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Thursday, 16 July 2009

New Drug Approvals - Pt. XII - Dronedarone (Multaq)

Another drug reaching the market this year is Dronedarone (trade name Multaq), approved on July 1st. Dronedarone is a antiarrythmic agent indicated to reduce the risk of cardiovascular hospitalization in patients with a history of heart rhythm disorders. The drug is approved to be used in patients whose hearts have returned to normal rhythm or who will undergo drug or electric-shock treatment to restore a normal heart beat. Dronedarone is an antiarrythmic agent of unknown detailed mechanism of action (specifically it does not fit into one of the existing Vaughn Williams classification scheme), but is known to be a multi-channel blocker that affects calcium, potassium and sodium channels and also has anti-adrenergic receptor activity. Dronedarone (previously known by the research code SR33589) is a relatively large small molecule drug (Molecular Weight of 556.8 g.mol-1 for Dronedarone itself, and 593.2 g.mol-1 for the HCl salt), highly lipophilic and practically insoluble in water. Dronedarone has low systemic bioavailabity (~4%, increasing to ~15% if administrated with high fat meal, this low absolute oral bioavailability is due to extensive first-pass metabolism). Dronedarone has a volume of distribution of 1400L, and a high plasma protein binding of >98%. Dronedarone is extensively metabolized, mainly by CYP3A4, to the active N-debutyl metabolite and also to some inactive metabolites. The N-debutyl metabolite exhibits some pharmacologic activity but is much less potent than Dronedarone itself. Dronedarone is mostly excreted in the feces, mainly as metabolites. It has a plasma clearance of 130-150 L/hour and an elimination half-life of 13-19 hours. Recommended dosage is one tablet of 400 mg (equivalent to ca. 670 umol) twice a day, taken with morning and evening meals (see the higher bioavailability when taken with food discussed above). The full prescribing information can be found here.

Dronedarone has a boxed warning (colloquially known as 'black box').

The Dronedarone structure is N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide. It contains an aryl sulfonamide and a tertiary amine. The amine is clearly basic in nature, but aryl sulphonamides are often weak acids, and are surprisingly common in drug structures. Dronedarone is a benzofuran derivative, chemically similar to Amiodarone, a widely used and early (discovered in 1961) class III antiarrhythmic agent, whose clinical use is often limited by a multitude of side effects.

Dronedarone canonical SMILES: O=S(=O)(Nc3cc1c(oc(c1C(=O)c2ccc(OCCCN(CCCC)CCCC)cc2)CCCC)cc3)C Dronedarone InChI: InChI=1/C31H44N2O5S/c1-5-8-12-29-30(27-23-25(32-39(4,35)36)15-18- 28(27)38-29)31(34)24-13-16-26(17-14-24)37-22-11-21-33(19-9-6-2)20 -10-7-3/h13-18,23,32H,5-12,19-22H2,1-4H3 Dronedarone InChIKey: ZQTNQVWKHCQYLQ-UHFFFAOYAL Dronedarone CAS registry: 141626-36-0 Dronedarone ChemDraw: Dronedarone.cdx

The license holder for Dronedarone is Sanofi-Aventis and the product website is www.multaq.com.

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