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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	229.76	33.76	115	3165	105430	56183357
Bone marrow failure	126.06	33.76	51	3229	28235	56260552
Capillary leak syndrome	93.86	33.76	22	3258	1944	56286843
Acute lymphocytic leukaemia	91.52	33.76	23	3257	2721	56286066
Multiple organ dysfunction syndrome	87.29	33.76	48	3232	52722	56236065
Mucosal inflammation	79.33	33.76	42	3238	42768	56246019
Haematotoxicity	73.97	33.76	25	3255	8358	56280429
Staphylococcal bacteraemia	68.34	33.76	21	3259	5188	56283599
Septic shock	58.26	33.76	39	3241	60796	56227991
Palmar-plantar erythrodysaesthesia syndrome	57.78	33.76	27	3253	21038	56267749
Blood bilirubin increased	54.17	33.76	30	3250	33324	56255463
Acute myeloid leukaemia	53.61	33.76	24	3256	16948	56271839
Pyrexia	52.53	33.76	90	3190	418683	55870104
Pancytopenia	51.37	33.76	42	3238	88673	56200114
Leukaemia recurrent	48.63	33.76	12	3268	1316	56287471
Hyperbilirubinaemia	47.41	33.76	19	3261	10216	56278571
Transaminases increased	47.05	33.76	26	3254	28744	56260043
Blood culture positive	46.51	33.76	15	3265	4331	56284456
Staphylococcal sepsis	42.40	33.76	16	3264	7333	56281454
Neutropenia	42.33	33.76	49	3231	158118	56130669
Acute myeloid leukaemia recurrent	37.32	33.76	10	3270	1518	56287269
Sepsis	36.86	33.76	43	3237	139797	56148990
Graft versus host disease	36.37	33.76	14	3266	6767	56282020
Enterobacter bacteraemia	35.81	33.76	7	3273	259	56288528
Alanine aminotransferase increased	35.63	33.76	35	3245	93627	56195160
Aspartate aminotransferase increased	35.47	33.76	33	3247	82569	56206218
Respiratory failure	35.20	33.76	35	3245	95027	56193760
Thrombocytopenia	34.43	33.76	41	3239	136183	56152604
Venoocclusive liver disease	34.37	33.76	12	3268	4409	56284378

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	211.49	28.24	161	4537	121688	31570958
Haematotoxicity	117.56	28.24	43	4655	7094	31685552
Blood bilirubin increased	117.54	28.24	70	4628	35066	31657580
Capillary leak syndrome	99.55	28.24	28	4670	1985	31690661
Multiple organ dysfunction syndrome	96.12	28.24	80	4618	68123	31624523
Palmar-plantar erythrodysaesthesia syndrome	94.41	28.24	46	4652	15437	31677209
Oedema	93.29	28.24	65	4633	42496	31650150
Sepsis	84.63	28.24	108	4590	151821	31540825
Acute lymphocytic leukaemia	80.26	28.24	27	4671	3479	31689167
Skin toxicity	75.74	28.24	27	4671	4132	31688514
Aplasia	75.46	28.24	27	4671	4176	31688470
Mucosal inflammation	71.73	28.24	51	4647	34376	31658270
Hepatotoxicity	71.53	28.24	41	4657	19085	31673561
Aspartate aminotransferase increased	69.09	28.24	64	4634	62655	31629991
Alanine aminotransferase increased	63.26	28.24	66	4632	74590	31618056
Neutropenia	60.20	28.24	88	4610	140276	31552370
Cystitis haemorrhagic	52.19	28.24	22	4676	5267	31687379
Acute lymphocytic leukaemia recurrent	51.80	28.24	19	4679	3151	31689495
Bone marrow failure	50.41	28.24	38	4660	27970	31664676
Pancytopenia	48.33	28.24	62	4636	87254	31605392
Streptococcal sepsis	45.72	28.24	14	4684	1333	31691313
Pneumonia fungal	45.26	28.24	21	4677	6308	31686338
Venoocclusive liver disease	45.08	28.24	22	4676	7390	31685256
Adenovirus infection	41.07	28.24	18	4680	4736	31687910
Acute myeloid leukaemia	39.64	28.24	28	4670	18644	31674002
Transaminases increased	39.37	28.24	31	4667	24310	31668336
Enterococcal bacteraemia	38.62	28.24	13	4685	1675	31690971
Hyperbilirubinaemia	36.67	28.24	25	4673	15725	31676921
Nephropathy toxic	33.73	28.24	21	4677	11332	31681314
Staphylococcal infection	33.17	28.24	31	4667	30601	31662045
Venoocclusive disease	32.80	28.24	13	4685	2659	31689987
Tumour lysis syndrome	32.48	28.24	23	4675	15362	31677284
Blood culture positive	32.08	28.24	15	4683	4583	31688063
Pulmonary haemorrhage	31.67	28.24	19	4679	9596	31683050
Bacterial sepsis	31.38	28.24	15	4683	4813	31687833
Acute graft versus host disease in skin	31.37	28.24	15	4683	4817	31687829
Graft versus host disease in liver	30.73	28.24	10	4688	1160	31691486
Neutropenic colitis	29.26	28.24	12	4686	2680	31689966
Respiratory failure	28.96	28.24	53	4645	101396	31591250

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	359.19	28.92	234	6893	204084	70717233
Haematotoxicity	179.64	28.92	63	7064	13611	70907706
Blood bilirubin increased	165.41	28.92	92	7035	59809	70861508
Multiple organ dysfunction syndrome	162.87	28.92	113	7014	108402	70812915
Capillary leak syndrome	159.80	28.92	42	7085	3420	70917897
Palmar-plantar erythrodysaesthesia syndrome	134.33	28.92	64	7063	30183	70891134
Acute lymphocytic leukaemia	131.62	28.92	40	7087	5505	70915812
Mucosal inflammation	126.68	28.92	81	7046	67769	70853548
Bone marrow failure	123.69	28.92	71	7056	48939	70872378
Aplasia	109.14	28.92	37	7090	7214	70914103
Oedema	100.11	28.92	83	7044	103498	70817819
Sepsis	93.93	28.92	119	7008	244426	70676891
Skin toxicity	93.87	28.92	33	7094	7165	70914152
Aspartate aminotransferase increased	91.24	28.92	86	7041	126892	70794425
Alanine aminotransferase increased	89.39	28.92	91	7036	147389	70773928
Neutropenia	87.66	28.92	118	7009	257038	70664279
Acute lymphocytic leukaemia recurrent	77.65	28.92	26	7101	4878	70916439
Cystitis haemorrhagic	73.83	28.92	29	7098	8564	70912753
Transaminases increased	72.83	28.92	50	7077	46968	70874349
Pancytopenia	71.79	28.92	82	7045	151025	70770292
Hepatotoxicity	71.04	28.92	48	7079	43938	70877379
Acute myeloid leukaemia	67.96	28.92	41	7086	30899	70890418
Hyperbilirubinaemia	65.88	28.92	36	7091	22532	70898785
Venoocclusive liver disease	64.45	28.92	28	7099	10650	70910667
Blood culture positive	62	28.92	25	7102	7901	70913416
Pyrexia	61.99	28.92	166	6961	606786	70314531
Pneumonia fungal	59.75	28.92	26	7101	9927	70911390
Fusarium infection	56.53	28.92	16	7111	1716	70919601
Toxic erythema of chemotherapy	55.85	28.92	11	7116	241	70921076
Adenovirus infection	55.63	28.92	23	7104	7745	70913572
Acute myeloid leukaemia recurrent	55.62	28.92	18	7109	3036	70918281
Staphylococcal bacteraemia	53.94	28.92	25	7102	11057	70910260
Respiratory failure	52.22	28.92	74	7053	168661	70752656
Staphylococcal infection	51.95	28.92	43	7084	53361	70867956
Septic shock	51.73	28.92	60	7067	112198	70809119
Venoocclusive disease	50.00	28.92	18	7109	4182	70917135
Leukaemia recurrent	49.09	28.92	16	7111	2759	70918558
Aspergillus infection	45.33	28.92	26	7101	17842	70903475
Acute graft versus host disease in skin	44.00	28.92	19	7108	7118	70914199
Graft versus host disease	41.19	28.92	23	7104	15000	70906317
Fatigue	40.84	28.92	16	7111	824303	70097014
Bacterial sepsis	39.56	28.92	18	7109	7629	70913688
Enterococcal bacteraemia	37.46	28.92	13	7114	2713	70918604
Enterococcal infection	36.41	28.92	21	7106	14561	70906756
Tumour lysis syndrome	36.12	28.92	24	7103	21336	70899981
Nephropathy toxic	34.24	28.92	22	7105	18492	70902825
Bronchopulmonary aspergillosis	34.08	28.92	23	7104	20979	70900338
Graft versus host disease in skin	31.50	28.92	14	7113	5616	70915701
Acute graft versus host disease	29.98	28.92	16	7111	9546	70911771
Neutropenic colitis	29.53	28.92	13	7114	5101	70916216
Acute lymphocytic leukaemia refractory	29.33	28.92	6	7121	160	70921157

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 | Suggest Off label Use Form| |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
DNA polymerase alpha catalytic subunit	Enzyme	P09884	DPOLA_HUMAN	INHIBITOR			WOMBAT-PK	CHEMBL
Ribonucleoside-diphosphate reductase large subunit	Enzyme	P23921	RIR1_HUMAN	INHIBITOR	IC50	8.30	IUPHAR	CHEMBL
Ribonucleoside-diphosphate reductase subunit M2	Enzyme	P31350	RIR2_HUMAN	INHIBITOR	IC50	8.30	IUPHAR	CHEMBL
Ribose-phosphate pyrophosphokinase 1	Kinase	P60891	PRPS1_HUMAN				WOMBAT-PK
Uridine-cytidine kinase 1	Kinase	Q9HA47	UCK1_HUMAN				WOMBAT-PK
Uridine-cytidine kinase 2	Kinase	Q9BZX2	UCK2_HUMAN				WOMBAT-PK
cGMP-dependent 3',5'-cyclic phosphodiesterase	Enzyme	O00408	PDE2A_HUMAN		IC50	5.51	CHEMBL

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	30 sections
Clolar	HUMAN PRESCRIPTION DRUG LABEL	1	0024-5860	INJECTION	1 mg	INTRAVENOUS	NDA	30 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	24 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	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	60505-6166	INJECTION	1 mg	INTRAVENOUS	ANDA	27 sections
Clofarabine	HUMAN PRESCRIPTION DRUG LABEL	1	60505-6166	INJECTION	1 mg	INTRAVENOUS	ANDA	27 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	27 sections
clofarabine	HUMAN PRESCRIPTION DRUG LABEL	1	67457-546	INJECTION	1 mg	INTRAVENOUS	ANDA	27 sections
Clofarabine	Human Prescription Drug Label	1	68083-386	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	25 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	25 sections
CLOFARABINE	HUMAN PRESCRIPTION DRUG LABEL	1	72266-108	INJECTION	1 mg	INTRAVENOUS	ANDA	26 sections
CLOFARABINE	HUMAN PRESCRIPTION DRUG LABEL	1	72266-108	INJECTION	1 mg	INTRAVENOUS	ANDA	26 sections