U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C10H12ClN5O3
Molecular Weight 285.6873
Optical Activity UNSPECIFIED
Defined Stereocenters 3 / 3
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of CLADRIBINE

SMILES

C1[C@@]([H])([C@@]([H])(CO)O[C@@]1([H])n2cnc3c(N)nc(Cl)nc32)O

InChI

InChIKey=PTOAARAWEBMLNO-KVQBGUIXSA-N
InChI=1S/C10H12ClN5O3/c11-10-14-8(12)7-9(15-10)16(3-13-7)6-1-4(18)5(2-17)19-6/h3-6,17-18H,1-2H2,(H2,12,14,15)/t4-,5+,6+/m0/s1

HIDE SMILES / InChI

Description
Curator's Comment:: Description was created using several sources including: https://www.scripps.edu/newsandviews/e_20090601/MS.html; http://comtecmed.com/CONY/2008/Uploads/assets/speakers%20abstracts/stelmasiak.pdf

Cladribine is used for the treatment of hairy cell leukemia and multiple sclerosis (MS). As a purine analog, it is a synthetic anti-cancer agent that also suppresses the immune system. Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA. It can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair. Cladribine injection is a potent antineoplastic agent with potentially significant toxic side effects. In MS, the novel mechanism of action of cladribine is expected to reduce inflammation, autoimmune effects and autoreactive cell damage, thereby improving the integrity of the blood–brain barrier. Thus, the effects of cladribine may target some of the key events that are central to the pathophysiology of MS.

CNS Activity

Curator's Comment:: As cladribine can cross the blood brain barrier and can kill dividing and non-dividing T and B cells and can apparently kill plasma cells. It could target plasma cells in the brain, unlike any other MS drug.

Originator

Curator's Comment:: The drug, cladribine, which is currently marketed under the name LEUSTATIN® by Ortho Biotech, Inc. (an affiliate of Johnson & Johnson) for the treatment of hairy cell leukemia, was initially identified and developed using a single treatment of the new compound to target abnormal white blood cells in patients suffering from hairy cell leukemia by Dennis Carson in collaboration with Ernest Beutler a Scripps Research scientists who licensed caldribine as an orphan drug in 1994. Merck Serono's CLARITY study, involving 1326 Multiple Sclerosis patients, began in 2004 and was completed in December 2008.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: P06746
Gene ID: 5423.0
Gene Symbol: POLB
Target Organism: Homo sapiens (Human)
Target ID: P23526
Gene ID: 191.0
Gene Symbol: AHCY
Target Organism: Homo sapiens (Human)
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
CLADRIBINE

Approved Use

the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms.

Launch Date

7.9185602E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
20.57 ng/mL
3 mg single, intravenous
dose: 3 mg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
CLADRIBINE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
29.05 ng/mL
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
CLADRIBINE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
69.4 ng × h/mL
3 mg single, intravenous
dose: 3 mg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
CLADRIBINE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
99.17 ng × h/mL
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
CLADRIBINE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
18.4 h
3 mg single, intravenous
dose: 3 mg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
CLADRIBINE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
19.7 h
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
CLADRIBINE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
5.25 mg/kg multiple, oral (total)
Highest studied dose
Dose: 5.25 mg/kg
Route: oral
Route: multiple
Dose: 5.25 mg/kg
Sources: Page: p.262
unhealthy, ADULT
n = 204
Health Status: unhealthy
Condition: multiple sclerosis
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 204
Sources: Page: p.262
Disc. AE: Lymphopenia...
AEs leading to
discontinuation/dose reduction:
Lymphopenia (grade 3-4)
Sources: Page: p.262
8 mg/m2 1 times / day multiple, intravenous
MTD
Dose: 8 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 8 mg/m2, 1 times / day
Sources: Page: p.170
unhealthy, ADULT
n = 4
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 4
Sources: Page: p.170
DLT: Neutropenia, Leukopenia...
Dose limiting toxicities:
Neutropenia (grade 4, 50%)
Leukopenia (grade 4, 50%)
Sources: Page: p.170
0.07 mg/kg 1 times / day multiple, subcutaneous
Studied dose
Dose: 0.07 mg/kg, 1 times / day
Route: subcutaneous
Route: multiple
Dose: 0.07 mg/kg, 1 times / day
Sources: Page: p.1152
unhealthy, ADULT
n = 52
Health Status: unhealthy
Condition: multiple sclerosis
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 52
Sources: Page: p.1152
AEs

AEs

AESignificanceDosePopulation
Lymphopenia grade 3-4
Disc. AE
5.25 mg/kg multiple, oral (total)
Highest studied dose
Dose: 5.25 mg/kg
Route: oral
Route: multiple
Dose: 5.25 mg/kg
Sources: Page: p.262
unhealthy, ADULT
n = 204
Health Status: unhealthy
Condition: multiple sclerosis
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 204
Sources: Page: p.262
Leukopenia grade 4, 50%
DLT
8 mg/m2 1 times / day multiple, intravenous
MTD
Dose: 8 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 8 mg/m2, 1 times / day
Sources: Page: p.170
unhealthy, ADULT
n = 4
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 4
Sources: Page: p.170
Neutropenia grade 4, 50%
DLT
8 mg/m2 1 times / day multiple, intravenous
MTD
Dose: 8 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 8 mg/m2, 1 times / day
Sources: Page: p.170
unhealthy, ADULT
n = 4
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 4
Sources: Page: p.170
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
Drug as victimTox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Severe skin rash in two consecutive patients treated with 2-chlorodeoxyadenosine for hairy cell leukaemia at a single institution.
2000 Apr
Delayed onset of autoimmune hemolytic anemia complicating cladribine therapy for Waldenström macroglobulinemia.
2000 Mar
[Nucleoside analogues--new drugs for the treatment of lymphatic cancers].
2001
Flow cytometry of peripheral blood and bone marrow cells from patients with hairy cell leukemia: phenotype of hairy cells, lymphocyte subsets and detection of minimal residual disease after treatment.
2001
Immunomodulatory drugs for multiple sclerosis: a systematic review of clinical and cost effectiveness.
2001 Apr
Effect of cladribine treatment on beta-2 microglobulin and soluble intercellular adhesion molecule 1 (ICAM-1) in patients with multiple sclerosis.
2001 Aug
A phase II study of sequential combination chemotherapy with cyclophosphamide, prednisone, and 2-chlorodeoxyadenosine in previously untreated patients with chronic lymphocytic leukemia.
2001 Aug
Sin of omission? Pharmaceutical trade group failed to disclose that ad subject was employee.
2001 Aug 6
Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation.
2001 Feb 1
Unexpectedly high incidence of hypoplastic/aplastic foci in bone marrow biopsies of hairy cell leukemia patients in remission following 2-chlorodeoxyadenosine therapy.
2001 Jan
Activation of deoxycytidine kinase by inhibition of DNA synthesis in human lymphocytes.
2001 Jan 15
Treatment of systemic mast-cell disease with cladribine.
2001 Jan 25
Effect of immunosuppressive cladribine treatment on serum leucocytes system in two-year clinical trial in patients with chronic progressive multiple sclerosis.
2001 Jan-Feb
Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia.
2001 Jul 26
Gynecomastia in a case of hairy cell leukaemia--cladribine induced?
2001 Jun
Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment.
2001 Jun
Pure red cell aplasia in patients with chronic lymphocytic leukaemia treated with cladribine.
2001 Mar
Immunosuppressive and cytotoxic drugs in the treatment of rheumatic skin disorders.
2001 Mar
Human cytosolic 5'-nucleotidase I: characterization and role in nucleoside analog resistance.
2001 Mar 30
Does intensive treatment with high dose chlorambucil and prednisone as first line and cladribine as second line influence the survival of the patients with chronic lymphocytic leukemia?
2001 May
Successful application of nonmyeloablative transplantation for paroxysmal nocturnal hemoglobinuria.
2001 May
Prolymphocytic leukemia or prolymphocytic transformation of mantle cell lymphoma.
2001 Nov
Resistance to 2-chloro-2'-deoxyadenosine of the human B-cell leukemia cell line EHEB.
2001 Nov
Exposure-disease continuum for 2-chloro-2'-deoxyadenosine, a prototype ocular teratogen. 1. Dose-response analysis.
2001 Sep
Cladribine decreases the level of angiogenic factors in patients with chronic lymphocytic leukemia.
2002
Gateways to Clinical Trials.
2002 Apr
The role of mitoxantrone in non-Hodgkin's lymphoma.
2002 Apr
[Hairy cell leukemia treated with cladribine].
2002 Apr 30
Cladribine underdosing in hairy-cell leukemia: a cause for apparent response failure.
2002 Feb
Fludarabine therapy in Waldenström's macroglobulinemia patients treated previously with 2-chlorodeoxyadenosine.
2002 Feb
Radiation therapy and combination of cladribine, cyclophosphamide, and prednisone as treatment of Bing-Neel syndrome: Case report and review of the literature.
2002 Feb
2-Chloro-2'-deoxyadenosine inhibits DNA repair synthesis and potentiates UVC cytotoxicity in chronic lymphocytic leukemia B lymphocytes.
2002 Jan
Cladribine (2-chlorodeoxyadenosine) therapy in hairy cell leukemia variant. A report of three cases.
2002 Jan
Treatment of late-stage Sézary syndrome with 2-Chlorodeoxyadenosine.
2002 Jun
Alkylating agents and nucleoside analogues in the treatment of B cell chronic lymphocytic leukemia.
2002 Jun
Oral cladribine for B-cell chronic lymphocytic leukaemia: report of a phase II trial with a 3-d, 3-weekly schedule in untreated and pretreated patients, and a long-term follow-up of 126 previously untreated patients.
2002 Mar
Patents

Sample Use Guides

In Vivo Use Guide
Sources: www.accessdata.fda.gov/drugsatfda_docs/label/2012/020229s034lbl.pdf
0.09 mg/kg/day
Route of Administration: Intravenous
In Vitro Use Guide
Curator's Comment:: The lethal dose of cytarabine for CTRL cells (Mantle cell lymphoma cell line ) ranged from 0.05 to 0.4 μM determined in In vitro cytotoxicity assay that was used to analyze cells relative responsiveness to araC (cladribine).
0.05 - 0.4 uM
Name Type Language
CLADRIBINE
EMA EPAR   EP   HSDB   INN   JAN   MART.   MI   ORANGE BOOK   USAN   USP   USP-RS   VANDF   WHO-DD  
USAN   INN  
Official Name English
CLADRIBINE [HSDB]
Common Name English
CLADRIBINE [EP MONOGRAPH]
Common Name English
MAVENCLAD
Common Name English
NSC-05014
Code English
2-CHLORODEOXYADENOSINE
Systematic Name English
2-CDA
Common Name English
CLADRIBINE [USP MONOGRAPH]
Common Name English
CLADRIBINE [USP-RS]
Common Name English
LITAK
Brand Name English
CLADRIBINE [INN]
Common Name English
CLADRIBINE [WHO-DD]
Common Name English
CLADRIBINE [MART.]
Common Name English
ADENOSINE, 2-CHLORO-2'-DEOXY-
Systematic Name English
2-CHLORO-2'-DEOXYADENOSINE
Systematic Name English
CLADRIBINE [USP]
Common Name English
CLADRIBINE [ORANGE BOOK]
Common Name English
NSC-105014
Code English
CLADRIBINE [EMA EPAR]
Common Name English
LEUSTATIN
Brand Name English
CLADRIBINE [MI]
Common Name English
CLADRIBINE [VANDF]
Common Name English
CLADRIBINE [JAN]
Common Name English
RWJ-26251
Code English
NSC-105014-F
Code English
CLADRIBINE [USAN]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C2157
Created by admin on Fri Jun 25 20:57:04 UTC 2021 , Edited by admin on Fri Jun 25 20:57:04 UTC 2021
FDA ORPHAN DRUG 54190
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FDA ORPHAN DRUG 51690
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WHO-VATC QL01BB04
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EU-Orphan Drug EU/3/01/055
Created by admin on Fri Jun 25 20:57:04 UTC 2021 , Edited by admin on Fri Jun 25 20:57:04 UTC 2021
EMA ASSESSMENT REPORTS LITAK (AUTHORIZED: LEUKEMIA, HAIRY CELL)
Created by admin on Fri Jun 25 20:57:04 UTC 2021 , Edited by admin on Fri Jun 25 20:57:04 UTC 2021
FDA ORPHAN DRUG 467214
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LIVERTOX 213
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FDA ORPHAN DRUG 68092
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NCI_THESAURUS C1556
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FDA ORPHAN DRUG 77793
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WHO-ATC L04AA40
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NCI_THESAURUS C798
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FDA ORPHAN DRUG 47990
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NDF-RT N0000175712
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WHO-ATC L01BB04
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Code System Code Type Description
DRUG CENTRAL
667
Created by admin on Fri Jun 25 20:57:04 UTC 2021 , Edited by admin on Fri Jun 25 20:57:04 UTC 2021
PRIMARY
LACTMED
Cladribine
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PRIMARY
ChEMBL
CHEMBL1619
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PRIMARY
WIKIPEDIA
CLADRIBINE
Created by admin on Fri Jun 25 20:57:04 UTC 2021 , Edited by admin on Fri Jun 25 20:57:04 UTC 2021
PRIMARY
FDA UNII
47M74X9YT5
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PRIMARY
MESH
D017338
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PRIMARY
RXCUI
44157
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PRIMARY RxNorm
USP_CATALOG
1134200
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PRIMARY USP-RS
DRUG BANK
DB00242
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PRIMARY
CAS
4291-63-8
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PRIMARY
EPA CompTox
4291-63-8
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PRIMARY
EVMPD
SUB06635MIG
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PRIMARY
PUBCHEM
20279
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PRIMARY
IUPHAR
4799
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PRIMARY
MERCK INDEX
M3606
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PRIMARY Merck Index
INN
6997
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PRIMARY
NCI_THESAURUS
C1336
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PRIMARY
HSDB
7564
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PRIMARY