Plerixafor

Overview

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. WP

Uses, dosage and effects

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. The drug is approved for patients with lymphoma and multiple myeloma.[1][2] WP

Phase 2 clinical trials started in 2021 exploring the combination of plerixafor and MGTA-145, a CXCL2 ligand.[3][4] WP

Risks and side effects

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.[2] WP

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.[2][5] WP

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.[6] WP

Interactions

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.[2] WP

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. 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. Additionally, plerixafor inhibits CD20 expression on B cells by interfering with CXCR4/SDF1 axis that regulates its expression.[7][8] WP⚠ Wikipedia itself has flagged this text: citation needed.⚠ A word may be missing here. It reads this way in the source too.

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.[2] WP

Research

Anti-cancer properties

Plerixafor was seen to reduce metastasis in mice in several studies. 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.[9][10] WP

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.[11] WP

In a 2020 study, researchers did not find evidence that plerixafor assisted in the healing of diabetic-related arterial insufficiency ulcers.[12] WP

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.[13] WP

History

History

The molecule was first synthesised in 1987 to carry out basic studies on the redox chemistry of dimetallic coordination compounds. 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). 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][15] WP

Legal status

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. In the European Union, the drug was approved after a positive Committee for Medicinal Products for Human Use assessment report on 29 May 2009. The drug was approved for use in Canada by Health Canada on 8 December 2011.[6][16][17] WP

Chemistry

Formula

C28H54N8 PC

CAS number

110078-46-1 PC

Molar mass (g/mol)

502.8 PC

IUPAC name (computed by PubChem)

1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane PC

SMILES

C1CNCCNCCCN(CCNC1)CC2=CC=C(C=C2)CN3CCCNCCNCCCNCC3 PC

InChIKey

YIQPUIGJQJDJOS-UHFFFAOYSA-N PC

PubChem CID

65015

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Plerixafor: AMD 3100, AMD3100, JM 3100, SDZ SID 791. Drugs in R&D. 2007. doi:10.2165/00126839-200708020-00006 · PMID 17324009
2. Other Austria-Codex. 2009
3. Other Stanford University. 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. 2021-08-16
4. Other Magenta Therapeutics, Inc. 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. 2021-08-23
5. Journal / agency Wagstaff AJ. Plerixafor: in patients with non-Hodgkin's lymphoma or multiple myeloma. Drugs. 2009. doi:10.2165/00003495-200969030-00007 · PMID 19275275
6. Journal / agency CHMP Assessment Report for Mozobil
7. Journal / agency Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N. AMD3100 is a CXCR7 ligand with allosteric agonist properties. Molecular Pharmacology. May 2009. doi:10.1124/mol.108.053389 · PMID 19255243
8. Journal / agency Cashen AF, Nervi B, DiPersio J. AMD3100: CXCR4 antagonist and rapid stem cell-mobilizing agent. Future Oncology. February 2007. doi:10.2217/14796694.3.1.19 · PMID 17280498
9. Journal / agency Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, Luker GD. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Research. December 2004. doi:10.1158/0008-5472.CAN-04-1844 · PMID 15574767
10. Journal / agency Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. The Journal of Clinical Investigation. March 2010. doi:10.1172/JCI40283 · PMID 20179352 · PMC2827954
11. Journal / agency Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell. January 2009. doi:10.1016/j.stem.2008.10.017 · PMID 19128793
12. Journal / agency Bonora BM, Cappellari R, Mazzucato M, Rigato M, Grasso M, Menegolo M, Bruttocao A, Avogaro A, Fadini GP. Stem cell mobilization with plerixafor and healing of diabetic ischemic wounds: A phase IIa, randomized, double-blind, placebo-controlled trial. Stem Cells Translational Medicine. September 2020. doi:10.1002/sctm.20-0020 · PMID 32485785 · PMC7445026
13. Journal / agency Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA. CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain, Behavior, and Immunity. March 2011. doi:10.1016/j.bbi.2010.12.014 · PMID 21193025 · PMC3039030
14. Journal / agency Ciampolini M, Fabbrizzi L, Perotti A, Poggi A, Seghi B, Zanobini F. 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. 1987. doi:10.1021/ic00268a022
15. Journal / agency Davies SL, Serradell N, Bolos J, Bayes M. Plerixafor Hydrochloride. Drugs of the Future. 2007. doi:10.1358/dof.2007.032.02.1071897
16. Other Mozobil approved for non-Hodgkin's lymphoma and multiple myeloma. December 18, 2008
17. Other Notice of Compliance information

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