clofarabine 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
arabinofuranosyl derivatives	691	123318-82-1

Description:

Molecule	Description
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

Molecule

Description

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:

Property	Value	Reference
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

Approvals:

Date	Agency	Company	Orphan
Nov. 14, 2019	EMA	ORPHELIA PHARMA SAS
Dec. 28, 2004	FDA	GENZYME

FDA Adverse Event Reporting System (Female)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Febrile neutropenia	221.01	34.57	112	3073	97555	50504384
Bone marrow failure	116.69	34.57	49	3136	27575	50574364
Capillary leak syndrome	93.04	34.57	22	3163	1868	50600071
Multiple organ dysfunction syndrome	85.95	34.57	48	3137	50289	50551650
Mucosal inflammation	78.83	34.57	42	3143	40100	50561839
Haematotoxicity	73.55	34.57	25	3160	7870	50594069
Staphylococcal bacteraemia	68.11	34.57	21	3164	4856	50597083
Septic shock	57.74	34.57	39	3146	57136	50544803
Palmar-plantar erythrodysaesthesia syndrome	57.01	34.57	27	3158	20071	50581868
Blood bilirubin increased	53.14	34.57	30	3155	32008	50569931
Pyrexia	51.18	34.57	88	3097	380115	50221824
Pancytopenia	50.53	34.57	42	3143	83988	50517951
Hyperbilirubinaemia	47.23	34.57	19	3166	9551	50592388
Transaminases increased	45.99	34.57	26	3159	27798	50574141
Blood culture positive	45.50	34.57	15	3170	4293	50597646
Leukaemia recurrent	43.41	34.57	11	3174	1243	50600696
Neutropenia	41.92	34.57	49	3136	147916	50454023
Staphylococcal sepsis	41.88	34.57	16	3169	7020	50594919
Graft versus host disease	36.62	34.57	14	3171	6152	50595787
Enterobacter bacteraemia	35.76	34.57	7	3178	241	50601698
Alanine aminotransferase increased	35.08	34.57	35	3150	88324	50513615
Aspartate aminotransferase increased	34.91	34.57	33	3152	77965	50523974

FDA Adverse Event Reporting System (Male)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Febrile neutropenia	208.13	29.37	157	4421	112083	29457866
Haematotoxicity	118.40	29.37	43	4535	6656	29563293
Blood bilirubin increased	117.07	29.37	70	4508	33823	29536126
Capillary leak syndrome	99.96	29.37	28	4550	1871	29568078
Multiple organ dysfunction syndrome	98.53	29.37	80	4498	63036	29506913
Palmar-plantar erythrodysaesthesia syndrome	94.61	29.37	46	4532	14713	29555236
Oedema	93.69	29.37	65	4513	40418	29529531
Sepsis	84.71	29.37	107	4471	142575	29427374
Skin toxicity	77.18	29.37	27	4551	3744	29566205
Aplasia	75.21	29.37	27	4551	4036	29565913
Mucosal inflammation	73.69	29.37	51	4527	31544	29538405
Hepatotoxicity	69.78	29.37	40	4538	17827	29552122
Aspartate aminotransferase increased	69.40	29.37	64	4514	59661	29510288
Alanine aminotransferase increased	63.68	29.37	66	4512	70878	29499071
Neutropenia	58.65	29.37	86	4492	131625	29438324
Cystitis haemorrhagic	53.15	29.37	22	4556	4820	29565129
Bone marrow failure	49.63	29.37	38	4540	27411	29542538
Pancytopenia	48.60	29.37	62	4516	83106	29486843
Pneumonia fungal	46.22	29.37	21	4557	5756	29564193
Venoocclusive liver disease	45.62	29.37	22	4556	6895	29563054
Streptococcal sepsis	45.37	29.37	14	4564	1309	29568640
Adenovirus infection	41.47	29.37	18	4560	4429	29565520
Transaminases increased	40.14	29.37	31	4547	22631	29547318
Hyperbilirubinaemia	36.89	29.37	25	4553	14909	29555040
Acute lymphocytic leukaemia recurrent	36.56	29.37	14	4564	2502	29567447
Enterococcal bacteraemia	35.33	29.37	12	4566	1521	29568428
Nephropathy toxic	33.94	29.37	21	4557	10735	29559214
Tumour lysis syndrome	33.72	29.37	23	4555	13861	29556088
Staphylococcal infection	33.25	29.37	31	4547	29209	29540740
Venoocclusive disease	32.90	29.37	13	4565	2526	29567423
Pulmonary haemorrhage	31.55	29.37	19	4559	9251	29560698
Blood culture positive	31.52	29.37	15	4563	4562	29565387
Acute graft versus host disease in skin	31.25	29.37	15	4563	4649	29565300
Bacterial sepsis	31.13	29.37	15	4563	4688	29565261
Neutropenic colitis	30.03	29.37	12	4566	2399	29567550

FDA Adverse Event Reporting System (Geriatric)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Febrile neutropenia	344.61	28.34	227	6745	187430	64304330
Haematotoxicity	178.76	28.34	63	6909	12833	64478927
Blood bilirubin increased	162.58	28.34	92	6880	57461	64434299
Multiple organ dysfunction syndrome	162.34	28.34	113	6859	101300	64390460
Capillary leak syndrome	158.80	28.34	42	6930	3255	64488505
Palmar-plantar erythrodysaesthesia syndrome	132.83	28.34	64	6908	28755	64463005
Mucosal inflammation	127.26	28.34	81	6891	62503	64429257
Bone marrow failure	115.09	28.34	69	6903	47883	64443877
Aplasia	108.02	28.34	37	6935	6916	64484844
Oedema	103.49	28.34	83	6889	91852	64399908
Skin toxicity	94.31	28.34	33	6939	6569	64485191
Aspartate aminotransferase increased	90.16	28.34	86	6886	119702	64372058
Alanine aminotransferase increased	88.33	28.34	91	6881	138940	64352820
Sepsis	88.00	28.34	116	6856	230225	64261535
Neutropenia	84.40	28.34	116	6856	239508	64252252
Cystitis haemorrhagic	73.94	28.34	29	6943	7927	64483833
Transaminases increased	71.93	28.34	50	6922	44544	64447216
Pancytopenia	70.46	28.34	82	6890	143227	64348533
Hepatotoxicity	69.64	28.34	47	6925	39915	64451845
Hyperbilirubinaemia	65.52	28.34	36	6936	21169	64470591
Pyrexia	61.02	28.34	164	6808	558480	63933280
Pneumonia fungal	60.79	28.34	26	6946	8851	64482909
Blood culture positive	60.41	28.34	25	6947	7843	64483917
Venoocclusive liver disease	57.78	28.34	26	6946	9989	64481771
Fusarium infection	56.94	28.34	16	6956	1553	64490207
Toxic erythema of chemotherapy	55.95	28.34	11	6961	221	64491539
Adenovirus infection	55.53	28.34	23	6949	7232	64484528
Staphylococcal bacteraemia	53.81	28.34	25	6947	10330	64481430
Acute lymphocytic leukaemia recurrent	53.21	28.34	19	6953	4007	64487753
Acute myeloid leukaemia recurrent	51.90	28.34	17	6955	2767	64488993
Staphylococcal infection	51.18	28.34	43	6929	50635	64441125
Respiratory failure	50.68	28.34	74	6898	161109	64330651
Venoocclusive disease	49.64	28.34	18	6954	3967	64487793
Septic shock	49.57	28.34	59	6913	105378	64386382
Acute graft versus host disease in skin	43.41	28.34	19	6953	6836	64484924
Aspergillus infection	43	28.34	25	6947	16354	64475406
Graft versus host disease	41.42	28.34	23	6949	13790	64477970
Leukaemia recurrent	41.04	28.34	14	6958	2580	64489180
Fatigue	39.30	28.34	16	6956	748714	63743046
Bacterial sepsis	38.74	28.34	18	6954	7439	64484321
Tumour lysis syndrome	36.59	28.34	24	6948	19416	64472344
Enterococcal infection	35.96	28.34	21	6951	13845	64477915
Bronchopulmonary aspergillosis	34.56	28.34	23	6949	19062	64472698
Acute lymphocytic leukaemia	33.93	28.34	14	6958	4357	64487403
Nephropathy toxic	33.88	28.34	22	6950	17492	64474268
Enterococcal bacteraemia	33.78	28.34	12	6960	2493	64489267
Graft versus host disease in skin	31.21	28.34	14	6958	5333	64486427
Neutropenic colitis	29.99	28.34	13	6959	4568	64487192
Acute graft versus host disease	29.65	28.34	16	6956	9068	64482692

FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

Source	Code	Description
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 (View source of the data)

Disease	Relation	SNOMED_ID	DOID
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 level	Dissociation constant	Type (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:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Ribonucleoside-diphosphate reductase large subunit	Enzyme	P23921	RIR1_HUMAN	INHIBITOR	IC50	8.30	IUPHAR	CHEMBL
DNA polymerase alpha catalytic subunit	Enzyme	P09884	DPOLA_HUMAN	INHIBITOR			WOMBAT-PK	CHEMBL
Ribonucleoside-diphosphate reductase subunit M2	Enzyme	P31350	RIR2_HUMAN	INHIBITOR	IC50	8.30	IUPHAR	CHEMBL
Uridine-cytidine kinase 1	Kinase	Q9HA47	UCK1_HUMAN				WOMBAT-PK
cGMP-dependent 3',5'-cyclic phosphodiesterase	Enzyme	O00408	PDE2A_HUMAN		IC50	5.51	CHEMBL
Uridine-cytidine kinase 2	Kinase	Q9BZX2	UCK2_HUMAN				WOMBAT-PK
Ribose-phosphate pyrophosphokinase 1	Kinase	P60891	PRPS1_HUMAN				WOMBAT-PK

External reference:

ID	Source
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:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Clolar	HUMAN PRESCRIPTION DRUG LABEL	1	0024-5860	INJECTION	1 mg	INTRAVENOUS	NDA	29 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	23 sections
CLOFARABINE	HUMAN PRESCRIPTION DRUG LABEL	1	49315-003	INJECTION	1 mg	INTRAVENOUS	ANDA	1 sections
Clofarabine	HUMAN PRESCRIPTION DRUG LABEL	1	60505-6166	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	67457-546	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	24 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