenous infusion over 2 hours daily for 5 consecutive days of a 28-day cycle. Repeat cycles every 2-6 week.

Route of Administration: Intravenous

In Vitro Use Guide

HL-60 cells or HL/ara-C20 cells were incubated with different concentrations of clofarabine for 72 h. The 50%-growth-inhibitory concentration IC50 was 50 nM for HL60 and 320 nM for HL/ara-C20 cells.

Name

Type

Language

CLOFARABINE

Official Name

English

CLOFARABINE [VANDF]

Common Name

English

CLOFARABINE [MI]

Common Name

English

9H-PURIN-6-AMINE, 2-CHLORO-9-(2-DEOXY-2-FLUORO-.BETA.-D-ARABINOFURANOSYL)

Common Name

English

CLOLAR

Brand Name

English

clofarabine [INN]

Common Name

English

CLOFARABINE [ORANGE BOOK]

Common Name

English

Clofarabine [WHO-DD]

Common Name

English

NSC-759857

Code

English

CLOFARABINE [EMA EPAR]

Common Name

English

CLOFARABINE [USAN]

Common Name

English

CLOFARABINE [MART.]

Common Name

English

EVOLTRA

Brand Name

English

CLOFARABINE [JAN]

Common Name

English

2-CHLORO-9-(2-DEOXY-2-FLUORO-.BETA.-D-ARABINOFURANOSYL)-9H-PURIN-6-AMINE

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

668118