Oxaliplatin

Oxaliplatin

Systematic (IUPAC) name
[(1R,2R)-cyclohexane-1,2-diamine](ethanedioato-O,O')platinum(II)
Clinical data
Trade names	Eloxatin
AHFS/Drugs.com	monograph
MedlinePlus	a607035
Pregnancy category	US: D (Evidence of risk)
Legal status	US: ℞-only
Routes of administration	Intravenous
Pharmacokinetic data
Bioavailability	Complete
Biological half-life	~10 - 25 minutes
Excretion	Renal
Identifiers
CAS Number	61825-94-3 Y
ATC code	L01XA03 (WHO)
PubChem	CID: 77994
DrugBank	DB00526 N
ChemSpider	8062727 N
UNII	04ZR38536J N
KEGG	D01790 Y
ChEMBL	CHEMBL414804 N
PDB ligand ID	1PT (PDBe, RCSB PDB)
Chemical data
Formula	C8H14N2O4Pt
Molecular mass	397.2858 g/mol
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Oxaliplatin, marketed as Eloxatin by Sanofi, is a platinum-based antineoplastic agent used in cancer chemotherapy.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.

Medical uses

Oxaliplatin is used for treatment of colorectal cancer, typically along with folinic acid and 5-fluorouracil in a combination known as FOLFOX. Oxaliplatin has been compared with other platinum compounds used for advanced cancers, such as cisplatin and carboplatin.

Advanced colorectal cancer

In clinical studies, oxaliplatin by itself has modest activity against advanced colorectal cancer. 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.

Adjuvant treatment of colorectal cancer

After and/or before the curative resection of colorectal cancer, chemotherapy based on 5-fluorouracil and folinic acid reduces the risk of relapse. The benefit is clinically relevant when cancer has spread to locoregional lymph nodes or penetrated through the wall of the rectum or colon (stage III, Dukes C). The addition of oxaliplatin improves relapse-free survival, but data on overall survival have not yet been published in extenso.

When cancer has not spread to the locoregional lymph nodes, nor penetrated through the wall of the rectum or colon (stage II, Dukes B) the benefit of chemotherapy is marginal and the decision on whether to give adjuvant chemotherapy should be carefully evaluated by discussing with the patient the realistic benefits and the possible toxic side effects of treatment. This is even more relevant when the oncologist proposes treatment with oxaliplatin.

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.
• 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
• Persistent hiccups

In addition, some patients may experience an allergic reaction to platinum-containing drugs. This is more common in women.

Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin.

Structure and mechanism

The compound features a square planar platinum(II) center. In contrast to cisplatin and carboplatin, oxaliplatin features the bidentate ligand 1,2-diaminocyclohexane in place of the two monodentate ammine ligands. It also features a bidentate oxalate group.

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, which prevent DNA replication and transcription, causing cell death.

History

Oxaliplatin was discovered in 1976 at Nagoya City University by Professor Yoshinori Kidani, who was granted U.S. Patent 4,169,846 in 1979. Oxaliplatin was subsequently in-licensed by Debiopharm and developed as an advanced colorectal cancer treatment. Debiopharm licensed the drug to Sanofi-Aventis in 1994. It gained European approval in 1996 (initially in France) and approval by the U.S. Food and Drug Administration in 2002. Generic oxaliplatin was first approved in the United States in August 2009. Patent disputes caused generic production to stop in 2010, but it restarted in 2012.

Patent information

Eloxatin is covered by patent numbers 5338874 (Expiry Apr 07,2013), 5420319 (Expiry Aug 08,2016), 5716988 (Expiry Aug 07,2015) and 5290961 (Expiry Jan 12, 2013) (see Electronic Orange Book patent info for Eloxatin). Exclusivity code I-441, which expired on Nov 04, 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 Aug 09, 2007.

External links

• Oxaliplatin - Official web site of manufacturer.
• Oxaliplatin Prescribing Information - Official prescribing information.
• NCI Drug Information Summary on Oxaliplatin