 | |
 | |
| Clinical data | |
|---|---|
| Trade names | Mozobil |
| Other names | JM 3100, AMD3100 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a609018 |
| License data | |
| Pregnancy category |
|
| Routes of administration | Subcutaneous |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Protein binding | Up to 58% |
| Metabolism | None |
| Eliminationhalf-life | 3–5 hours |
| Excretion | Kidney |
| Identifiers | |
| |
| CAS Number |
|
| PubChemCID | |
| 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) | |
| |
| |
 N Y (what is this?) (verify) | |
Plerixafor, sold under the brand nameMozobil, is animmunostimulant used to mobilizehematopoietic stem cells in cancer patients into the bloodstream. The stem cells are then extracted from the blood andtransplanted back to the patient. The drug was developed by AnorMED, which was subsequently bought byGenzyme.
Peripheral blood stem cell mobilization, which is important as a source ofhematopoietic stem cells fortransplantation, is generally performed usinggranulocyte 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 withlymphoma andmultiple myeloma.[5]
Phase 2 clinical trials started in 2021 exploring the combination of plerixafor and MGTA-145, aCXCL2 ligand.[6][7]
Studies in pregnant animals have shownteratogenic effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to usecontraception. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.[5]
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]
TheEuropean Medicines Agency has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities ofspleen rupture and tumor cell mobilisation. The first concern has been raised becausesplenomegaly 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]
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]
In the form of its zinc complex, plerixafor acts as anantagonist (or perhaps more accurately apartial agonist) of the alphachemokine receptorCXCR4 and anallosteric agonist ofCXCR7.[10]The CXCR4 alpha-chemokine receptor and one of itsligands,SDF-1, are important inhematopoietic stem cell homing to thebone marrow and inhematopoietic stem cellquiescence. Thein vivo effect of plerixafor with regard toubiquitin, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization ofhematopoietic stem cells from the bone marrow to the bloodstream asperipheral blood stem cells.[11] Additionally, plerixafor inhibitsCD20 expression on B cells by interfering with CXCR4/SDF1 axis that regulates its expression.[citation needed]
Followingsubcutaneous 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 inextravascular compartments. The drug is notmetabolized in significant amounts; no interaction with thecytochrome P450 enzymes orP-glycoproteins has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via thekidneys, with 70% of the drug being excreted within 24 hours.[5]
Plerixafor is amacrocyclic compound and a bicyclam derivative, the cyclam rings being linked at the amine nitrogen atoms by a 1,4-xylyl spacer.[4] It is a base; all eight nitrogen atoms acceptprotons readily. The two macrocyclic rings formchelate complexes with bivalent metal ions, especiallyzinc,copper andnickel, as well ascobalt andrhodium. The biologically active form of plerixafor is its zinc complex.[12]
Three of the four nitrogen atoms of the macrocycle cyclam... (1,4,8,11-tetraazacyclotetradecane) are protected withtosyl groups. The product is treated with 1,4-bis(brommethyl)benzene andpotassium carbonate inacetonitrile. After cleaving of the tosyl groups withhydrobromic acid, plerixafor octahydrobromide is obtained.[13]
The molecule was first synthesised in 1987 to carry out basic studies on theredox chemistry of dimetallic coordination compounds.[14] Then, it wasserendipitously 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 andcardiac disturbances. Further studies led to the new indication for cancer patients.[15]
Plerixafor hasorphan drug status in the United States and European Union for the mobilization ofhematopoietic 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 positiveCommittee for Medicinal Products for Human Use assessment report on 29 May 2009.[9] The drug was approved for use in Canada byHealth Canada on 8 December 2011.[17]
Plerixafor was seen to reduce metastasis in mice in several studies.[18] It has also been shown to reduce recurrence ofglioblastoma 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]
Researchers at Imperial College have demonstrated that plerixafor in combination withvascular endothelial growth factor (VEGF) can mobilisemesenchymal stem cells andendothelial progenitor cells into the peripheral blood of mice.[20]
In a 2020 study, researchers did not find evidence that plerixafor assisted in the healing of diabetic-relatedarterial insufficiency ulcers.[21]
Blockade ofCXCR4 signalling by plerixafor has also unexpectedly been found to be effective at counteractingopioid-induced hyperalgesia produced by chronic treatment withmorphine, though only animal studies have been conducted as yet.[22]
{{cite journal}}:Cite journal requires|journal= (help){{cite journal}}:Cite journal requires|journal= (help)