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Revision as of 13:26, 5 December 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456636386 of page Plerixafor for the Chem/Drugbox validation project (updated: 'CAS_number').  Latest revision as of 07:47, 1 July 2024 edit InternetArchiveBot (talk | contribs)Bots, Pending changes reviewers5,384,277 edits Rescuing 1 sources and tagging 0 as dead.) #IABot (v2.0.9.5) (Whywhenwhohow - 20275 
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{{Short description|Chemical compound}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Use dmy dates|date=September 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox {{Drugbox
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed | Watchedfields = changed
| verifiedrevid = 408957776 | verifiedrevid = 464208649
| image = Plerixafor.svg
| IUPAC_name = 1,1′-bis
| image = JM 3100.svg
| width = 250 | width = 250
| alt =
| image2 = JM 3100 3D.png
| image2 = Plerixafor ball-and-stick model.png
| alt2 =


<!--Clinical data--> <!--Clinical data-->
| tradename = | tradename = Mozobil
| Drugs.com = {{drugs.com|CDI|plerixafor}} | Drugs.com = {{drugs.com|monograph|plerixafor}}
| MedlinePlus = a609018 | MedlinePlus = a609018
| DailyMedID = Plerixafor
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = D | pregnancy_AU = D
| pregnancy_category = | pregnancy_category =
| routes_of_administration = ]
| ATC_prefix = L03
| ATC_suffix = AX16

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA = Rx-only
| legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=Health Canada | date=February 2024 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=24 March 2024}}</ref>
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> | legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = Rx-only | legal_US = Rx-only
| legal_US_comment = <ref name="Mozobil FDA label">{{cite web | title=Mozobil- plerixafor injection, solution | website=DailyMed | date=26 June 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ed08d2b-5051-46b2-aa37-1d6275bf9003 | access-date=13 September 2023}}</ref>
| legal_status =
| legal_EU = Rx-only
| routes_of_administration = ]
| legal_EU_comment = <ref>{{cite web | title=Plerixafor Accord EPAR | website=European Medicines Agency | date=12 October 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/plerixafor-accord | access-date=7 February 2023}}</ref>
| legal_status = Rx-only


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
Line 28: Line 38:
| metabolism = None | metabolism = None
| elimination_half-life = 3–5 hours | elimination_half-life = 3–5 hours
| excretion = ] | excretion = ]


<!--Identifiers--> <!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = <!-- blanked - oldvalue: 155148-31-5 --> | CAS_number = 110078-46-1
| ATC_prefix = L03
| ATC_suffix = AX16
| PubChem = 65015 | PubChem = 65015
| IUPHAR_ligand = 844 | IUPHAR_ligand = 844
| DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB06809 | DrugBank = DB06809
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 58531 | ChemSpiderID = 58531
| UNII_Ref = {{fdacite|changed|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = S915P5499N | UNII = S915P5499N
| KEGG_Ref = {{keggcite|changed|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08971 | KEGG = D08971
| ChEBI = 125354
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 18442 | ChEMBL = 18442
| synonyms = JM 3100, AMD3100

| index2_label = as salt
| CAS_number2_Ref = {{cascite|correct|CAS}}
| CAS_number2 = 155148-31-5
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = OD49913540
<!--Chemical data--> <!--Chemical data-->
| IUPAC_name = 1,1’-(1,4-phenylenebismethylene)bis(1,4,8,11- tetraazacyclotetradecane)
| C=28 | H=54 | N=8
| C=28 | H=54 | N=8
| molecular_weight = 502.782 g/mol
| smiles = N1CCNCCCN(CCNCCC1)Cc2ccc(cc2)CN3CCCNCCNCCCNCC3 | smiles = N1CCNCCCN(CCNCCC1)Cc2ccc(cc2)CN3CCCNCCNCCCNCC3
| InChI = 1/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
| InChIKey = YIQPUIGJQJDJOS-UHFFFAOYAC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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 | StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = YIQPUIGJQJDJOS-UHFFFAOYSA-N | StdInChIKey = YIQPUIGJQJDJOS-UHFFFAOYSA-N
| synonyms = JM 3100, AMD3100
}} }}

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

==Medical uses==
], which is important as a source of ] for ], is generally performed using ] (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.<ref name="DrugsRD">{{cite journal | vauthors = | title = Plerixafor: AMD 3100, AMD3100, JM 3100, SDZ SID 791 | journal = Drugs in R&D | volume = 8 | issue = 2 | pages = 113–9 | year = 2007 | pmid = 17324009 | doi = 10.2165/00126839-200708020-00006 | s2cid = 20824572 }}</ref> The drug is approved for patients with ] and ].<ref name="AustriaCodex">{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2009|edition=2009/2010|isbn=978-3-85200-196-8|language=de}}</ref>

Phase 2 clinical trials started in 2021 exploring the combination of plerixafor and MGTA-145, a ] ligand.<ref>{{cite journal|last=Stanford University|date=2021-08-16|title=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|url=https://clinicaltrials.gov/ct2/show/NCT04552743}}</ref><ref>{{cite journal|last=Magenta Therapeutics, Inc.|date=2021-08-23|others=National Marrow Donor Program|title=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|url=https://clinicaltrials.gov/ct2/show/NCT04762875}}</ref>

==Contraindications==

===Pregnancy and lactation===
Studies in pregnant animals have shown ] effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to use ]. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.<ref name="AustriaCodex" />

==Adverse effects==
], ] 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.<ref name="AustriaCodex" /><ref name="Wagstaff">{{cite journal | vauthors = Wagstaff AJ | title = Plerixafor: in patients with non-Hodgkin's lymphoma or multiple myeloma | journal = Drugs | volume = 69 | issue = 3 | pages = 319–26 | year = 2009 | pmid = 19275275 | doi = 10.2165/00003495-200969030-00007 | s2cid = 195684110 }}</ref>

The ] has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of ] rupture and tumor cell mobilisation. The first concern has been raised because ] 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.<ref name="CHMP">{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001030/WC500030689.pdf|publisher=]|title=CHMP Assessment Report for Mozobil|access-date=12 October 2010|archive-date=18 June 2018|archive-url=https://web.archive.org/web/20180618010759/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001030/WC500030689.pdf|url-status=dead}}</ref>

== 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.<ref name="AustriaCodex" />

==Pharmacology==

===Mechanism of action===
In the form of its zinc complex, plerixafor acts as an ] (or perhaps more accurately a ]) of the alpha ] ] and an ] agonist of ].<ref>{{cite journal | vauthors = Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N | title = AMD3100 is a CXCR7 ligand with allosteric agonist properties | journal = Molecular Pharmacology | volume = 75 | issue = 5 | pages = 1240–7 | date = May 2009 | pmid = 19255243 | doi = 10.1124/mol.108.053389 | s2cid = 28540154 }}</ref>
The CXCR4 alpha-] receptor and one of its ]s, ], are important in ] homing to the ] and in ] ]. The '']'' effect of plerixafor with regard to ], the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of ] from the bone marrow to the bloodstream as ].<ref>{{cite journal | vauthors = Cashen AF, Nervi B, DiPersio J | title = AMD3100: CXCR4 antagonist and rapid stem cell-mobilizing agent | journal = Future Oncology | volume = 3 | issue = 1 | pages = 19–27 | date = February 2007 | pmid = 17280498 | doi = 10.2217/14796694.3.1.19 }}</ref> Additionally, plerixafor inhibits ] expression on B cells by interfering with CXCR4/SDF1 axis that regulates its expression.{{cn|date=November 2018}}

===Pharmacokinetics===
Following ], 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 ]s. The drug is not ] in significant amounts; no interaction with the ] enzymes or ]s has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the ]s, with 70% of the drug being excreted within 24 hours.<ref name="AustriaCodex" />

==Chemistry==
Plerixafor is a ] and a bi] derivative, the cyclam rings being linked at the amine nitrogen atoms by a 1,4-] spacer.<ref name="DrugsRD" /> It is a base; all eight nitrogen atoms accept ]s readily. The two macrocyclic rings form ]es with bivalent metal ions, especially ], ] and ], as well as ] and ]. The biologically active form of plerixafor is its zinc complex.<ref>{{cite journal | vauthors = Esté JA, Cabrera C, De Clercq E, Struyf S, Van Damme J, Bridger G, Skerlj RT, Abrams MJ, Henson G, Gutierrez A, Clotet B, Schols D | title = Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor | journal = Molecular Pharmacology | volume = 55 | issue = 1 | pages = 67–73 | date = January 1999 | pmid = 9882699 | doi = 10.1124/mol.55.1.67 | s2cid = 8565063 }}</ref>

===Synthesis===
Three of the four nitrogen atoms of the macrocycle cyclam... (1,4,8,11-tetraazacyclotetradecane) are protected with ] groups. The product is treated with 1,4-bis(brommethyl)benzene and ] in ]. After cleaving of the tosyl groups with ], plerixafor octahydrobromide is obtained.<ref>{{cite patent| country = WO | number = 93012096 | inventor = Bridger G, Padmanabhan S, Skerlj RT, Thornton DM | assign1 = Johnson Matthey Public Limited Company | pubdate = 24 June 1993 |title=Linked cyclic polyamines with activity against HIV }}</ref>

==History==
The molecule was first synthesised in 1987 to carry out basic studies on the ] chemistry of dimetallic coordination compounds.<ref name="De Clercq">{{cite journal | vauthors = Ciampolini M, Fabbrizzi L, Perotti A, Poggi A, Seghi B, Zanobini F | doi = 10.1021/ic00268a022 | title = 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 | journal = Inorganic Chemistry | volume = 26 | issue = 21 | pages = 3527–3533 | year = 1987 }}</ref> Then, it was ] 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).<ref name="Ciampolini">{{cite journal | vauthors = Davies SL, Serradell N, Bolos J, Bayes M | title = Plerixafor Hydrochloride | journal = Drugs of the Future | volume = 32 | issue = 2| pages = 123 | year = 2007 | doi = 10.1358/dof.2007.032.02.1071897 }}</ref> Development of this indication was terminated because of lacking oral availability and ] disturbances. Further studies led to the new indication for cancer patients.<ref name="Ciampolini"/>

==Society and culture==
Plerixafor has ] status in the United States and European Union for the mobilization of ]. It was approved by the U.S. ] (FDA) for this indication on 15 December 2008.<ref>{{cite press release |url=http://www.prescribingreference.com/news/showNews/which/MozobilApprovedForNonHodgkinsLymphomaAndMultipleMyeloma121801 |title=Mozobil approved for non-Hodgkin's lymphoma and multiple myeloma |date=December 18, 2008 |publisher=Monthly Prescribing Reference |access-date=January 3, 2009 |archive-url=https://web.archive.org/web/20090106115028/http://www.prescribingreference.com/news/showNews/which/MozobilApprovedForNonHodgkinsLymphomaAndMultipleMyeloma121801 |archive-date=January 6, 2009 |url-status=dead }}</ref> In the European Union, the drug was approved after a positive ] assessment report on 29 May 2009.<ref name="CHMP" /> The drug was approved for use in Canada by ] on 8 December 2011.<ref></ref>

==Research==

===Anti-cancer properties===
Plerixafor was seen to reduce metastasis in mice in several studies.<ref>{{cite journal | vauthors = Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, Luker GD | title = CXCR4 regulates growth of both primary and metastatic breast cancer | journal = Cancer Research | volume = 64 | issue = 23 | pages = 8604–12 | date = December 2004 | pmid = 15574767 | doi = 10.1158/0008-5472.CAN-04-1844 | doi-access = free }}</ref> It has also been shown to reduce recurrence of ] 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.<ref>{{cite journal | vauthors = Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM | title = Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice | journal = The Journal of Clinical Investigation | volume = 120 | issue = 3 | pages = 694–705 | date = March 2010 | pmid = 20179352 | pmc = 2827954 | doi = 10.1172/JCI40283 }}</ref>

===Use in stem cell research===
Researchers at Imperial College have demonstrated that plerixafor in combination with ] (VEGF) can mobilise ] and ]s into the peripheral blood of mice.<ref>{{cite journal | vauthors = Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM | title = Differential mobilization of subsets of progenitor cells from the bone marrow | journal = Cell Stem Cell | volume = 4 | issue = 1 | pages = 62–72 | date = January 2009 | pmid = 19128793 | doi = 10.1016/j.stem.2008.10.017 | hdl-access = free | hdl = 10044/1/23497 }}</ref>

In a 2020 study, researchers did not find evidence that plerixafor assisted in the healing of diabetic-related ].<ref>{{cite journal | vauthors = Bonora BM, Cappellari R, Mazzucato M, Rigato M, Grasso M, Menegolo M, Bruttocao A, Avogaro A, Fadini GP | title = Stem cell mobilization with plerixafor and healing of diabetic ischemic wounds: A phase IIa, randomized, double-blind, placebo-controlled trial | journal = Stem Cells Translational Medicine | volume = 9 | issue = 9 | pages = 965–973 | date = September 2020 | pmid = 32485785 | pmc = 7445026 | doi = 10.1002/sctm.20-0020 | s2cid = 219285881 }}</ref>

===Neurologic===
Blockade of ] signalling by plerixafor has also unexpectedly been found to be effective at counteracting ] produced by chronic treatment with ], though only animal studies have been conducted as yet.<ref name="pmid21193025">{{cite journal | vauthors = Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA | title = CXCR4 signaling mediates morphine-induced tactile hyperalgesia | journal = Brain, Behavior, and Immunity | volume = 25 | issue = 3 | pages = 565–73 | date = March 2011 | pmid = 21193025 | pmc = 3039030 | doi = 10.1016/j.bbi.2010.12.014 }}</ref>

== References ==
{{Reflist}}

{{Immunostimulants}}
{{Chemokine receptor modulators}}
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