Deferasirox

Deferasirox, sold under the brand name Exjade among others, is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias.[2][3] It is the first oral medication approved in the United States for this purpose.[4]

Deferasirox

Clinical data
Pronunciation	de FER a sir ox
Trade names	Exjade, Jadenu
Other names	CGP-72670, ICL-670A, IC L670
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN US DailyMed: Deferasirox
Pregnancy category	AU: C
Routes of administration	By mouth
ATC code	V03AC03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only EU: Rx-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	70%
Protein binding	99%
Metabolism	Hepatic glucuronidation
Elimination half-life	8 to 16 hours
Excretion	Fecal (84%) and renal (8%)
Identifiers
IUPAC name 4-(3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid
CAS Number	201530-41-8
PubChem CID	214348
DrugBank	DB01609
ChemSpider	4591431
UNII	V8G4MOF2V9
KEGG	D03669
ChEBI	CHEBI:49005
ChEMBL	ChEMBL550348
CompTox Dashboard (EPA)	DTXSID1048596
ECHA InfoCard	100.211.077
Chemical and physical data
Formula	C21H15N3O4
Molar mass	373.368 g·mol^−1
3D model (JSmol)	Interactive image
Density	1.4±0.1 g/cm^3 [1]
SMILES OC(=O)c1ccc(cc1)n2nc(nc2c3ccccc3O)c4ccccc4O
InChI InChI=1S/C21H15N3O4/c25-17-7-3-1-5-15(17)19-22-20(16-6-2-4-8-18(16)26)24(23-19)14-11-9-13(10-12-14)21(27)28/h1-12,25-26H,(H,27,28) Key:BOFQWVMAQOTZIW-UHFFFAOYSA-N
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It was approved by the U.S.Food and Drug Administration (FDA) in November 2005.[2][4] According to the FDA (May 2007), kidney failure and cytopenias have been reported in patients receiving deferasirox oral suspension tablets. It is approved in the European Union by the European Medicines Agency (EMA) for children six years and older for chronic iron overload from repeated blood transfusions.[5][6][7]

In July 2020, Teva decided to discontinue deferasirox.[8] It is available as a generic medication.[9]

Properties

Two deferasirox molecules binding iron

The half-life of deferasirox is between 8 and 16 hours allowing once a day dosing. Two molecules of deferasirox are capable of binding to 1 atom of iron which are subsequently eliminated by fecal excretion. Its low molecular weight and high lipophilicity allows the drug to be taken orally unlike deferoxamine which has to be administered by IV route (intravenous infusion). Together with deferiprone, deferasirox seems to be capable of removing iron from cells (cardiac myocytes and hepatocytes) as well as removing iron from the blood.

Synthesis

Deferasirox can be prepared from simple commercially available starting materials (salicylic acid, salicylamide and 4-hydrazinobenzoic acid) in the following two-step synthetic sequence:

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The condensation of salicyloyl chloride (formed in situ from salicylic acid and thionyl chloride) with salicylamide under dehydrating reaction conditions results in formation of 2-(2-hydroxyphenyl)-1,3(4H)-benzoxazin-4-one. This intermediate is isolated and reacted with 4-hydrazinobenzoic acid in the presence of base to give 4-(3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl)benzoic acid (deferasirox).[10]

Risks

Deferasirox was the #2 drug on the list of 'Most frequent suspected drugs in reported patient deaths' compiled by the Institute for Safe Medical Practices in 2009. There were 1320 deaths reported, perhaps explained by an update to the ADE data of Novartis, and a new boxed warning about gastrointestinal haemorrhage as well as kidney and liver failure.[11]

References

1. "Material Safety Data Sheet (MSDS): Deferasirox". ChemSrc. 2018.
2. Choudhry VP, Naithani R (August 2007). "Current status of iron overload and chelation with deferasirox". Indian Journal of Pediatrics. 74 (8): 759–64. doi:10.1007/s12098-007-0134-7. PMID 17785900. S2CID 19930076. Free full text Archived 2014-04-29 at the Wayback Machine
3. Yang LP, Keam SJ, Keating GM (2007). "Deferasirox : a review of its use in the management of transfusional chronic iron overload". Drugs. 67 (15): 2211–30. doi:10.2165/00003495-200767150-00007. PMID 17927285.
4. "FDA Approves First Oral Drug for Chronic Iron Overload" (Press release). United States Food and Drug Administration. November 9, 2005. Retrieved 2007-10-31.
5. "Exjade – deferasirox" (PDF). European Medicines Agency. 2018.
6. Kontoghiorghes GJ (April 2013). "Turning a blind eye to deferasirox's toxicity?". Lancet. 381 (9873): 1183–4. doi:10.1016/S0140-6736(13)60799-0. PMID 23561999. S2CID 27794849.
7. "Review: Exjade side effects".
8. "Deferasirox Discontinuation". U.S. Food and Drug Administration (FDA). Retrieved 20 July 2020.
9. "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration. Retrieved 15 August 2020.
10. Steinhauser S, Heinz U, Bartholomä M, Weyhermüller T, Nick H, Hegetschweiler K (2004). "Complex Formation of ICL670 and Related Ligands with Fe^III and Fe^II". European Journal of Inorganic Chemistry. 2004 (21): 4177–4192. doi:10.1002/ejic.200400363.]
11. ISMP (2010). "ISMP QuarterWatch(TM)". 15 (12). ISMP Medication Safety Alert. pp. 1–3.

External links

• "Deferasirox". Drug Information Portal. U.S. National Library of Medicine.