View source for Pemetrexed

{{Short description|Chemical compound}}
{{Use dmy dates|date=November 2022}}
{{Infobox drug
| Verifiedfields = changed
| verifiedrevid = 464197624
| image = Pemetrexed.svg
| image2 = Pemetrexed ball-and-stick.png

<!--Clinical data-->
| tradename = Alimta, Pemfexy, Ciambra, others
| Drugs.com = {{drugs.com|monograph|pemetrexed-disodium}}
| DailyMedID = Pemetrexed
| pregnancy_AU = D
| routes_of_administration = [[Intravenous therapy|Intravenous]]
| ATC_prefix = L01
| ATC_suffix = BA04
| ATC_supplemental =

| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}</ref>
| legal_UK = POM
| legal_US = Rx-only
| legal_US_comment = <ref name="Alimta FDA label" /><ref name="Pemfexy FDA label">{{cite web | title=Pemfexy- pemetrexed injection | website=DailyMed | date=20 January 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2308f4e8-21c8-49c1-a5b8-deb8610bac6a | access-date=20 May 2022 | archive-date=21 May 2022 | archive-url=https://web.archive.org/web/20220521021818/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2308f4e8-21c8-49c1-a5b8-deb8610bac6a | url-status=live }}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Alimta EPAR">{{cite web | title=Alimta EPAR | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/alimta | access-date=14 October 2022 | archive-date=18 January 2021 | archive-url=https://web.archive.org/web/20210118214202/https://www.ema.europa.eu/en/medicines/human/EPAR/alimta | url-status=live }}</ref><ref>{{cite web | title=Pemetrexed Baxter: Pending EC decision | website=European Medicines Agency | date=14 October 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/pemetrexed-baxter | access-date=14 October 2022 | archive-date=14 October 2022 | archive-url=https://web.archive.org/web/20221014175806/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/pemetrexed-baxter | url-status=live }}</ref>

<!--Pharmacokinetic data-->
| bioavailability = NA
| protein_bound = 81%
| metabolism = Negligible
| elimination_half-life = 3.5 hours
| excretion = [[Kidney]]

<!--Identifiers-->
| index2_label = as salt
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 137281-23-3
| PubChem = 135410875
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00642
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 393879
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 04Q9AIZ7NO
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07472
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D06503
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 225072

<!--Chemical data-->
| IUPAC_name = (2''S'')-2-<nowiki/>{[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-''d'']pyrimidin-5-yl)ethyl]benzoyl]amino}pentanedioic acid
| C=20 | H=21 | N=5 | O=6 
| smiles = Nc3nc2[nH]cc(CCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)c2c(=O)[nH]3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H21N5O6/c21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29)/t13-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = WBXPDJSOTKVWSJ-ZDUSSCGKSA-N
}}

'''Pemetrexed''', sold under the brand name '''Alimta''' among others, is a [[chemotherapy]] medication for the treatment of [[pleural]] [[mesothelioma]] and [[non-small cell lung cancer]] (NSCLC).<ref name="Alimta FDA label" />

It is available as a [[generic medication]].<ref>{{cite web | title=2022 First Generic Drug Approvals | website=U.S. [[Food and Drug Administration]] (FDA) | date=3 March 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003602/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-date=30 June 2023 | url-status=live | access-date=30 June 2023}}</ref><ref>{{cite web | title=Competitive Generic Therapy Approvals | website=U.S. [[Food and Drug Administration]] (FDA) | date=29 June 2023 | url=https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | access-date=29 June 2023 | archive-date=29 June 2023 | archive-url=https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | url-status=live }}</ref>

==Medical use==
In February 2004, the U.S. [[Food and Drug Administration]] (FDA) approved pemetrexed for treatment of malignant pleural mesothelioma, a type of tumor of the [[mesothelium]], the thin layer of tissue that covers many of the internal organs, in combination with [[cisplatin]]<ref>{{cite journal | vauthors = Manegold C | title = Pemetrexed (Alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma | journal = Seminars in Oncology | volume = 30 | issue = 4 Suppl 10 | pages = 32–36 | date = August 2003 | pmid = 12917819 | doi = 10.1016/S0093-7754(03)00283-5 }}</ref> for patients whose disease is either unresectable or who are not otherwise candidates for curative surgery.<ref>National Cancer Institute: [http://www.cancer.gov/cancertopics/druginfo/fda-pemetrexed-disodium#malignant_pleural FDA Approval for Pemetrexed Disodium] {{Webarchive|url=https://web.archive.org/web/20150406010932/http://www.cancer.gov/cancertopics/druginfo/fda-pemetrexed-disodium#malignant_pleural |date=6 April 2015 }}</ref> In September 2008, the FDA granted approval as a first-line treatment, in combination with cisplatin, against locally advanced and metastatic [[non-small cell lung cancer]] (NSCLC) in patients with non-squamous histology.<ref>{{cite journal | vauthors = Cohen MH, Justice R, Pazdur R | title = Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer | journal = The Oncologist | volume = 14 | issue = 9 | pages = 930–935 | date = September 2009 | pmid = 19737998 | doi = 10.1634/theoncologist.2009-0092 | s2cid = 28209589 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Rossi A, Ricciardi S, Maione P, de Marinis F, Gridelli C | title = Pemetrexed in the treatment of advanced non-squamous lung cancer | journal = Lung Cancer | volume = 66 | issue = 2 | pages = 141–149 | date = November 2009 | pmid = 19577816 | doi = 10.1016/j.lungcan.2009.06.006 }}</ref><ref name="Alimta FDA label" />

===Carboplatin===
Pemetrexed is also recommended in combination with [[carboplatin]] and [[pembrolizumab]] for the first-line treatment of advanced non-small cell lung cancer.<ref>{{cite web | vauthors = Ettinger DS, etal | work = NCCN Clinical Practice Guidelines in Oncology | title = Non-small Cell Lung Cancer V.1.2007 | publisher =  National Comprehensive Cancer Network (NCCN) | url = https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf | archive-url = https://web.archive.org/web/20070323012050/https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf | archive-date = 23 March 2007 }}</ref><ref>{{cite journal | vauthors = Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC | display-authors = 6 | title = Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer | journal = The New England Journal of Medicine | volume = 378 | issue = 22 | pages = 2078–2092 | date = May 2018 | pmid = 29658856 | doi = 10.1056/NEJMoa1801005 | collaboration = KEYNOTE-189 Investigators | doi-access = free | hdl = 10138/298862 | hdl-access = free }}</ref> However, the relative efficacy or toxicity of pemetrexed-cisplatin versus pemetrexed-carboplatin has not been established beyond what is generally thought about cisplatin or carboplatin doublet drug therapy.<ref>{{cite journal | vauthors = Azzoli CG, Kris MG, Pfister DG | title = Cisplatin versus carboplatin for patients with metastatic non-small-cell lung cancer--an old rivalry renewed | journal = Journal of the National Cancer Institute | volume = 99 | issue = 11 | pages = 828–829 | date = June 2007 | pmid = 17551137 | doi = 10.1093/jnci/djk222 | doi-access = free }}</ref>

===Supplementation===
Patients are recommended to take [[folic acid]] and [[vitamin B12|vitamin B<sub>12</sub>]] supplement even if levels are normal when they are on pemetrexed therapy.<ref>{{cite journal | vauthors = Hazarika M, White RM, Johnson JR, Pazdur R | title = FDA drug approval summaries: pemetrexed (Alimta) | journal = The Oncologist | volume = 9 | issue = 5 | pages = 482–488 | year = 2004 | pmid = 15477632 | doi = 10.1634/theoncologist.9-5-482 | s2cid = 11444611 }}</ref><ref name="Alimta FDA label">{{cite web | title=Alimta- pemetrexed disodium injection, powder, lyophilized, for solution | website=DailyMed | date=25 March 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5a860f3-37ec-429c-ae04-9c88d7c55c08 | access-date=20 October 2020 | archive-date=20 October 2020 | archive-url=https://web.archive.org/web/20201020074626/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5a860f3-37ec-429c-ae04-9c88d7c55c08 | url-status=live }}</ref> (In clinical trials for mesothelioma, folic acid and B12 supplementation reduced the frequency of adverse events.)  It is also recommended for patients to be on a [[glucocorticoid]] (e.g. [[dexamethasone]]) on the day prior, day of, and day after pemetrexed infusion to avoid skin rashes.<ref name="Alimta FDA label" />

==Drug interaction==
The administration of cisplatin and [[vitamin B12|vitamin B<sub>12</sub>]] concomitantly does not modify the [[pharmacokinetics]] of the pemetrexed.
It was recently shown that pemetrexed may play a role in cisplatin resistance in lung cancer by increasing the expression of Orai3 calcium channels as well as the expression of certain ABC transporters like MDR1 and MRP-5 responsible for cisplatin efflux and therefore a reduction of the effect of cisplatin<ref>{{cite bioRxiv |last1=Daoudi |first1=Redoane |date=26 September 2024 |title=Characterization and implication of the Orai3 channel and ABC type transporters in the phenomenon of chemoresistance to cisplatin and pemetrexed in lung cancer. |biorxiv=10.1101/2024.09.22.613742}}</ref>
As current therapies are based on the co-administration of pemetrexed and cisplatin, there may be interactions between pemetrexed and cisplatin, including a reduction in the therapeutic effects of cisplatin caused by pemetrexed.

==Mechanism of action==
[[File:Pathway of tetrahydrofolate and antimetabolites.pdf|thumb|Pathway of tetrahydrofolate and antimetabolites]]
Pemetrexed is chemically similar to [[folic acid]] and is in the class of chemotherapy drugs called [[folate antimetabolite]]s.  It works by inhibiting three enzymes used in [[purine]] and [[pyrimidine]] synthesis—[[thymidylate synthase]] (TS), [[dihydrofolate reductase]] (DHFR), and [[glycinamide ribonucleotide formyltransferase]]<ref>{{cite journal | vauthors = McLeod HL, Cassidy J, Powrie RH, Priest DG, Zorbas MA, Synold TW, Shibata S, Spicer D, Bissett D, Pithavala YK, Collier MA, Paradiso LJ, Roberts JD | display-authors = 6 | title = Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034 | journal = Clinical Cancer Research | volume = 6 | issue = 7 | pages = 2677–2684 | date = July 2000 | pmid = 10914709 | url = http://clincancerres.aacrjournals.org/cgi/content/abstract/6/7/2677 | access-date = 2 December 2008 | url-status = live | archive-url = https://web.archive.org/web/20090728001330/http://clincancerres.aacrjournals.org/cgi/content/abstract/6/7/2677 | archive-date = 28 July 2009 }}</ref><ref>{{cite book | vauthors = Avendano C, Menendez JC | title = Medicinal Chemistry of Anticancer Drugs | publisher = [[Elsevier]] | date = April 2008 | location = Amsterdam | page = 37 | url = https://books.google.com/books?id=GjhXyqB5iLcC | isbn = 978-0-444-52824-7 }}</ref> (GARFT). By inhibiting the formation of precursor purine and pyrimidine [[nucleotide]]s, pemetrexed prevents the formation of [[DNA]] and [[RNA]], which are required for the growth and survival of both normal cells and cancer cells.

==Society and culture==
===Economics===
In the United States, {{as of|2015|lc=yes}}, each vial of the medication costs between {{US$|2,623}} and {{US$|3,100}}.<ref>{{cite news| vauthors = Langreth R |title=Decoding Big Pharma's Secret Drug Pricing Practices|url=https://www.bloomberg.com/graphics/2016-drug-prices/|access-date=15 July 2016|publisher=Bloomberg|date=29 June 2016|archive-date=13 July 2016|archive-url=https://web.archive.org/web/20160713133019/http://www.bloomberg.com/graphics/2016-drug-prices/|url-status=live}}</ref>

===Brand names===
In February 2020, Pemfexy was approved for use in the United States.<ref>{{cite web | title=Pemfexy: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=209472 | access-date=13 February 2020 | archive-date=19 October 2020 | archive-url=https://web.archive.org/web/20201019041806/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=209472 | url-status=dead }}</ref>

==Research==
A Phase III study showed benefits of maintenance use of pemetrexed for non-squamous NSCLC.<ref>{{cite journal | vauthors = Belani CP, Brodowicz T, Ciuleanu T, Kim JH, Krzakowski M, Laack E, Wu YL, Peterson P, Krejcy K, Zielinski C | display-authors = 6 
  | title = Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC). | journal = Journal of Clinical Oncology | date = June 2009 | volume = 27 | issue = 18 suppl | pages = CRA8000 | publisher = [[American Society of Clinical Oncology]] | doi = 10.1200/jco.2009.27.18_suppl.cra8000 
 | url = http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=33019 | access-date = 22 July 2009 | archive-date = 16 June 2009
| archive-url = https://web.archive.org/web/20090616132533/http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=33019 | url-status = dead | url-access = subscription }}</ref> Activity has been shown in malignant peritoneal mesothelioma.<ref>{{cite journal | vauthors = Carteni G, Manegold C, Garcia GM, Siena S, Zielinski CC, Amadori D, Liu Y, Blatter J, Visseren-Grul C, Stahel R | display-authors = 6 | title = Malignant peritoneal mesothelioma-Results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent | journal = Lung Cancer | volume = 64 | issue = 2 | pages = 211–218 | date = May 2009 | pmid = 19042053 | doi = 10.1016/j.lungcan.2008.08.013 }}</ref>

== References ==
{{reflist}}

== External links ==
* {{cite web | title=Pemetrexed disodium | work=NCI Drug Dictionary | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/pemetrexed-disodium }}
* {{cite web | title=Pemetrexed disodium | website=National Cancer Institute | date=5 October 2006 | url=https://www.cancer.gov/about-cancer/treatment/drugs/pemetrexeddisodium }}

{{Chemotherapeutic agents}}
{{Purinergics}}
{{Eli Lilly and Company}}
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[[Category:Mammalian dihydrofolate reductase inhibitors]]
[[Category:Drugs developed by Eli Lilly and Company]]
[[Category:Pyrrolopyrimidines]]
[[Category:Benzamides]]
[[Category:Antifolates]]
[[Category:Thymidylate synthase inhibitors]]
[[Category:Purines]]