Chemistry:Oxaliplatin
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| Trade names | Eloxatin |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a607035 |
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| Routes of administration | Intravenous |
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| Pharmacokinetic data | |
| Bioavailability | Complete |
| Elimination half-life | ~10 – 25 minutes[2] |
| Excretion | Kidney |
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| Chemical and physical data | |
| Formula | C8H14N2O4Pt |
| Molar mass | 397.294 g·mol−1 |
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Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication (platinum-based antineoplastic class) used to treat colorectal cancer.[3] It is given by injection into a vein.[3]
Common side effects include numbness, feeling tired, nausea, diarrhea, and low blood cell counts.[3][4] Other serious side effects include allergic reactions.[4][3] Use in pregnancy is known to harm the baby.[3] Oxaliplatin is in the platinum-based antineoplastic family of medications.[5] It is believed to work by blocking the duplication of DNA.[3]
Oxaliplatin was patented in 1976 in Japan and approved for medical use in 1996 in Europe.[6] It is on the 2023 World Health Organization's List of Essential Medicines.[7]
Medical uses
Oxaliplatin is used for treatment of colorectal cancer, typically along with folinic acid (leucovorin) and fluorouracil in a combination known as FOLFOX[8] or along with capecitabine in a combination known as CAPOX[9] or XELOX.[10] It may also be effective against breast cancer, germ cell tumor, ovarian cancer, non-small-cell lung cancer, and pancreatic cancer.[11]
Advanced colorectal cancer
Oxaliplatin by itself has modest activity against advanced colorectal cancer.[12] When compared with just 5-fluorouracil and folinic acid administered according to the de Gramont regimen, a FOLFOX4 regime produced no significant increase in overall survival, but did produce an improvement in progression-free survival, the primary end-point of the phase III randomized trial.[13]
Adverse effects
Side-effects of oxaliplatin treatment can potentially include:
- Neurotoxicity leading to chemotherapy-induced peripheral neuropathy, a progressive, enduring and often irreversible tingling numbness, intense pain and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs, often with deficits in proprioception.[14] This chronic neuropathy may also be preceded by a transient acute neuropathy occurring at the time of infusion and associated with excitation of voltage-gated Na+ channels.[15][16]
- Fatigue
- Nausea, vomiting, or diarrhea
- Neutropenia (low number of a type of white blood cells)
- Ototoxicity (hearing loss)
- Extravasation if oxaliplatin leaks from the infusion vein it may cause severe damage to the connective tissues.
- Hypokalemia (low blood potassium), which is more common in women than men[17]
- Persistent hiccups[18]
- Rhabdomyolysis[19]
In addition, some patients may experience an allergic reaction to platinum-containing drugs. This is more common in women.[17]
Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin.[14]
Structure and mechanism
The compound features a square planar platinum(II) center. In contrast to other drugs of the platinum-based antineoplastic class of drugs cisplatin and carboplatin, oxaliplatin features the bidentate ligand trans-1,2-diaminocyclohexane in place of the two monodentate ammine ligands. It also features a bidentate oxalate group.[5] The three-dimensional structure of the molecule has been elucidated by X-ray crystallography, although the presence of pseudosymmetry in the crystal structure has caused confusion in its interpretation.[20]
According to in vivo studies, oxaliplatin fights carcinoma of the colon through non-targeted cytotoxic effects. Like other platinum compounds, its cytotoxicity is thought to result from inhibition of DNA synthesis in cells. In particular, oxaliplatin forms both inter- and intra-strand cross links in DNA,[21] which prevent DNA replication and transcription, causing cell death.
History
Oxaliplatin was first synthesized in 1978 at Nagoya City University by Yoshinori Kidani.[22] It was later developed in Europe as a less toxic and more effective alternative to cisplatin. It gained European approval in 1996,[23] and approval by the U.S. Food and Drug Administration in 2002.[24] Generic oxaliplatin was first approved in the United States in August 2009.[25] Patent disputes caused generic production to stop in 2010, but it restarted in 2012.[26][27]
Patent information
Eloxatin was covered by patent numbers 5338874 (expired April 7, 2013), 5420319 (expired August 8, 2016), 5716988 (expired August 7, 2015) and 5290961 (expired January 12, 2013) (see Electronic Orange Book patent info for Eloxatin).[28] Exclusivity code I-441, which expired on November 4, 2007, is for use combination with infusional 5-FU/LV for adjuvant treatment stage III colon cancer patients who have undergone complete resection primary tumor-based on improvement in disease free survival with no demonstrated benefit overall survival after 4 years. Exclusivity code NCE, New Chemical Entity, expired on August 9, 2007.[28]
References
- ↑ "Eloxatin- oxaliplatin injection, solution, concentrate". 22 October 2019. https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=432559.
- ↑ "Pharmacokinetics of oxaliplatin in humans". Medical Oncology 19 (4): 261–265. 2002. doi:10.1385/MO:19:4:261. PMID 12512920.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Oxaliplatin". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/oxaliplatin.html.
- ↑ 4.0 4.1 "The side effects of platinum-based chemotherapy drugs: a review for chemists". Dalton Transactions 47 (19): 6645–6653. May 2018. doi:10.1039/c8dt00838h. PMID 29632935.
- ↑ 5.0 5.1 "The state-of-play and future of platinum drugs". Endocrine-Related Cancer 22 (4): R219–R233. August 2015. doi:10.1530/ERC-15-0237. PMID 26113607.
- ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 513. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA513.
- ↑ The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. WHO/MHP/HPS/EML/2023.02.
- ↑ "FOLFOX". 18 September 2009. https://www.cancer.gov/about-cancer/treatment/drugs/folfox.
- ↑ "CAPOX". 4 April 2012. https://www.cancer.gov/about-cancer/treatment/drugs/capox.
- ↑ "XELOX". 6 January 2012. https://www.cancer.gov/about-cancer/treatment/drugs/xelox.
- ↑ "Oxaliplatin". xPharm: The Comprehensive Pharmacology Reference. Elsevier. 2007. pp. 1–4. doi:10.1016/B978-008055232-3.62973-3. ISBN 9780080552323.
- ↑ "Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers". Journal of Clinical Oncology 16 (8): 2739–2744. August 1998. doi:10.1200/JCO.1998.16.8.2739. PMID 9704726.
- ↑ "Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer". Journal of Clinical Oncology 18 (16): 2938–2947. August 2000. doi:10.1200/JCO.2000.18.16.2938. PMID 10944126.
- ↑ 14.0 14.1 "Oxaliplatin-related neurotoxicity: how and why?". Critical Reviews in Oncology/Hematology 59 (2): 159–168. August 2006. doi:10.1016/j.critrevonc.2006.01.001. PMID 16806962.
- ↑ "Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels". British Journal of Pharmacology 146 (7): 1027–1039. December 2005. doi:10.1038/sj.bjp.0706407. PMID 16231011.
- ↑ "The incidence of acute oxaliplatin-induced neuropathy and its impact on treatment in the first cycle: a systematic review". BMC Cancer 18 (1): 410. April 2018. doi:10.1186/s12885-018-4185-0. PMID 29649985.
- ↑ 17.0 17.1 "An association between transient hypokalemia and severe acute oxaliplatin-related toxicity predominantly in women". Acta Oncologica 49 (4): 515–517. May 2010. doi:10.3109/02841860903464015. PMID 20092386.
- ↑ "Oxaliplatin Side Effects". Drugs.com. https://www.drugs.com/sfx/oxaliplatin-side-effects.html.
- ↑ "Eloxatin information" (in de). mein.sanofi.de. https://mein.sanofi.de/produkte/Eloxatin/Downloads?id=dafcc9b3-4397-4205-aeb3-581a3fa90edd.
- ↑ "The Crystal Structure of Oxaliplatin: A Case of Overlooked Pseudo Symmetry". Polyhedron 67: 429–435. January 2014. doi:10.1016/j.poly.2013.10.003. PMID 24415827.
- ↑ "Oxaliplatin". Nature Reviews. Drug Discovery 3 (1): 11–12. January 2004. doi:10.1038/nrd1287. PMID 14756144.
- ↑ "3.25 - Metal–DNA Coordination Complexes". Comprehensive Inorganic Chemistry II (2nd ed.). Elsevier. 2013. pp. 751–784. doi:10.1016/B978-0-08-097774-4.00330-2. ISBN 9780080965291.
- ↑ "Chapter 24 - The Colon and Rectum". Radiation Oncology (9th ed.). Mosby. 2010. pp. 560–605. ISBN 978-0-323-04971-9.
- ↑ "Eloxatin FDA Approval History". https://www.drugs.com/history/eloxatin.html.
- ↑ "Generic Eloxatin availability". Drugs.com. https://www.drugs.com/availability/generic-eloxatin.html.
- ↑ "Hospira Announces U.S. Re-Launch Of Generic Oxaliplatin Injection" (Press release). Archived from the original on 2015-09-24. Retrieved 2015-08-25.
- ↑ "Top 10 best-selling cancer drugs: Eloxatin–$1.2 billion". FiercePharma. 15 May 2012. http://www.fiercepharma.com/special-reports/top-10-best-selling-cancer-drugs/eloxatin-12-billion.
- ↑ 28.0 28.1 "Patent and Exclusivity Search Results from query on Appl No 021759 Product 001 in the OB_Rx list.". Orange Book. U.S. Food and Drug Administrartion. http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021759&Product_No=001&table1=OB_Rx.. Accessed on: July 22, 2007.
Further reading
- "Oxaliplatin". Nature Reviews. Drug Discovery 3 (1): 11–12. January 2004. doi:10.1038/nrd1287. PMID 14756144. http://www.dresources.com/nature/ntr_0104.pdf. Retrieved 2005-07-19.
External links
- "Oxaliplatin". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/oxaliplatin.
- "Oxaliplatin". 5 October 2006. https://www.cancer.gov/about-cancer/treatment/drugs/oxaliplatin.
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