dronedarone

Dronedarone has been termed a "multichannel blocker".{{cn|date=March 2024}} However, it is unclear which channel(s) play a pivotal role in its success.{{cite journal | vauthors = Guillemare E, Marion A, Nisato D, Gautier P | title = Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells | journal = Journal of Cardiovascular Pharmacology | volume = 36 | issue = 6 | pages = 802–5 | date = December 2000 | pmid = 11117382 | doi = 10.1097/00005344-200012000-00017 | doi-access = free }} Thus, dronedarone's actions at the cellular level are controversial, with most studies suggesting an inhibition in multiple outward potassium currents including rapid delayed rectifier, slow delayed rectifier and ACh-activated inward rectifier.{{cite journal | vauthors = Aimond F, Beck L, Gautier P, Chérif OK, Davy JM, Lorente P, Nisato D, Vassort G | title = Cellular and in vivo electrophysiological effects of dronedarone in normal and postmyocardial infarcted rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 292 | issue = 1 | pages = 415–424 | date = January 2000 | pmid = 10604978 | doi = 10.1016/S0022-3565(24)35307-8}} It is also believed to reduce inward rapid Na current and L-type Ca channels.{{medcn|date=March 2024}} The reduction in K current in some studies was shown to be due to the inhibition of the K-ACh channel or associated GTP-binding proteins. Reduction of K+ current by 69% led to increased AP duration and increased effective refractory periods, thus shown to suppress pacemaker potential of the SA node and return patients to a normal heart rhythm. In a European trial, the average time to recurrence of an arrhythmia was 41 days in the placebo group vs. 96 days in the dronedarone group (similar results obtained in the non-European trial, 59 and 158 days respectively).{{cite journal | vauthors = Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, Radzik D, Aliot EM, Hohnloser SH | title = Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter | journal = The New England Journal of Medicine | volume = 357 | issue = 10 | pages = 987–999 | date = September 2007 | pmid = 17804843 | doi = 10.1056/NEJMoa054686 | collaboration = EURIDIS and ADONIS Investigators | doi-access = free }}

Chemically, dronedarone is a benzofuran derivative related to amiodarone, a popular antiarrhythmic.{{medcn|date=March 2024}} The use of amiodarone is limited by toxicity due its high iodine content (pulmonary fibrosis, thyroid disease) as well as by liver disease.{{medcn|date=March 2024}} In dronedarone, the iodine moieties are not present, reducing toxic effects on the thyroid and other organs.{{medcn|date=March 2024}} A methylsulfonamide group is added to reduce solubility in fats (lipophobicity) and thus reduce neurotoxic effects.

Dronedarone displays amiodarone-like class III antiarrhythmic activity in vitro{{cite journal | vauthors = Sun W, Sarma JS, Singh BN | title = Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart : comparison with amiodarone | journal = Circulation | volume = 100 | issue = 22 | pages = 2276–2281 | date = November 1999 | pmid = 10578003 | doi = 10.1161/01.CIR.100.22.2276 | doi-access = free }} and in clinical trials. The drug also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes.{{Cite web|url=http://www.medscape.com/druginfo/monograph?cid=med&drugid=152656&drugname=Multaq+Oral&monotype=monograph&print=1.|title = Medscape Drugs & Diseases - Comprehensive peer-reviewed medical condition, surgery, and clinical procedure articles with symptoms, diagnosis, staging, treatment, drugs and medications, prognosis, follow-up, and pictures}}

Dronedarone is less lipophilic than amiodarone, has a much smaller volume of distribution, and has an elimination half-life of 13–19 hours—this stands in contrast to amiodarone's half-life of several weeks.{{cite journal | vauthors = Dale KM, White CM | title = Dronedarone: an amiodarone analog for the treatment of atrial fibrillation and atrial flutter | journal = The Annals of Pharmacotherapy | volume = 41 | issue = 4 | pages = 599–605 | date = April 2007 | pmid = 17389667 | doi = 10.1345/aph.1H524 | s2cid = 22339555 }} As a result of these pharmacokinetic characteristics, dronedarone dosing may be less complicated than amiodarone.{{medcn|date=March 2024}}

• Permanent AF (patients in whom normal sinus rhythm will not or cannot be restored)
• Recently decompensated heart failure requiring hospitalization or Class IV heart failure.
• Second-or third-degree AV block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker)
• Bradycardia
• Concomitant use of a strong CYP3A inhibitor
• Concomitant use of drugs or herbal products that prolong the QT interval and may induce Torsade de Pointes
• Liver or lung toxicity related to the previous use of amiodarone
• Severe hepatic impairment
• QTc Bazett interval ≥500 ms, or use with drugs or herbal supplements that prolong QT interval or increase risk of torsades de points (Class I or III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, certain oral macrolides, ephedra).{{Citation needed|date=March 2014}}
• Pregnancy and nursing mothers
• Hypersensitivity to dronedarone
• Hepatic impairment. In January 2011, the FDA advised about cases of rare, but severe, liver injury, including two cases of acute liver failure leading to liver transplant in patients treated with dronedarone (Multaq). It is not known whether routine periodic monitoring of serum liver enzymes (ALT, AST, and alkaline phosphatase) and bilirubin in patients taking dronedarone will prevent the development of severe liver injury.
• PR interval exceeding 280 ms {{Citation needed|date=March 2014}}
• Use of cytochrome P-450 (CYP) 3a isoenzyme inhibitors (includes: clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole)

Clinical trials have compared dronedarone to placebo and to amiodarone, for its ability to reduce atrial fibrillation, to reduce mortality overall and from cardiac causes, and for its adverse effects, including excess mortality. Dronedarone is a non-iodinated class III anti-arrhythmic drug which helps patients return to normal sinus rhythm.{{medcn|date=March 2024}} This treatment for AF is also known to reduce associated mortality and hospitalizations compared to other similar antiarrhythmic agents.

In the EURIDIS and ADONIS trials in atrial fibrillation (2007), dronedarone was significantly more effective than placebo in maintaining sinus rhythm, with no difference in lung and thyroid function in the short term.{{cite journal | vauthors = Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, Radzik D, Aliot EM, Hohnloser SH | title = Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter | journal = The New England Journal of Medicine | volume = 357 | issue = 10 | pages = 987–999 | date = September 2007 | pmid = 17804843 | doi = 10.1056/NEJMoa054686 | hdl-access = free | hdl = 11566/54713 }}

However, in the ANDROMEDA study (2007), dronedarone doubled the death rate compared to placebo, and the trial was halted early. ANDROMEDA enrolled patients with moderate to severe congestive heart failure, a relatively sicker patient population.{{medcn|date=March 2024}}

In a later atrial fibrillation trial, ATHENA, with 4628 subjects, dronedarone was significantly more effective than placebo in reducing the composite endpoint of first hospitalization due to cardiovascular events or death.{{cite journal | vauthors = Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ | title = Effect of dronedarone on cardiovascular events in atrial fibrillation | journal = The New England Journal of Medicine | volume = 360 | issue = 7 | pages = 668–678 | date = February 2009 | pmid = 19213680 | doi = 10.1056/NEJMoa0803778 | doi-access = free }} There was a significant reduction in the rate of cardiovascular death, but not in the rate of death from any cause. Later post-hoc analysis of the ATHENA-results showed a significant reduction in the rate of stroke.{{cite journal | vauthors = Connolly SJ, Crijns HJ, Torp-Pedersen C, van Eickels M, Gaudin C, Page RL, Hohnloser SH | title = Analysis of stroke in ATHENA: a placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400 mg BID for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter | journal = Circulation | volume = 120 | issue = 13 | pages = 1174–1180 | date = September 2009 | pmid = 19752319 | doi = 10.1161/CIRCULATIONAHA.109.875252 | doi-access = free }}

Patients randomized to dronedarone were more likely to develop bradycardia and QT-interval prolongation (but only 1 case of Torsades).{{medcn|date=March 2024}} Nausea, diarrhea, rash, and creatinine elevation also were more common in the dronedarone arm.{{medcn|date=March 2024}}

The PALLAS trial (2011) was stopped for safety concerns due to the finding that "dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events".{{cite journal | vauthors = Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum Á, Blomström P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacrétaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB, Heidbüchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsányi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH | title = Dronedarone in high-risk permanent atrial fibrillation | journal = The New England Journal of Medicine | volume = 365 | issue = 24 | pages = 2268–2276 | date = December 2011 | pmid = 22082198 | pmc = 3860949 | doi = 10.1056/NEJMoa1109867 }} A Black Box warning was subsequently added by the FDA stating that the risk of death, stroke, and hospitalization for congestive heart failure doubled in patients with permanent atrial fibrillation.{{medcn|date=March 2024}}

Dronedarone has been tested in some trials as a way to improve the success rate of electrical cardioversion.{{medcn|date=March 2024}} In one such trial by the Veteran's Administration it was used prepare patients for electrical conversion to sinus rhythm.{{medcn|date=March 2024}} In the ATHENA study, 25% of patients were started on dronedarone before cardioversion. The results of a recently concluded randomized study (ELECTRA) may clarify the safety and ideal modalities of dronedarone use at the time of cardioversion.{{ClinicalTrialsGov|NCT01026090|A Phase IV, Double-blind, Placebo-controlled, Canadian Multicentre Study Comparing Two Treatment Strategies of Dronedarone Administration Following ELECTive caRdioversion for Prevention of Symptomatic Atrial Fibrillation (AF) Recurrence}}

Originally submitted as a New Drug Application in 2005, dronedarone was reviewed and recommended for approval in March 2009, by an Advisory Committee of the United States Food and Drug Administration (FDA).{{Cite web |url=https://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4417b1-02-Sanofi_Aventis.pdf |title=FDA briefing document on dronedarone |website=Food and Drug Administration |access-date=December 16, 2019 |archive-date=March 3, 2017 |archive-url=https://web.archive.org/web/20170303105803/https://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4417b1-02-Sanofi_Aventis.pdf |url-status=dead }} The FDA approved dronedarone in July 2009.{{cn|date=March 2024}}

Health Canada was the second major regulatory body to approve the drug, giving its approval in August 2009.{{cn|date=March 2024}} The approval is for "treatment of patients with a history of, or current atrial fibrillation to reduce their risk of cardiovascular hospitalization due to this condition."{{cite web|url=http://insciences.org/article.php?article_id%3D6454 |title=Multaq® (Dronedarone) for Atrial Fibrillation Now Approved in Canada - insciences |access-date=August 13, 2009 |url-status=dead |archive-url=https://web.archive.org/web/20110718112952/http://insciences.org/article.php?article_id=6454 |archive-date=July 18, 2011 }}

The European Medicines Agency issued a Summary of Positive Opinion regarding dronedarone in September 2009, recommending to the European Commission to grant a marketing authorization within the European Union.{{cite web | url = https://www.ema.europa.eu/documents/smop-initial/committee-medicinal-products-human-use-summary-positive-opinion-multaq_en.pdf | title = Summary of Positive Opinion for Multaq | publisher = European Medicines Agency | date = September 24, 2009 | access-date = December 1, 2009 }}

In July 2019, a new drug called poyendarone was patented by the department of pharmacy of National University of Singapore (NUS).{{Cite patent|number=US20220267288A1|title=Poyendarone, a cardiac therapeutic|gdate=2022-08-25|invent1=Chan|invent2=Karkhanis|invent3=Venkatesan|inventor1-first=Chun Yong Eric|inventor2-first=Aneesh Vidyadhar|inventor3-first=Gopalakrishnan|url=https://patents.google.com/patent/US20220267288A1/en}} It was developed by modifying the dronedarone molecule to remove its tendency to cause ventricular arrhythmia.{{cite journal | vauthors = Karkhanis AV, Venkatesan G, Kambayashi R, Leow JW, Han MQ, Izumi-Nakaseko H, Goto A, Pang JK, Soh BS, Kojodjojo P, Sugiyama A, Chan EC | title = Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts | journal = Acta Pharmaceutica Sinica. B | volume = 12 | issue = 10 | pages = 3905–3923 | date = October 2022 | pmid = 36213535 | pmc = 9532722 | doi = 10.1016/j.apsb.2022.03.008 }}{{cite web | url = https://medicalxpress.com/news/2022-07-drug-molecule-treatment-atrial-fibrillation.html | title = New drug molecule for treatment of atrial fibrillation | work = Medicalxpress | date = July 18, 2022 }}

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