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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	228.86	35.41	115	3208	118334	63367365
Bone marrow failure	136.72	35.41	53	3270	29237	63456462
Capillary leak syndrome	104.35	35.41	24	3299	2176	63483523
Multiple organ dysfunction syndrome	94.47	35.41	50	3273	56702	63428997
Mucosal inflammation	85.68	35.41	44	3279	46884	63438815
Haematotoxicity	73.85	35.41	25	3298	9351	63476348
Staphylococcal bacteraemia	69.33	35.41	21	3302	5509	63480190
Septic shock	58.84	35.41	39	3284	66590	63419109
Palmar-plantar erythrodysaesthesia syndrome	58.27	35.41	27	3296	22988	63462711
Pancytopenia	54.19	35.41	43	3280	96890	63388809
Blood bilirubin increased	54.16	35.41	30	3293	37110	63448589
Pyrexia	53.24	35.41	91	3232	470387	63015312
Transaminases increased	47.55	35.41	26	3297	31341	63454358
Hyperbilirubinaemia	47.54	35.41	19	3304	11295	63474404
Blood culture positive	46.83	35.41	15	3308	4720	63480979
Graft versus host disease	45.37	35.41	16	3307	6747	63478952
Leukaemia recurrent	44.71	35.41	11	3312	1327	63484372
Neutropenia	42.57	35.41	49	3274	174956	63310743
Staphylococcal sepsis	42.50	35.41	16	3307	8112	63477587
Sepsis	40.87	35.41	45	3278	153078	63332621
Venoocclusive liver disease	38.49	35.41	13	3310	4822	63480877
Respiratory failure	36.33	35.41	35	3288	101823	63383876
Aspartate aminotransferase increased	35.99	35.41	33	3290	90244	63395455
Alanine aminotransferase increased	35.77	35.41	35	3288	103735	63381964

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	208.92	28.73	162	4606	136687	34815476
Blood bilirubin increased	117.34	28.73	70	4698	38226	34913937
Haematotoxicity	115.25	28.73	43	4725	8151	34944012
Capillary leak syndrome	98.67	28.73	28	4740	2230	34949933
Palmar-plantar erythrodysaesthesia syndrome	94.48	28.73	46	4722	16749	34935414
Oedema	93.94	28.73	65	4703	45676	34906487
Multiple organ dysfunction syndrome	93.84	28.73	80	4688	76486	34875677
Sepsis	82.29	28.73	107	4661	166454	34785709
Aplasia	75.34	28.73	27	4741	4561	34947602
Skin toxicity	74.24	28.73	27	4741	4757	34947406
Mucosal inflammation	70.27	28.73	51	4717	38571	34913592
Hepatotoxicity	70.26	28.73	41	4727	21444	34930719
Aspartate aminotransferase increased	69.39	28.73	64	4704	67719	34884444
Alanine aminotransferase increased	63.46	28.73	66	4702	80749	34871414
Neutropenia	58.35	28.73	88	4680	156690	34795473
Cystitis haemorrhagic	52.44	28.73	22	4746	5657	34946506
Bone marrow failure	51.76	28.73	38	4730	29215	34922948
Pancytopenia	48.19	28.73	62	4706	95095	34857068
Graft versus host disease in liver	47.53	28.73	14	4754	1270	34950893
Venoocclusive liver disease	45.31	28.73	22	4746	7944	34944219
Streptococcal sepsis	44.92	28.73	14	4754	1538	34950625
Pneumonia fungal	44.62	28.73	21	4747	7079	34945084
Adenovirus infection	40.76	28.73	18	4750	5239	34946924
Graft versus host disease in gastrointestinal tract	39.90	28.73	16	4752	3667	34948496
Acute lymphocytic leukaemia recurrent	39.24	28.73	15	4753	3029	34949134
Transaminases increased	38.98	28.73	31	4737	26792	34925371
Enterococcal bacteraemia	38.20	28.73	13	4755	1884	34950279
Hyperbilirubinaemia	37.03	28.73	25	4743	16818	34935345
Acute graft versus host disease in skin	34.59	28.73	16	4752	5185	34946978
Bacterial sepsis	34.45	28.73	16	4752	5234	34946929
Staphylococcal infection	33.59	28.73	31	4737	32729	34919434
Nephropathy toxic	33.34	28.73	21	4747	12567	34939596
Venoocclusive disease	32.96	28.73	13	4755	2854	34949309
Blood culture positive	32.70	28.73	15	4753	4768	34947395
Tumour lysis syndrome	32.07	28.73	23	4745	17036	34935127
Pulmonary haemorrhage	31.92	28.73	19	4749	10285	34941878
Respiratory failure	29.54	28.73	53	4715	108519	34843644
Graft versus host disease in skin	29.02	28.73	13	4755	3912	34948251
Pyrexia	28.79	28.73	105	4663	332908	34619255

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	357.60	29.66	235	6986	230764	79506403
Haematotoxicity	178.25	29.66	63	7158	15456	79721711
Capillary leak syndrome	168.51	29.66	44	7177	3881	79733286
Blood bilirubin increased	165.71	29.66	92	7129	66140	79671027
Multiple organ dysfunction syndrome	163.00	29.66	113	7108	120133	79617034
Palmar-plantar erythrodysaesthesia syndrome	135.11	29.66	64	7157	33070	79704097
Bone marrow failure	133.31	29.66	73	7148	51034	79686133
Mucosal inflammation	131.37	29.66	83	7138	75497	79661670
Aplasia	110.17	29.66	37	7184	7783	79729384
Oedema	97.24	29.66	83	7138	119497	79617670
Sepsis	96.20	29.66	120	7101	269308	79467859
Skin toxicity	92.58	29.66	33	7188	8281	79728886
Aspartate aminotransferase increased	92.42	29.66	86	7135	138555	79598612
Alanine aminotransferase increased	89.89	29.66	91	7130	162479	79574688
Neutropenia	88.42	29.66	119	7102	287591	79449576
Cystitis haemorrhagic	74.92	29.66	29	7192	9143	79728024
Pancytopenia	74.28	29.66	83	7138	165662	79571505
Transaminases increased	73.21	29.66	50	7171	51693	79685474
Hepatotoxicity	68.83	29.66	48	7173	51304	79685863
Hyperbilirubinaemia	66.59	29.66	36	7185	24482	79712685
Venoocclusive liver disease	64.63	29.66	28	7193	11743	79725424
Pyrexia	64.22	29.66	169	7052	678540	79058627
Blood culture positive	63.03	29.66	25	7196	8404	79728763
Pneumonia fungal	59.38	29.66	26	7195	11184	79725983
Acute lymphocytic leukaemia recurrent	57.35	29.66	20	7201	4704	79732463
Fusarium infection	57.29	29.66	16	7205	1816	79735351
Toxic erythema of chemotherapy	56.86	29.66	11	7210	244	79736923
Adenovirus infection	56.08	29.66	23	7198	8424	79728743
Respiratory failure	54.20	29.66	74	7147	180837	79556330
Septic shock	54.12	29.66	61	7160	122740	79614427
Staphylococcal bacteraemia	54.09	29.66	25	7196	12193	79724974
Staphylococcal infection	52.57	29.66	43	7178	58252	79678915
Acute myeloid leukaemia recurrent	51.60	29.66	17	7204	3366	79733801
Venoocclusive disease	50.33	29.66	18	7203	4555	79732612
Graft versus host disease	49.17	29.66	25	7196	15001	79722166
Acute graft versus host disease in skin	47.96	29.66	20	7201	7638	79729529
Aspergillus infection	46.16	29.66	26	7195	19135	79718032
Bacterial sepsis	43.37	29.66	19	7202	8179	79728988
Leukaemia recurrent	42.55	29.66	14	7207	2760	79734407
Fatigue	41.95	29.66	16	7205	929711	78807456
Enterococcal bacteraemia	37.28	29.66	13	7208	3055	79734112
Enterococcal infection	37.05	29.66	21	7200	15639	79721528
Acute graft versus host disease	36.46	29.66	18	7203	10149	79727018
Tumour lysis syndrome	35.91	29.66	24	7197	23915	79713252
Bronchopulmonary aspergillosis	35.01	29.66	23	7198	22271	79714896
Acute lymphocytic leukaemia	34.59	29.66	14	7207	4955	79732212
Nephropathy toxic	34.36	29.66	22	7199	20397	79716770
Graft versus host disease in skin	31.88	29.66	14	7207	6059	79731108

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	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	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	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	26 sections
Clofarabine	HUMAN PRESCRIPTION DRUG LABEL	1	71288-128	INJECTION	1 mg	INTRAVENOUS	ANDA	26 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
CLOFARABINE	HUMAN PRESCRIPTION DRUG LABEL	1	72266-108	INJECTION	1 mg	INTRAVENOUS	ANDA	26 sections