Plerixafor

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Plerixafor
Plerixafor.svg
Plerixafor ball-and-stick model.png
Clinical data
Trade names Mozobil
Other namesJM 3100, AMD3100
AHFS/Drugs.com Monograph
MedlinePlus a609018
License data
Pregnancy
category
  • AU:D
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding Up to 58%
Metabolism None
Elimination half-life 3–5 hours
Excretion Kidney
Identifiers
  • 1,1’-(1,4-phenylenebismethylene)bis(1,4,8,11- tetraazacyclotetradecane)
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C28H54N8
Molar mass 502.796 g·mol−1
3D model (JSmol)
  • N1CCNCCCN(CCNCCC1)Cc2ccc(cc2)CN3CCCNCCNCCCNCC3
  • 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 Yes check.svgY
  • Key:YIQPUIGJQJDJOS-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Plerixafor, sold under the brand name Mozobil, is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients into the bloodstream. The stem cells are then extracted from the blood and transplanted back to the patient. The drug was developed by AnorMED, which was subsequently bought by Genzyme.

Contents

Medical uses

Peripheral blood stem cell mobilization, which is important as a source of hematopoietic stem cells for transplantation, is generally performed using granulocyte colony-stimulating factor (G-CSF), but is ineffective in around 15 to 20% of patients. Combination of G-CSF with plerixafor increases the percentage of persons that respond to the therapy and produce enough stem cells for transplantation. [3] The drug is approved for patients with lymphoma and multiple myeloma. [4]

Phase 2 clinical trials started in 2021 exploring the combination of plerixafor and MGTA-145, a CXCL2 ligand. [5] [6]

Contraindications

Pregnancy and lactation

Studies in pregnant animals have shown teratogenic effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to use contraception. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy. [4]

Adverse effects

Nausea, diarrhea and local reactions were observed in over 10% of patients. Other problems with digestion and general symptoms like dizziness, headache, and muscular pain are also relatively common; they were found in more than 1% of patients. Allergies occur in less than 1% of cases. Most adverse effects in clinical trials were mild and transient. [4] [7]

The European Medicines Agency has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of spleen rupture and tumor cell mobilisation. The first concern has been raised because splenomegaly was observed in animal studies, and G-CSF can cause spleen rupture in rare cases. Mobilisation of tumor cells has occurred in patients with leukaemia treated with plerixafor. [8]

Interactions

No interaction studies have been conducted. The fact that plerixafor does not interact with the cytochrome system indicates a low potential for interactions with other drugs. [4]

Pharmacology

Mechanism of action

In the form of its zinc complex, plerixafor acts as an antagonist (or perhaps more accurately a partial agonist) of the alpha chemokine receptor CXCR4 and an allosteric agonist of CXCR7. [9] The CXCR4 alpha-chemokine receptor and one of its ligands, SDF-1, are important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. The in vivo effect of plerixafor with regard to ubiquitin, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral blood stem cells. [10] Additionally, plerixafor inhibits CD20 expression on B cells by interfering with CXCR4/SDF1 axis that regulates its expression.[ citation needed ]

Pharmacokinetics

Following subcutaneous injection, plerixafor is absorbed quickly and peak concentrations are reached after 30 to 60 minutes. Up to 58% are bound to plasma proteins, the rest mostly resides in extravascular compartments. The drug is not metabolized in significant amounts; no interaction with the cytochrome P450 enzymes or P-glycoproteins has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the kidneys, with 70% of the drug being excreted within 24 hours. [4]

Chemistry

Plerixafor is a macrocyclic compound and a bicyclam derivative, the cyclam rings being linked at the amine nitrogen atoms by a 1,4-xylyl spacer. [3] It is a base; all eight nitrogen atoms accept protons readily. The two macrocyclic rings form chelate complexes with bivalent metal ions, especially zinc, copper and nickel, as well as cobalt and rhodium. The biologically active form of plerixafor is its zinc complex. [11]

Synthesis

Three of the four nitrogen atoms of the macrocycle cyclam... (1,4,8,11-tetraazacyclotetradecane) are protected with tosyl groups. The product is treated with 1,4-bis(brommethyl)benzene and potassium carbonate in acetonitrile. After cleaving of the tosyl groups with hydrobromic acid, plerixafor octahydrobromide is obtained. [12]

History

The molecule was first synthesised in 1987 to carry out basic studies on the redox chemistry of dimetallic coordination compounds. [13] Then, it was serendipitously discovered by another chemist that such a molecule could have a potential use in the treatment of HIV because of its role in the blocking of CXCR4, a chemokine receptor which acts as a co-receptor for certain strains of HIV (along with the virus's main cellular receptor, CD4). [14] Development of this indication was terminated because of lacking oral availability and cardiac disturbances. Further studies led to the new indication for cancer patients. [14]

Society and culture

Plerixafor has orphan drug status in the United States and European Union for the mobilization of hematopoietic stem cells. It was approved by the U.S. Food and Drug Administration (FDA) for this indication on 15 December 2008. [15] In the European Union, the drug was approved after a positive Committee for Medicinal Products for Human Use assessment report on 29 May 2009. [8] The drug was approved for use in Canada by Health Canada on 8 December 2011. [16]

Research

Anti-cancer properties

Plerixafor was seen to reduce metastasis in mice in several studies. [17] It has also been shown to reduce recurrence of glioblastoma in a mouse model after radiotherapy. In this model, the cancer cells that survived radiation critically depended on bone marrow derived cells for vasculogenesis, and the recruitment of the latter was mediated by SDF-1 CXCR4 interactions, which are blocked by plerixafor. [18]

Use in stem cell research

Researchers at Imperial College have demonstrated that plerixafor in combination with vascular endothelial growth factor (VEGF) can mobilise mesenchymal stem cells and endothelial progenitor cells into the peripheral blood of mice. [19]

In double‐blind, randomized, placebo‐controlled trial, stem cell mobilization with plerixafor did not improve healing of ischemic diabetic wounds. [20]

Neurologic

Blockade of CXCR4 signalling by plerixafor has also unexpectedly been found to be effective at counteracting opioid-induced hyperalgesia produced by chronic treatment with morphine, though only animal studies have been conducted as yet. [21]

Related Research Articles

<span class="mw-page-title-main">Bone marrow</span> Semi-solid tissue in the spongy portions of bones

Bone marrow is a semi-solid tissue found within the spongy portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production. It is composed of hematopoietic cells, marrow adipose tissue, and supportive stromal cells. In adult humans, bone marrow is primarily located in the ribs, vertebrae, sternum, and bones of the pelvis. Bone marrow comprises approximately 5% of total body mass in healthy adult humans, such that a man weighing 73 kg (161 lbs) will have around 3.7 kg (8 lbs) of bone marrow.

<span class="mw-page-title-main">Multiple myeloma</span> Cancer of plasma cells

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, kidney dysfunction, and infections may occur. Complications may include hypercalcemia and amyloidosis.

<span class="mw-page-title-main">Granulocyte colony-stimulating factor</span> Mammalian protein found in humans

Granulocyte colony-stimulating factor, also known as colony-stimulating factor 3, is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce additional normal blood cells. It may be autologous, allogeneic or syngeneic.

<span class="mw-page-title-main">Stromal cell-derived factor 1</span> Mammalian protein found in Homo sapiens

The stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is a chemokine protein that in humans is encoded by the CXCL12 gene on chromosome 10. It is ubiquitously expressed in many tissues and cell types. Stromal cell-derived factors 1-alpha and 1-beta are small cytokines that belong to the chemokine family, members of which activate leukocytes and are often induced by proinflammatory stimuli such as lipopolysaccharide, TNF, or IL1. The chemokines are characterized by the presence of 4 conserved cysteines that form 2 disulfide bonds. They can be classified into 2 subfamilies. In the CC subfamily, the cysteine residues are adjacent to each other. In the CXC subfamily, they are separated by an intervening amino acid. The SDF1 proteins belong to the latter group. CXCL12 signaling has been observed in several cancers. The CXCL12 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Hematopoietic stem cell</span> Stem cells that give rise to other blood cells

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition. In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

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<span class="mw-page-title-main">CXCR4</span> Protein

C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene. The protein is a CXC chemokine receptor.

<span class="mw-page-title-main">CXCL2</span> Mammalian protein found in Homo sapiens

Chemokine ligand 2 (CXCL2) is a small cytokine belonging to the CXC chemokine family that is also called macrophage inflammatory protein 2-alpha (MIP2-alpha), Growth-regulated protein beta (Gro-beta) and Gro oncogene-2 (Gro-2). CXCL2 is 90% identical in amino acid sequence as a related chemokine, CXCL1. This chemokine is secreted by monocytes and macrophages and is chemotactic for polymorphonuclear leukocytes and hematopoietic stem cells. The gene for CXCL2 is located on human chromosome 4 in a cluster of other CXC chemokines. CXCL2 mobilizes cells by interacting with a cell surface chemokine receptor called CXCR2.

<span class="mw-page-title-main">KIT (gene)</span> Mammalian protein and protein-coding gene

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<span class="mw-page-title-main">WHIM syndrome</span> Medical condition

WHIM syndrome is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.

<span class="mw-page-title-main">FMS-like tyrosine kinase 3 ligand</span> Protein-coding gene in the species Homo sapiens

Fms-related tyrosine kinase 3 ligand (FLT3LG) is a protein which in humans is encoded by the FLT3LG gene.

<span class="mw-page-title-main">ACKR3</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Peripheral stem cell transplantation</span> Method of replacing blood-forming stem cells

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Gero Hütter is a German hematologist. Hütter and his medical team transplanted bone marrow deficient in a key HIV receptor to a leukemia patient, Timothy Ray Brown, who was also infected with human immunodeficiency virus (HIV). Subsequently, the patient's circulating HIV dropped to undetectable levels. The case was widely reported in the media, and Hütter was named one of the "Berliners of the year" for 2008 by the Berliner Morgenpost, a Berlin newspaper.

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A CXCR4 antagonist is a substance which blocks the CXCR4 receptor and prevent its activation. Blocking the receptor stops the receptor's ligand, CXCL12, from binding which prevents downstream effects. CXCR4 antagonists are especially important for hindering cancer progression because one of the downstream effects initiated by CXCR4 receptor activation is cell movement which helps the spread of cancer, known as metastasis. The CXCR4 receptor has been targeted by antagonistic substances since being identified as a co-receptor in HIV and assisting the development of cancer. Macrocyclic ligands have been utilised as CXCR4 antagonists.

<span class="mw-page-title-main">Motixafortide</span> Medication

Motixafortide, sold under the brand name Aphexda, is a medication used for the treatment of multiple myeloma. Motixafortide is a hematopoietic stem cell mobilizer and a CXCR4 antagonist. It is given by subcutaneous injection.

References

  1. ↑ "Mozobil- plerixafor injection, solution". DailyMed. 26 June 2023. Retrieved 13 September 2023.
  2. ↑ "Plerixafor Accord EPAR". European Medicines Agency. 12 October 2022. Retrieved 7 February 2023.
  3. 1 2 "Plerixafor: AMD 3100, AMD3100, JM 3100, SDZ SID 791". Drugs in R&D. 8 (2): 113–9. 2007. doi:10.2165/00126839-200708020-00006. PMID   17324009. S2CID   20824572.
  4. 1 2 3 4 5 Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN   978-3-85200-196-8.
  5. ↑ Stanford University (16 August 2021). "Phase II Study of MGTA-145 in Combination With Plerixafor in the Mobilization of Hematopoietic Stem Cells for Autologous Transplantation in Patients With Multiple Myeloma".{{cite journal}}: Cite journal requires |journal= (help)
  6. ↑ Magenta Therapeutics, Inc. (23 August 2021). "A Phase II Study Evaluating the Safety and Efficacy of MGTA-145 in Combination With Plerixafor for the Mobilization and Transplantation of HLA-Matched Donor Hematopoietic Stem Cells in Recipients With Hematological Malignancies". National Marrow Donor Program.{{cite journal}}: Cite journal requires |journal= (help)
  7. ↑ Wagstaff AJ (2009). "Plerixafor: in patients with non-Hodgkin's lymphoma or multiple myeloma". Drugs. 69 (3): 319–26. doi:10.2165/00003495-200969030-00007. PMID   19275275. S2CID   195684110.
  8. 1 2 "CHMP Assessment Report for Mozobil" (PDF). European Medicines Agency.
  9. ↑ Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N (May 2009). "AMD3100 is a CXCR7 ligand with allosteric agonist properties". Molecular Pharmacology. 75 (5): 1240–7. doi:10.1124/mol.108.053389. PMID   19255243. S2CID   28540154.
  10. ↑ Cashen AF, Nervi B, DiPersio J (February 2007). "AMD3100: CXCR4 antagonist and rapid stem cell-mobilizing agent". Future Oncology. 3 (1): 19–27. doi:10.2217/14796694.3.1.19. PMID   17280498.
  11. ↑ Esté JA, Cabrera C, De Clercq E, Struyf S, Van Damme J, Bridger G, et al. (January 1999). "Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor". Molecular Pharmacology. 55 (1): 67–73. doi:10.1124/mol.55.1.67. PMID   9882699. S2CID   8565063.
  12. ↑ WO 93012096,Bridger G, Padmanabhan S, Skerlj RT, Thornton DM,"Linked cyclic polyamines with activity against HIV",published 24 June 1993, assigned to Johnson Matthey Public Limited Company
  13. ↑ Ciampolini M, Fabbrizzi L, Perotti A, Poggi A, Seghi B, Zanobini F (1987). "Dinickel and dicopper complexes with N,N-linked bis(cyclam) ligands. An ideal system for the investigation of electrostatic effects on the redox behavior of pairs of metal ions". Inorganic Chemistry. 26 (21): 3527–3533. doi:10.1021/ic00268a022.
  14. 1 2 Davies SL, Serradell N, Bolos J, Bayes M (2007). "Plerixafor Hydrochloride". Drugs of the Future. 32 (2): 123. doi:10.1358/dof.2007.032.02.1071897.
  15. ↑ "Mozobil approved for non-Hodgkin's lymphoma and multiple myeloma" (Press release). Monthly Prescribing Reference. 18 December 2008. Archived from the original on 6 January 2009. Retrieved 3 January 2009.
  16. ↑ Notice of Compliance information
  17. ↑ Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, et al. (December 2004). "CXCR4 regulates growth of both primary and metastatic breast cancer". Cancer Research. 64 (23): 8604–12. doi: 10.1158/0008-5472.CAN-04-1844 . PMID   15574767.
  18. ↑ Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM (March 2010). "Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice". The Journal of Clinical Investigation. 120 (3): 694–705. doi:10.1172/JCI40283. PMC   2827954 . PMID   20179352.
  19. ↑ Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM (January 2009). "Differential mobilization of subsets of progenitor cells from the bone marrow". Cell Stem Cell. 4 (1): 62–72. doi:10.1016/j.stem.2008.10.017. hdl: 10044/1/23497 . PMID   19128793.
  20. ↑ Bonora BM, Cappellari R, Mazzucato M, Rigato M, Grasso M, Menegolo M, et al. (September 2020). "Stem cell mobilization with plerixafor and healing of diabetic ischemic wounds: A phase IIa, randomized, double-blind, placebo-controlled trial". Stem Cells Translational Medicine. 9 (9): 965–973. doi:10.1002/sctm.20-0020. PMC   7445026 . PMID   32485785. S2CID   219285881.
  21. ↑ Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA (March 2011). "CXCR4 signaling mediates morphine-induced tactile hyperalgesia". Brain, Behavior, and Immunity. 25 (3): 565–73. doi:10.1016/j.bbi.2010.12.014. PMC   3039030 . PMID   21193025.
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