Plerixafor

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Plerixafor
Clinical data
Trade namesMozobil
Other namesJM 3100, AMD3100
AHFS/Drugs.comMonograph
MedlinePlusa609018
License data
Pregnancy
category
  • AU: D
Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein bindingUp to 58%
MetabolismNone
Elimination half-life3–5 hours
ExcretionKidney
Identifiers
  • 1,1’-(1,4-phenylenebismethylene)bis(1,4,8,11- tetraazacyclotetradecane)
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 checkY
  • Key:YIQPUIGJQJDJOS-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Plerixafor, sold under the brand name Mozobil, is an

transplanted back to the patient. The drug was developed by AnorMED, which was subsequently bought by Genzyme
.

Medical uses

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.[4] The drug is approved for patients with lymphoma and multiple myeloma.[5]

Phase 2 clinical trials started in 2021 exploring the combination of plerixafor and MGTA-145, a CXCL2 ligand.[6][7]

Contraindications

Pregnancy and lactation

Studies in pregnant animals have shown

contraception. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.[5]

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.[5][8]

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.[9]

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.[5]

Pharmacology

Mechanism of action

In the form of its zinc complex, plerixafor acts as an

CXCR7.[10]
The CXCR4 alpha-
peripheral blood stem cells.[11] Additionally, plerixafor inhibits CD20 expression on B cells by interfering with CXCR4/SDF1 axis that regulates its expression.[citation needed
]

Pharmacokinetics

Following

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.[5]

Chemistry

Plerixafor is a

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.[12]

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.[13]

History

The molecule was first synthesised in 1987 to carry out basic studies on the

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).[15] Development of this indication was terminated because of lacking oral availability and cardiac disturbances. Further studies led to the new indication for cancer patients.[15]

Society and culture

Plerixafor has

hematopoietic stem cells. It was approved by the U.S. Food and Drug Administration (FDA) for this indication on 15 December 2008.[16] In the European Union, the drug was approved after a positive Committee for Medicinal Products for Human Use assessment report on 29 May 2009.[9] The drug was approved for use in Canada by Health Canada on 8 December 2011.[17]

Research

Anti-cancer properties

Plerixafor was seen to reduce metastasis in mice in several studies.[18] 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.[19]

Use in stem cell research

Researchers at Imperial College have demonstrated that plerixafor in combination with

mesenchymal stem cells and endothelial progenitor cells into the peripheral blood of mice.[20]

In double‐blind, randomized, placebo‐controlled trial, stem cell mobilization with plerixafor did not improve healing of ischemic diabetic wounds.[21]

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.[22]

References

  1. ^ "Product monograph brand safety updates". Health Canada. February 2024. Retrieved 24 March 2024.
  2. ^ "Mozobil- plerixafor injection, solution". DailyMed. 26 June 2023. Retrieved 13 September 2023.
  3. ^ "Plerixafor Accord EPAR". European Medicines Agency. 12 October 2022. Retrieved 7 February 2023.
  4. ^
    S2CID 20824572
    .
  5. ^
    ISBN 978-3-85200-196-8
    .
  6. ^ 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)
  7. ^ 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)
  8. S2CID 195684110
    .
  9. ^ a b "CHMP Assessment Report for Mozobil" (PDF). European Medicines Agency.
  10. S2CID 28540154
    .
  11. PMID 17280498
    .
  12. S2CID 8565063
    .
  13. ^ 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 
  14. doi:10.1021/ic00268a022
    .
  15. ^
    doi:10.1358/dof.2007.032.02.1071897
    .
  16. ^ "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.
  17. ^ Notice of Compliance information
  18. PMID 15574767
    .
  19. PMID 20179352
    .
  20. PMID 19128793
    .
  21. S2CID 219285881
    .
  22. PMID 21193025
    .
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