Chemistry:Pemetrexed

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Short description: Chemical compound
Pemetrexed
Pemetrexed.svg
Pemetrexed ball-and-stick.png
Clinical data
Trade namesAlimta, Pemfexy, Ciambra, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: D
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNA
Protein binding81%
MetabolismNegligible
Elimination half-life3.5 hours
ExcretionKidney
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC20H21N5O6
Molar mass427.417 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

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).[1].

It is available as a generic medication.[5][6]

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[7] for patients whose disease is either unresectable or who are not otherwise candidates for curative surgery.[8] 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.[9][10][1]

Carboplatin

Pemetrexed is also recommended in combination with carboplatin and pembrolizumab for the first-line treatment of advanced non-small cell lung cancer.[11][12] 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.[13]

Supplementation

Patients are recommended to take folic acid and vitamin B12 supplement even if levels are normal when they are on pemetrexed therapy.[14][1] (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.[1]

Side effects

Pemetrexed, whether used alone or in combination with cisplatin, has these side effects:[1]

  • Low blood cell counts, as measured by a complete blood count. This is a dose-limiting toxicity.
  • Mental fatigue and sleepiness. Fatigue can be reduced through an off-label prescription of modafinil.[15]
  • Nausea and vomiting. Pemetrexed's emetogenic effects are managed with prophylactic antiemetics.
  • Diarrhea
  • Oral mucositis (mouth, throat, or lip sores). Oral ulcers can be mitigated by proper oral hygiene, including rinsing of the mouth with salt water following consumption of food or drink.[16]
  • Loss of appetite
  • Skin rash. Physician-prescribed glucocorticoids administered on the day prior, day of, and day after infusion typically avoid skin rashes.
  • Constipation

Mechanism of action

Pathway of tetrahydrofolate and antimetabolites

Pemetrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites. It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase[17][18] (GARFT). By inhibiting the formation of precursor purine and pyrimidine nucleotides, 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), each vial of the medication costs between US$2,623 and US$3,100.[19]

Brand names

In February 2020, Pemfexy was approved for use in the United States.[20]

Research

A Phase III study showed benefits of maintenance use of pemetrexed for non-squamous NSCLC.[21] Activity has been shown in malignant peritoneal mesothelioma.[22]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Alimta- pemetrexed disodium injection, powder, lyophilized, for solution". 25 March 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5a860f3-37ec-429c-ae04-9c88d7c55c08. 
  2. ↑ "Pemfexy- pemetrexed injection". 20 January 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2308f4e8-21c8-49c1-a5b8-deb8610bac6a. 
  3. ↑ "Alimta EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/alimta. 
  4. ↑ "Pemetrexed Baxter: Pending EC decision". 14 October 2022. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/pemetrexed-baxter. 
  5. ↑ "2022 First Generic Drug Approvals". 3 March 2023. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals. 
  6. ↑ "Competitive Generic Therapy Approvals". 29 June 2023. https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals. 
  7. ↑ "Pemetrexed (Alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma". Seminars in Oncology 30 (4 Suppl 10): 32–36. August 2003. doi:10.1016/S0093-7754(03)00283-5. PMID 12917819. 
  8. ↑ National Cancer Institute: FDA Approval for Pemetrexed Disodium
  9. ↑ "Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer". The Oncologist 14 (9): 930–935. September 2009. doi:10.1634/theoncologist.2009-0092. PMID 19737998. 
  10. ↑ "Pemetrexed in the treatment of advanced non-squamous lung cancer". Lung Cancer 66 (2): 141–149. November 2009. doi:10.1016/j.lungcan.2009.06.006. PMID 19577816. 
  11. ↑ "Non-small Cell Lung Cancer V.1.2007". NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network (NCCN). https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. 
  12. ↑ "Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer". The New England Journal of Medicine 378 (22): 2078–2092. May 2018. doi:10.1056/NEJMoa1801005. PMID 29658856. 
  13. ↑ "Cisplatin versus carboplatin for patients with metastatic non-small-cell lung cancer--an old rivalry renewed". Journal of the National Cancer Institute 99 (11): 828–829. June 2007. doi:10.1093/jnci/djk222. PMID 17551137. 
  14. ↑ "FDA drug approval summaries: pemetrexed (Alimta)". The Oncologist 9 (5): 482–488. 2004. doi:10.1634/theoncologist.9-5-482. PMID 15477632. 
  15. ↑ "Scientists Help Breast Cancer Survivor Lift the Fog of "Chemo Brain"". Dialogue (James P Wilmot Cancer Center, University of Rochester Medical Center): 2–3. Fall 2007. http://www.urmc.rochester.edu/cancer-center/documents/fall07.pdf. Retrieved 1 December 2008. [yes|permanent dead link|dead link}}]
  16. ↑ "Oral Complications of Chemotherapy and Head/Neck Radiation". Cancer Topics – Coping with Cancer. National Cancer Institute. http://www.cancer.gov/cancertopics/pdq/supportivecare/oralcomplications/Patient/page5. 
  17. ↑ "Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034". Clinical Cancer Research 6 (7): 2677–2684. July 2000. PMID 10914709. http://clincancerres.aacrjournals.org/cgi/content/abstract/6/7/2677. Retrieved 2 December 2008. 
  18. ↑ Medicinal Chemistry of Anticancer Drugs. Amsterdam: Elsevier. April 2008. p. 37. ISBN 978-0-444-52824-7. https://books.google.com/books?id=GjhXyqB5iLcC. 
  19. ↑ "Decoding Big Pharma's Secret Drug Pricing Practices". Bloomberg. 29 June 2016. https://www.bloomberg.com/graphics/2016-drug-prices/. 
  20. ↑ "Pemfexy: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=209472. 
  21. ↑ "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 of Clinical Oncology (American Society of Clinical Oncology) 27 (18 suppl): CRA8000. June 2009. doi:10.1200/jco.2009.27.18_suppl.cra8000. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=33019. Retrieved 22 July 2009. 
  22. ↑ "Malignant peritoneal mesothelioma-Results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent". Lung Cancer 64 (2): 211–218. May 2009. doi:10.1016/j.lungcan.2008.08.013. PMID 19042053. 

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