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Identification
NamePlerixafor
Accession NumberDB06809
TypeSmall Molecule
GroupsApproved
Description

Plerixafor is a hematopoietic stem cell mobilizer. It is used to stimulate the release of stem cells from the bone marrow into the blood in patients with non-Hodgkin lymphoma and multiple myeloma for the purpose of stimulating the immune system. These stem cells are then collected and used in autologous stem cell transplantation to replace blood-forming cells that were destroyed by chemotherapy. Plerixafor has orphan drug status in the United States and European Union; it was approved by the U.S. Food and Drug Administration on December 15, 2008.

Structure
Thumb
Synonyms
AMD3100
LM3100
Mozobil
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Mozobilsolution24 mg/1.2mLsubcutaneousSanofi Aventis U.S. Llc2013-09-01Not applicableUs
Mozobilsolution20 mgsubcutaneousSanofi Aventis Canada Inc2012-03-26Not applicableCanada
Mozobilsolution24 mg/1.2mLsubcutaneousGenzyme Corporation2008-12-15Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIS915P5499N
CAS number110078-46-1
WeightAverage: 502.782
Monoisotopic: 502.447143768
Chemical FormulaC28H54N8
InChI KeyInChIKey=YIQPUIGJQJDJOS-UHFFFAOYSA-N
InChI
InChI=1S/C28H54N8/c1-9-29-15-17-31-13-3-21-35(23-19-33-11-1)25-27-5-7-28(8-6-27)26-36-22-4-14-32-18-16-30-10-2-12-34-20-24-36/h5-8,29-34H,1-4,9-26H2
IUPAC Name
1-{[4-(1,4,8,11-tetraazacyclotetradecan-1-ylmethyl)phenyl]methyl}-1,4,8,11-tetraazacyclotetradecane
SMILES
C(N1CCCNCCNCCCNCC1)C1=CC=C(CN2CCCNCCNCCCNCC2)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylmethylamines. These are compounds containing a phenylmethtylamine moiety, which consists of a phenyl group substituted by an methanamine.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenylmethylamines
Direct ParentPhenylmethylamines
Alternative Parents
Substituents
  • Phenylmethylamine
  • Benzylamine
  • Aralkylamine
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Organoheterocyclic compound
  • Secondary amine
  • Secondary aliphatic amine
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationUsed in combination with granulocyte-colony stimulating factor (G-CSF, filgrastim) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM).
PharmacodynamicsPlerixafor is a bicyclam derivative that antagonizes CXCR4 by binding to three acidic residues in the ligand-binding pocket: Asp171, Asp262, and Glu288. Blood levels of CD34+ cells peaked at 9 hours after administration of 0.24 mg/kg plerixafor in healthy subjects. In patients that have non-Hodgkin’s lymphoma or multiple myeloma, blood levels of CD34+ peaked at 6 hours. In combination with a G-CSF, circulating CD34+ cells in the peripheral blood peaked at 9-14 hours.
Mechanism of actionPlerixafor inhibits the CXCR4 chemokine receptors on CD34+ cells and reversibly blocks binding of the ligand, stromal cell-derived factor-1-alpha (SDF-1α). By blocking the interaction between SDF-1α and CXCR4 with plerixafor, mobilization of progenitor cells is triggered. Filgrastim, a granulocyte-colony stimulating factor, is added to enhance CD34+ cell mobilization, thus increasing the yield of stem cells- an important determinant of graft adequacy.
Related Articles
AbsorptionPharmacokinetic profile follows a two-compartment model with first-order absorption. A median peak plasma concentration of 0.24 mg/kg of plerixafor occurred 30-60 minutes after subcutaneous dose.
Volume of distribution

0.3 L/kg

Protein binding58%
Metabolism

Metabolism does not involved CYP isoenzymes

Route of elimination0.24 mg/kg, healthy subjects: ~70% of the parent drug is excreted in urine in the first 24 hours.
Half lifeTerminal elimination half-life, NHL patients: 4.4 hours; Terminal elimination half-life, MM patients: 5.6 hours; Terminal elimination half-life, Hodgkin's lymphoma patients: 3.5 hours; Distribution half-life: 0.3 hours
Clearance

Total plasma clearance: 4.38 L/h;
Renal clearance: 3.15 L/h

ToxicityLD50, mouse, SC: 16.3 mg/kg; LD50, rat, SC: >50 mg/kg; LD50, mouse and rat, IV injection: 5.2 mg/kg
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+0.932
Blood Brain Barrier+0.6867
Caco-2 permeable-0.5403
P-glycoprotein substrateSubstrate0.8076
P-glycoprotein inhibitor INon-inhibitor0.8119
P-glycoprotein inhibitor IINon-inhibitor0.7683
Renal organic cation transporterInhibitor0.5069
CYP450 2C9 substrateNon-substrate0.8905
CYP450 2D6 substrateSubstrate0.5274
CYP450 3A4 substrateNon-substrate0.7818
CYP450 1A2 substrateNon-inhibitor0.8787
CYP450 2C9 inhibitorNon-inhibitor0.9272
CYP450 2D6 inhibitorNon-inhibitor0.7149
CYP450 2C19 inhibitorNon-inhibitor0.9114
CYP450 3A4 inhibitorNon-inhibitor0.8817
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.926
Ames testNon AMES toxic0.7906
CarcinogenicityNon-carcinogens0.9106
BiodegradationNot ready biodegradable0.9824
Rat acute toxicity2.1178 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5
hERG inhibition (predictor II)Inhibitor0.6334
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Solutionsubcutaneous20 mg
Solutionsubcutaneous24 mg/1.2mL
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6,987,102 No2006-01-172023-07-22Us
US6987102 No2003-07-222023-07-22Us
US7,897,590 No2011-03-012023-03-22Us
US7897590 No2003-07-222023-07-22Us
USRE42152 No1998-12-102018-12-10Us
Properties
StateLiquid
Experimental Properties
PropertyValueSource
melting point131.5 °CFDA label
water solubilitySolubleMSDS
pKa6.0 - 7.5MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0472 mg/mLALOGPS
logP0.62ALOGPS
logP-0.43ChemAxon
logS-4ALOGPS
pKa (Strongest Basic)10.54ChemAxon
Physiological Charge4ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area78.66 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity155.01 m3·mol-1ChemAxon
Polarizability60.51 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
General References
  1. Uy GL, Rettig MP, Cashen AF: Plerixafor, a CXCR4 antagonist for the mobilization of hematopoietic stem cells. Expert Opin Biol Ther. 2008 Nov;8(11):1797-804. doi: 10.1517/14712598.8.11.1797 . [PubMed:18847313 ]
  2. Fricker SP: A novel CXCR4 antagonist for hematopoietic stem cell mobilization. Expert Opin Investig Drugs. 2008 Nov;17(11):1749-60. doi: 10.1517/13543784.17.11.1749 . [PubMed:18922110 ]
  3. DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, Maziarz RT, Hosing C, Fruehauf S, Horwitz M, Cooper D, Bridger G, Calandra G: Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009 Jun 4;113(23):5720-6. doi: 10.1182/blood-2008-08-174946. Epub 2009 Apr 10. [PubMed:19363221 ]
  4. Stewart DA, Smith C, MacFarland R, Calandra G: Pharmacokinetics and pharmacodynamics of plerixafor in patients with non-Hodgkin lymphoma and multiple myeloma. Biol Blood Marrow Transplant. 2009 Jan;15(1):39-46. doi: 10.1016/j.bbmt.2008.10.018. [PubMed:19135941 ]
  5. Brave M, Farrell A, Ching Lin S, Ocheltree T, Pope Miksinski S, Lee SL, Saber H, Fourie J, Tornoe C, Booth B, Yuan W, He K, Justice R, Pazdur R: FDA review summary: Mozobil in combination with granulocyte colony-stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation. Oncology. 2010;78(3-4):282-8. doi: 10.1159/000315736. Epub 2010 Jun 8. [PubMed:20530974 ]
  6. Choi HY, Yong CS, Yoo BK: Plerixafor for stem cell mobilization in patients with non-Hodgkin's lymphoma and multiple myeloma. Ann Pharmacother. 2010 Jan;44(1):117-26. doi: 10.1345/aph.1M380. Epub 2009 Dec 15. [PubMed:20009003 ]
  7. Keating GM: Plerixafor: a review of its use in stem-cell mobilization in patients with lymphoma or multiple myeloma. Drugs. 2011 Aug 20;71(12):1623-47. doi: 10.2165/11206040-000000000-00000. [PubMed:21861545 ]
External Links
ATC CodesL03AX16
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (270 KB)
MSDSDownload (86.2 KB)
Interactions
Drug InteractionsNo interactions found.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Virus receptor activity
Specific Function:
Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vasculari...
Gene Name:
CXCR4
Uniprot ID:
P61073
Molecular Weight:
39745.055 Da
References
  1. Uy GL, Rettig MP, Cashen AF: Plerixafor, a CXCR4 antagonist for the mobilization of hematopoietic stem cells. Expert Opin Biol Ther. 2008 Nov;8(11):1797-804. doi: 10.1517/14712598.8.11.1797 . [PubMed:18847313 ]
  2. Jujo K, Ii M, Sekiguchi H, Klyachko E, Misener S, Tanaka T, Tongers J, Roncalli J, Renault MA, Thorne T, Ito A, Clarke T, Kamide C, Tsurumi Y, Hagiwara N, Qin G, Asahi M, Losordo DW: CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism. Circulation. 2013 Jan 1;127(1):63-73. doi: 10.1161/CIRCULATIONAHA.112.099242. Epub 2012 Nov 30. [PubMed:23204107 ]
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Drug created on September 14, 2010 10:21 / Updated on August 24, 2016 01:52