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Identification
NameLenalidomide
Accession NumberDB00480  (APRD01303)
TypeSmall Molecule
GroupsApproved
Description

Lenalidomide (initially known as CC-5013 and marketed as Revlimid® by Celgene) is a derivative of thalidomide introduced in 2004. It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic modality, but has also shown efficacy in the hematological disorders known as the myelodysplastic syndromes. [Wikipedia] FDA approved on December 27, 2005.

Structure
Thumb
Synonyms
1-oxo-2-(2,6-Dioxopiperidin-3-yl)-4-aminoisoindoline
3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione
CC-5013
CDC 501
IMid-1
IMiD3
Revlimid
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Revlimidcapsule15 mgoralCelgene Inc2008-10-10Not applicableCanada
Revlimidcapsule2.5 mg/1oralCelgene Corporation2012-04-16Not applicableUs
Revlimidcapsule10 mgoralCelgene Inc2008-02-19Not applicableCanada
Revlimidcapsule5 mgoralCelgene Inc2008-02-19Not applicableCanada
Revlimidcapsule25 mg/1oralCelgene Corporation2006-06-29Not applicableUs
Revlimidcapsule20 mg/1oralCelgene Corporation2013-06-06Not applicableUs
Revlimidcapsule15 mg/1oralCelgene Corporation2006-06-29Not applicableUs
Revlimidcapsule20 mgoralCelgene Inc2015-09-28Not applicableCanada
Revlimidcapsule10 mg/1oralCelgene Corporation2005-12-27Not applicableUs
Revlimidcapsule25 mgoralCelgene Inc2008-10-10Not applicableCanada
Revlimidcapsule5 mg/1oralCelgene Corporation2005-12-27Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
LadevinaNot Available
Lenangio Not Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIF0P408N6V4
CAS number191732-72-6
WeightAverage: 259.2606
Monoisotopic: 259.095691297
Chemical FormulaC13H13N3O3
InChI KeyInChIKey=GOTYRUGSSMKFNF-UHFFFAOYSA-N
InChI
InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)
IUPAC Name
3-(4-amino-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione
SMILES
NC1=CC=CC2=C1CN(C1CCC(=O)NC1=O)C2=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as isoindolones. These are aromatic polycyclic compounds that an isoindole bearing a ketone.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassIsoindoles and derivatives
Sub ClassIsoindolines
Direct ParentIsoindolones
Alternative Parents
Substituents
  • Isoindolone
  • Isoindole
  • Piperidinedione
  • Piperidinone
  • Dicarboximide
  • Delta-lactam
  • 3-aminopiperidine
  • Benzenoid
  • Primary aromatic amine
  • Piperidine
  • Carboxylic acid imide, n-unsubstituted
  • Carboxylic acid imide
  • Tertiary amine
  • Lactam
  • Carboxamide group
  • Azacycle
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationLenalidomide is indicated for the treatment of multiple myeloma in combination with dexamethasone. It is also indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate- risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
PharmacodynamicsLenalidomide, a thalidomide analogue, is an immunomodulatory agent possessing immunomodulatory and antiangiogenic properties. Lenalidomide inhibits the secretion of pro-inflammatory cytokines and increases the secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells. Lenalidomide inhibits cell proliferation with varying effectiveness (IC50s) in some but not all cell lines. Lenalidomide is effective in inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) but is much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and other cell lines without chromosome 5 deletions. Lenalidomide does not prolong the QTc interval.
Mechanism of actionThe mechanism of action of lenalidomide remains to be fully characterized, however it has been demonstrated that lenalidomide inhibits the expression of cyclooxygenase-2 (COX-2), but not COX-1, in vitro. In vivo it induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity
Related Articles
AbsorptionRapidly absorbed following oral administration, with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. Co-administration with food does not alter the extent of absorption (AUC) but does reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of lenalidomide is linear. Accumulation does not occur following multiple doses.
Volume of distributionNot Available
Protein binding30% protein bound.
Metabolism

Lenalidomide undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation. The cytochrome P450 enzyme system is not involved with the metabolism of lenalidomide.

Route of eliminationElimination is primarily renal. When a single oral dose of 25 mg is given healthy subjects, 90% and 4% of the dose is eliminated in urine and feces, respectively. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively.
Half lifeHealthy subjects = 3 hours; Multiple myeloma or MDS patients = 3 - 5 hours.
Clearance

The renal clearance of lenalidomide exceeds the glomerular filtration rate.

ToxicityThe most frequently reported adverse events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9958
Blood Brain Barrier+0.9372
Caco-2 permeable-0.5981
P-glycoprotein substrateSubstrate0.6845
P-glycoprotein inhibitor IInhibitor0.6012
P-glycoprotein inhibitor IINon-inhibitor0.8927
Renal organic cation transporterNon-inhibitor0.726
CYP450 2C9 substrateNon-substrate0.8861
CYP450 2D6 substrateNon-substrate0.7878
CYP450 3A4 substrateSubstrate0.5855
CYP450 1A2 substrateNon-inhibitor0.8746
CYP450 2C9 inhibitorNon-inhibitor0.8405
CYP450 2D6 inhibitorNon-inhibitor0.8806
CYP450 2C19 inhibitorNon-inhibitor0.78
CYP450 3A4 inhibitorNon-inhibitor0.7469
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.843
Ames testNon AMES toxic0.8268
CarcinogenicityNon-carcinogens0.9068
BiodegradationNot ready biodegradable0.9967
Rat acute toxicity2.5145 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9803
hERG inhibition (predictor II)Non-inhibitor0.5098
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Celgene corp
  • Celgene Corporation
Packagers
Dosage forms
FormRouteStrength
Capsuleoral10 mg
Capsuleoral10 mg/1
Capsuleoral15 mg/1
Capsuleoral15 mg
Capsuleoral2.5 mg/1
Capsuleoral20 mg
Capsuleoral20 mg/1
Capsuleoral25 mg
Capsuleoral25 mg/1
Capsuleoral5 mg
Capsuleoral5 mg/1
Prices
Unit descriptionCostUnit
Revlimid 25 mg capsule411.71USD capsule
Revlimid 15 mg capsule407.7USD capsule
Revlimid 10 mg capsule406.05USD capsule
Revlimid 5 mg capsule388.0USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2342974 No2005-08-162014-02-24Canada
CA2477301 No2009-09-012023-04-13Canada
US5635517 No1999-10-042019-10-04Us
US6045501 No1998-08-282018-08-28Us
US6281230 No1996-07-242016-07-24Us
US6315720 No2000-10-232020-10-23Us
US6555554 No1996-07-242016-07-24Us
US6561976 No1998-08-282018-08-28Us
US6561977 No2000-10-232020-10-23Us
US6755784 No2000-10-232020-10-23Us
US6908432 No1998-08-282018-08-28Us
US7119106 No1996-07-242016-07-24Us
US7189740 No2003-04-112023-04-11Us
US7465800 No2007-04-272027-04-27Us
US7468363 No2003-10-072023-10-07Us
US7855217 No2004-11-242024-11-24Us
US7968569 No2003-10-072023-10-07Us
US8204763 No1998-08-282018-08-28Us
US8288415 No1996-07-242016-07-24Us
US8315886 No2000-10-232020-10-23Us
US8404717 No2003-04-112023-04-11Us
US8530498 No2003-05-152023-05-15Us
US8589188 No1998-08-282018-08-28Us
US8626531 No2000-10-232020-10-23Us
US8648095 No2003-05-152023-05-15Us
US8741929 No2008-03-082028-03-08Us
US9056120 No2003-04-112023-04-11Us
US9101621 No2003-05-152023-05-15Us
US9101622 No2003-05-152023-05-15Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilitySoluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/mL.Not Available
logP-0.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.33 mg/mLALOGPS
logP-0.43ALOGPS
logP-0.71ChemAxon
logS-2ALOGPS
pKa (Strongest Acidic)11.61ChemAxon
pKa (Strongest Basic)2.31ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area92.5 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity68.3 m3·mol-1ChemAxon
Polarizability25.55 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Surya Narayana Devarakonda, Sesha Reddy Yarraguntla, Vamsi Krishna Mudapaka, Rajasekhar Kadaboina, Veerender Murki, Amarendhar Manda, Venkata Rao Badisa, Naresh Vemula, Rama Seshagiri Rao Pulla, Venu Nalivela, “PREPARATION OF LENALIDOMIDE.” U.S. Patent US20110021567, issued January 27, 2011.

US20110021567
General References
  1. List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. [PubMed:15703420 ]
  2. Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Nimer SD, Jagannath S, Dhodapkar MV: Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006 Jul 15;108(2):618-21. Epub 2006 Mar 28. [PubMed:16569772 ]
  3. Anderson KC: Lenalidomide and thalidomide: mechanisms of action--similarities and differences. Semin Hematol. 2005 Oct;42(4 Suppl 4):S3-8. [PubMed:16344099 ]
External Links
ATC CodesL04AX04
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (400 KB)
MSDSDownload (225 KB)
Interactions
Drug Interactions
Drug
AbataceptThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Abatacept.
AnakinraThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Anakinra.
CanakinumabThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Canakinumab.
Certolizumab pegolLenalidomide may increase the immunosuppressive activities of Certolizumab pegol.
ChlorotrianiseneChlorotrianisene may increase the thrombogenic activities of Lenalidomide.
ClozapineThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Clozapine.
Darbepoetin alfaDarbepoetin alfa may increase the thrombogenic activities of Lenalidomide.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Lenalidomide.
DexamethasoneDexamethasone may increase the thrombogenic activities of Lenalidomide.
DigoxinThe serum concentration of Digoxin can be increased when it is combined with Lenalidomide.
ErythropoietinEpoetin alfa may increase the thrombogenic activities of Lenalidomide.
EstradiolEstradiol may increase the thrombogenic activities of Lenalidomide.
Estrone sulfateEstropipate may increase the thrombogenic activities of Lenalidomide.
LeflunomideThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Leflunomide.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Lenalidomide.
Methoxy polyethylene glycol-epoetin betaMethoxy polyethylene glycol-epoetin beta may increase the thrombogenic activities of Lenalidomide.
NatalizumabThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Natalizumab.
PamidronateThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Pamidronate.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Lenalidomide.
RilonaceptThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Rilonacept.
RoflumilastRoflumilast may increase the immunosuppressive activities of Lenalidomide.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Lenalidomide.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Lenalidomide.
TocilizumabTocilizumab may increase the immunosuppressive activities of Lenalidomide.
TofacitinibThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Lenalidomide.
VedolizumabThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Vedolizumab.
Food Interactions
  • When given with a fatty meal, the extent of absorption is reduced.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Metal ion binding
Specific Function:
Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2. Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8. May play a role in memory and learning by regulating the assembly an...
Gene Name:
CRBN
Uniprot ID:
Q96SW2
Molecular Weight:
50545.375 Da
References
  1. Zhu YX, Kortuem KM, Stewart AK: Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013 Apr;54(4):683-7. doi: 10.3109/10428194.2012.728597. Epub 2012 Sep 28. [PubMed:22966948 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Tumor necrosis factor receptor superfamily binding
Specific Function:
Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced b...
Gene Name:
TNFSF11
Uniprot ID:
O14788
Molecular Weight:
35477.81 Da
References
  1. Akobeng AK, Stokkers PC: Thalidomide and thalidomide analogues for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD007351. doi: 10.1002/14651858.CD007351.pub2. [PubMed:19370685 ]
  2. Melchert M, List A: The thalidomide saga. Int J Biochem Cell Biol. 2007;39(7-8):1489-99. Epub 2007 Jan 30. [PubMed:17369076 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
antagonist
General Function:
Receptor binding
Specific Function:
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. This cadherin may play a important role in endothelial cell biology through control of the cohesion and organization of the intercellular junctions. It associates with alpha-cate...
Gene Name:
CDH5
Uniprot ID:
P33151
Molecular Weight:
87527.715 Da
References
  1. Lu L, Payvandi F, Wu L, Zhang LH, Hariri RJ, Man HW, Chen RS, Muller GW, Hughes CC, Stirling DI, Schafer PH, Bartlett JB: The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res. 2009 Mar;77(2):78-86. doi: 10.1016/j.mvr.2008.08.003. Epub 2008 Sep 4. [PubMed:18805433 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
negative modulator
General Function:
Prostaglandin-endoperoxide synthase activity
Specific Function:
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, p...
Gene Name:
PTGS2
Uniprot ID:
P35354
Molecular Weight:
68995.625 Da
References
  1. Payvandi F, Wu L, Haley M, Schafer PH, Zhang LH, Chen RS, Muller GW, Stirling DI: Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. Cell Immunol. 2004 Aug;230(2):81-8. [PubMed:15598423 ]
  2. Zeldis JB, Schafer PH, Bennett BL, Mercurio F, Stirling DI: Potential new therapeutics for Waldenstrom's macroglobulinemia. Semin Oncol. 2003 Apr;30(2):275-81. [PubMed:12720152 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
Comments
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Drug created on June 13, 2005 07:24 / Updated on June 26, 2016 01:52