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Background: Amiodarone and dronedarone are both class III antiarrhythmic medications used to treat arrhythmias. The objective of this study was to enhance the current understanding of adverse drug reaction (ADR) associated with amiodarone and dronedarone by employing data mining methods on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), and providing a reference for safe and reasonable clinical use. Methods: The ADR records were selected by searching the FAERS database from 2011 Q3 to 2023 Q3. The disproportionality analysis algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM), were used to detect signals of amiodarone-related and dronedarone-related ADRs. The ADR profiles of amiodarone and dronedarone categorized by organ toxicity were compared through the Z-test and the Fisher exact test. Results: 9,295 reports specifically mentioned the use of amiodarone and 2,485 reports mentioned the use of dronedarone among 9,972,109 reports, with the majority of ADRs occurring in males over 60 years old. The United States was responsible for the highest proportion of reported ADRs. Significant system organ classes (SOC) for both included Cardiac disorders, Respiratory, thoracic and mediastinal disorders, and Investigations, etc. At the preferred terms (PTs) level, the more frequent ADR signals for amiodarone were drug interaction (n = 856), hyperthyroidism (n = 758), and dyspnoea (n = 607), while dronedarone were atrial fibrillation (n = 371), dyspnoea (n = 204), and blood creatinine increased (n = 123). Notably, unexpected ADRs, including electrocardiogram T wave alternans (n = 16; EBGM05 = 231.27), accessory cardiac pathway (n = 11; EBGM05 = 140), thyroiditis (n = 178; EBGM05 = 125.91) for amiodarone, and cardiac ablation (n = 11; EBGM05 = 31.86), cardioversion (n = 7; EBGM05 = 22.69), and dysphagia (n = 47; EBGM05 = 3.6) for dronedarone, were uncovered in the instructions. The analysis also revealed significant differences in the ADR profiles of amiodarone and dronedarone, with dronedarone showing higher proportions of cardiac toxicity but lower thyroid toxicity compared to amiodarone. Conclusion: These findings underscore the significance of vigilantly monitoring and comprehending the potential risks linked to the use of amiodarone and dronedarone. New ADRs discovered and clear ADR profiles of amiodarone and dronedarone enhance a thorough understanding of these drugs, which is essential for clinicians to ensure safe use of amiodarone and dronedarone. [ABSTRACT FROM AUTHOR]

Treatment options for patients with esophageal squamous cell carcinoma (ESCC) often result in poor prognosis and declining health-related quality of life. Screening FDA-approved drugs for cancer chemoprevention is a promising and cost-efficient strategy. Here, we found that dronedarone, an antiarrhythmic drug, could inhibit the proliferation of ESCC cells. Moreover, we conducted phosphorylomics analysis to investigate the mechanism of dronedarone-treated ESCC cells. Through computational docking models and pull-down assays, we demonstrated that dronedarone could directly bind to CDK4 and CDK6 kinases. We also proved that dronedarone effectively inhibited ESCC proliferation by targeting CDK4/CDK6 and blocking the G0/G1 phase through RB1 phosphorylation inhibition by in vitro kinase assays and cell cycle assays. Subsequently, we found that knocking out CDK4 and CDK6 decreased the susceptibility of ESCC cells to dronedarone. Furthermore, dronedarone suppressed the growth of ESCC in patient-derived tumor xenograft models in vivo. Thus, our study demonstrated that dronedarone could be repurposed as a CDK4/6 inhibitor for ESCC chemoprevention. [ABSTRACT FROM AUTHOR]

Background: Prolonged use of anti-arrhythmic drugs (AAD) beyond the post-ablation blanking period to maintain sinus rhythm has been adopted in clinical practice but without sufficient evidence. Dronedarone is an AAD valid for maintaining sinus rhythm with fewer side effects than other AAD for long-term use. Objective: We sought to investigate the effect of prolonged use of dronedarone on the recurrence of non-paroxysmal AF patients beyond 3 months within the first year after ablation. Methods: Non-paroxysmal AF patients will receive dronedarone for 3 months after radiofrequency ablation. Patients without drug side effects and atrial tachyarrhythmia (AT) recurrence will then be randomly divided into dronedarone and placebo groups and followed up until 1 year after ablation. The primary endpoint is the cumulative nonrecurrence rate post 3 months to 1 year after ablation. Patients will receive 7-day Holter monitoring (ECG patch) at 6, 9, and 12 months after ablation to evaluate AT recurrence. Secondary endpoints include dronedarone withdrawal due to side effects or intolerance of AT recurrence, time to the first recurrence, repeat ablation, electrical cardioversion, unscheduled emergency room visit, or re-hospitalization. Conclusion: This trial will evaluate whether prolonged use of dronedarone effectively reduces the recurrence rate after ablation in non-paroxysmal AF patients. The result of this trial will provide evidence for optimizing post-ablation anti-arrhythmic therapy. Trial registration: ClinicalTrials.gov; NCT05655468, 19-December-2022 [ABSTRACT FROM AUTHOR]

BackgroundAmiodarone and dronedarone are both class III antiarrhythmic medications used to treat arrhythmias. The objective of this study was to enhance the current understanding of adverse drug reaction (ADR) associated with amiodarone and dronedarone by employing data mining methods on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), and providing a reference for safe and reasonable clinical use.MethodsThe ADR records were selected by searching the FAERS database from 2011 Q3 to 2023 Q3. The disproportionality analysis algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM), were used to detect signals of amiodarone-related and dronedarone-related ADRs. The ADR profiles of amiodarone and dronedarone categorized by organ toxicity were compared through the Z-test and the Fisher exact test.Results9,295 reports specifically mentioned the use of amiodarone and 2,485 reports mentioned the use of dronedarone among 9,972,109 reports, with the majority of ADRs occurring in males over 60 years old. The United States was responsible for the highest proportion of reported ADRs. Significant system organ classes (SOC) for both included Cardiac disorders, Respiratory, thoracic and mediastinal disorders, and Investigations, etc. At the preferred terms (PTs) level, the more frequent ADR signals for amiodarone were drug interaction (n = 856), hyperthyroidism (n = 758), and dyspnoea (n = 607), while dronedarone were atrial fibrillation (n = 371), dyspnoea (n = 204), and blood creatinine increased (n = 123). Notably, unexpected ADRs, including electrocardiogram T wave alternans (n = 16; EBGM05 = 231.27), accessory cardiac pathway (n = 11; EBGM05 = 140), thyroiditis (n = 178; EBGM05 = 125.91) for amiodarone, and cardiac ablation (n = 11; EBGM05 = 31.86), cardioversion (n = 7; EBGM05 = 22.69), and dysphagia (n = 47; EBGM05 = 3.6) for dronedarone, were uncovered in the instructions. The analysis also revealed significant differences in the ADR profiles of amiodarone and dronedarone, with dronedarone showing higher proportions of cardiac toxicity but lower thyroid toxicity compared to amiodarone.ConclusionThese findings underscore the significance of vigilantly monitoring and comprehending the potential risks linked to the use of amiodarone and dronedarone. New ADRs discovered and clear ADR profiles of amiodarone and dronedarone enhance a thorough understanding of these drugs, which is essential for clinicians to ensure safe use of amiodarone and dronedarone.

Study objective: There is inadequate awareness of the effect of food on the bioavailability of dronedarone. We report results from two phase 1 studies assessing the effect of food on dronedarone's bioavailability. Design, setting and participants: Study 1; single-center, open-label, randomized study in healthy adults (males and females). Study 2; single-center, open-label, randomized study in healthy males. Interventions: Study 1; a single 400-mg oral dose of dronedarone (marketed formulation) in fed (high-fat [47.4 g] meal) and fasted states. Study 2; a single 800-mg oral dose of dronedarone (two 400-mg tablets) after fat-rich (37.3 g) and low-fat (5.3 g) meals, and after fasting. Main outcome measures: Pharmacokinetic parameters including maximum plasma concentration (Cmax) and area under the curve from time 0 to last measurable time (AUClast) were assessed for dronedarone and its active N-debutyl metabolite. Results: Twenty-six participants were included in Study 1 and nine in Study 2. In Study 1, administration of 400 mg dronedarone with a high-fat meal vs. fasted state resulted in 2.8-fold and 2.0-fold increases in Cmax and AUClast, respectively. In Study 2, administration of 800 mg dronedarone with a fat-rich or low-fat meal vs. fasted state resulted in 4.6-fold and 3.2-fold increases in Cmax, respectively, and 3.1-fold and 2.3-fold increases, respectively, in AUClast. Results for the N-debutyl metabolite were similar to dronedarone. No adverse events were considered related to dronedarone. Conclusion: With food, the bioavailability of dronedarone is markedly increased. In clinical practice, dronedarone should be administered with a complete meal to maximize drug absorption.

Objective: To describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA's surveillance database. Methods: Hepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020. Results: Among DILIN's 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause. Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes. Conclusion: Amiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity. [ABSTRACT FROM AUTHOR]

Yihan Li,1 Tong Hu,1 Mingjie Lin,1,2 Qinhong Wang,1 Wenqiang Han,1 Jingquan Zhong1,2 1Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong Province, People’s Republic of China; 2Department of Cardiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong Province, People’s Republic of ChinaCorrespondence: Jingquan Zhong, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong Province, People’s Republic of China, Tel: +008618560086597, Email 198762000778@email.sdu.edu.cnBackground: Dronedarone is an effective drug for maintaining the sinus rhythm in patients with atrial fibrillation (AF). The efficacy and safety of dronedarone versus amiodarone in patients with AF after catheter ablation (CA) needs more evidence. We retrospectively compared the efficacy and safety of dronedarone and amiodarone in our hospital.Methods: Patients who underwent CA from January 2021 to January 2022 and used dronedarone (n=229) or amiodarone (n=202) during the blind period were enrolled. The recurrence of AF in post-and during the blanking period was compared between the groups; the rehospitalization for re-ablation and adverse drug events (ADE) were also calculated.Results: During an average follow-up period of 14.28 months, the long-term recurrence rate of AF did not differ significantly between the amiodarone group and dronedarone group (22.71% vs 21.29%, hazard ratio [HR], 1.033, 95% confidence interval [CI], 0.661– 1.614; p=0.888). The recurrence rate in the blanking period also showed no statistically significant differences between the amiodarone group and dronedarone group (9.90% vs 14.41%, HR, 0.851; 95% CI, 0.463– 1.564; p=0.604). The re-hospitalization rates for re-ablation between two groups did not differ between the amiodarone group and dronedarone group (4.65% vs 13.46%; p =0.144). The incidence of ADE was higher in the dronedarone groups than that in the amiodarone group (16.59% vs 5.45%, p < 0.001). The main adverse drug events in the dronedarone and amiodarone groups were gastrointestinal (6.99%) and bradycardia (2.48%), respectively.Conclusion: Compared to the amiodarone group, the dronedarone group had a similar blank-period and long-term recurrence rate of AF and a higher incidence of ADE.Keywords: atrial fibrillation, catheter ablation, amiodarone, dronedarone

Background: Atrial tachyarrhythmias are common and difficult to treat in adults with congenital heart disease. Dronedarone has proven effective in patients without congenital heart disease, but data are limited about its use in adults with congenital heart disease of moderate to great complexity. Methods: A single-center, retrospective chart review of 21 adults with congenital heart disease of moderate to great complexity who were treated with dronedarone for atrial tachyarrhythmias was performed. Results: The median (IQR) age at dronedarone initiation was 35 (27.5-39) years. Eleven patients (52%) were male. Ten patients (48%) had New York Heart Association class I disease, 10 (48%) had class II disease, and 1 (5%) had class III disease. Ejection fraction at initiation was greater than 55% in 11 patients (52%), 35% to 55% in 9 patients (43%), and less than 35% in 1 patient (5%). Prior treatments included β-blockers (71%), sotalol (38%), amiodarone (24%), digoxin (24%), and catheter ablation (38%). Rhythm control was complete in 5 patients (24%), partial in 6 (29%), and inadequate in 10 (48%). Two patients (10%) experienced adverse events, including nausea in 1 (5%) and cardiac arrest in 1 (5%), which occurred 48 months after initiation of treatment. There were no deaths during the follow-up period. The median (IQR) follow-up time for patients with complete or partial rhythm control was 20 (1-54) months. Conclusion: Dronedarone can be effective for adult patients with congenital heart disease and atrial arrhythmias for whom more established therapies have failed, and with close monitoring it can be safely tolerated. [ABSTRACT FROM AUTHOR]

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Dronedarone (DRN), an antiarrhythmic drug, exhibits potent pharmacological effects in the management of cardiac arrhythmias. Despite its therapeutic potential, DRN faces formulation challenges due to its low aqueous solubility. Hence, the present study is dedicated to the examination of amorphous solid dispersions (ASDs) as a strategic approach for enhancing the solubility of DRN. Initially, the glass forming ability (GFA) of API was assessed alongside its thermal degradation profile, and it was revealed that DRN is a stable glass former (GFA III compound) that remains thermally stable up to approximately 200 °C. Subsequently, five commonly used ASD matrix/carriers, i.e., hydroxypropyl methylcellulose (HPMC), povidone (PVP), copovidone (PVP/VA), Soluplus® (SOL), and Eudragit® E PO (EPO), were screened for the formation of a DRN-based ASD using film casting and solvent shift methods, along with miscibility evaluation measurements. SOL proved to be the most promising matrix/carrier among the others, and, hence, was used to prepare DRN ASDs via the melt-quench method. The physicochemical characterization of the prepared systems (via pXRD) revealed the complete amorphization of the API within the matrix/carrier, while the system was physically stable for at least three months after its preparation. In vitro release studies for the ASDs, conducted under non-sink conditions, revealed the sustained supersaturation of the drug for at least 8 h. Finally, the use of attenuated total reflectance (ATR) FTIR spectroscopy showed the formation of a strong molecular interaction between the drug molecules and SOL. [ABSTRACT FROM AUTHOR]

For the first time, an UPLC-QTOF-MS method was developed and validated to simultaneously estimate dronedarone (DDN) and its four unlisted pharmacopoeial impurities: DDN impurities A, B, C, and D. UPLC separation was performed for 6 min on a BEH C18 (50 × 2.1 mm, 1.7 µm) columnwith 0.1% formic acid in water (A) and acetonitrile (B) as mobile phase delivered in gradient at a constant flow rate of 0.6 mL/min. Mass spectrometric detection was performed in ESI-QTOF-MS. The LOD and LOQ values for the analytes ranged from 0.5 to 10 and 0.8 to 75 ng/mL, respectively. The method was found to be linear for all analyte ranges with r2 values ≥0.9998. The method was precise with %RSD values ≤6.5% and overall analyte recovery was found to be 99.8 ± 1.0%. A novel, sensitive, selective, specific, linear, and accurate UPLC-QTOF-MS method was developed and validated to simultaneously estimate DDN and its impurities which are not listed in the pharmacopoeia. [ABSTRACT FROM AUTHOR]

Aims: Despite potential enzyme‐ and transporter‐mediated drug–drug interactions (DDIs) between dronedarone and rivaroxaban in atrial fibrillation (AF) patients, pharmacokinetic/pharmacodynamic data remain limited to guide clinical practice. We aimed to develop, verify and validate a physiologically based pharmacokinetic (PBPK) model of dronedarone and its major metabolite, N‐desbutyldronedarone (NDBD), to prospectively interrogate this clinically relevant DDI in healthy and mild renal impairment populations. Methods: The middle‐out development of our PBPK model combined literature‐derived or in‐house in vitro data, predicted in silico data and in vivo clinical data. Model verification was performed for intravenous and oral (single and multiple) dosing regimens. Model validation for the accurate prediction of cytochrome P450 (CYP)3A4‐ and P‐glycoprotein‐mediated DDI utilized simvastatin and digoxin as respective victim drugs. Rivaroxaban‐specific inhibitory parameters of dronedarone and/or NDBD against CYP3A4, CYP2J2, OAT3 and P‐glycoprotein were incorporated into the PBPK‐DDI model for prospective dronedarone–rivaroxaban DDI simulation. Results: Dronedarone and NDBD PK following clinically relevant doses of 400 mg dronedarone across single and multiple oral dosing were accurately simulated by incorporating effect of auto‐inactivation on dose nonlinearities. Following successful model validation, nondose‐adjusted rivaroxaban–dronedarone DDI in healthy and mild renal impairment populations revealed simulated rivaroxaban area under the plasma concentration–time curve up to 24 h fold change greater than dose exposure equivalence (0.70–1.43) at 1.65 and 1.84, respectively. Correspondingly, respective major bleeding risk was 4.24 and 4.70% compared with threshold of 4.5% representing contraindicated rivaroxaban–ketoconazole DDI. Conclusion: Our PBPK‐DDI model predicted clinically significant dronedarone–rivaroxaban DDI in both healthy and mild renal impairment subjects. Greater benefit vs. risk could be achieved with rivaroxaban dose reductions to at least 15 mg in mild renal impairment subjects on concomitant dronedarone and rivaroxaban. [ABSTRACT FROM AUTHOR]

Background: There are limited comparative data on safety and efficacy within commonly used Vaughan‐Williams (VW) class III antiarrhythmic drugs (AADs) for maintenance of sinus rhythm in adults with atrial fibrillation (AF). Hypothesis: We hypothesized that dronedarone and sotalol, two commonly prescribed VW class III AADs with class II properties, have different safety and efficacy effects in patients with nonpermanent AF. Methods: A systematic literature review was conducted searching MEDLINE®, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to June 15, 2021 (NCT05279833). Clinical trials and observational studies that evaluated safety and efficacy of dronedarone or sotalol in adults with AF were included. Bayesian random‐effects network meta‐analysis (NMA) was used to quantify comparative safety and efficacy. Where feasible, we performed sensitivity analyses by including only randomized controlled trials (RCTs). Results: Of 3581 records identified through database searches, 37 unique studies (23 RCTs, 13 observational studies, and 1 nonrandomized trial) were included in the NMA. Dronedarone was associated with a statistically significantly lower risk of all‐cause death versus sotalol (hazard ratio [HR] = 0.38 [95% credible interval, CrI: 0.19, 0.74]). The association was numerically similar in the sensitivity analysis (HR = 0.46 [95% CrI: 0.21, 1.02]). AF recurrence and cardiovascular death results were not significantly different between dronedarone and sotalol in all‐studies and sensitivity analyses. Conclusion: The NMA findings indicate that, across all clinical trials and observational studies included, dronedarone compared with sotalol was associated with a lower risk of all‐cause death, but with no difference in AF recurrence. [ABSTRACT FROM AUTHOR]

Aims Limited data compared antiarrhythmic drugs (AADs) with concomitant non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients, hence the aim of the study. Methods and results National health insurance database were retrieved during 2012–17 for study. We excluded patients not taking AADs, bradycardia, heart block, heart failure admission, mitral stenosis, prosthetic valve, incomplete demographic data, and follow-up <3 months. Outcomes were compared in Protocol 1, dronedarone vs. non-dronedarone; Protocol 2, dronedarone vs. amiodarone; and Protocol 3, dronedarone vs. propafenone. Outcomes were acute myocardial infarction (AMI), ischaemic stroke/systemic embolism, intracranial haemorrhage (ICH), major bleeding, cardiovascular death, all-cause mortality, and major adverse cardiovascular event (MACE) (including AMI, ischaemic stroke, and cardiovascular death). In Protocol 1, 2298 dronedarone users and 6984 non-dronedarone users (amiodarone = 4844; propafenone = 1914; flecainide = 75; sotalol = 61) were analysed. Dronedarone was associated with lower ICH (HR = 0.61, 95% CI = 0.38–0.99, P = 0.0436), cardiovascular death (HR = 0.24, 95% CI = 0.16–0.37, P < 0.0001), all-cause mortality (HR = 0.33, 95% CI = 0.27–0.42, P < 0.0001), and MACE (HR = 0.56, 95% CI = 0.45–0.70, P < 0.0001). In Protocol 2, 2231 dronedarone users and 6693 amiodarone users were analysed. Dronedarone was associated with significantly lower ICH (HR = 0.53, 95%=CI 0.33–0.84, P = 0.0078), cardiovascular death (HR = 0.20, 95% CI = 0.13–0.31, P < 0.0001), all-cause mortality (HR 0.27, 95% CI 0.22–0.34, P < 0.0001), and MACE (HR = 0.53, 95% CI = 0.43–0.66, P < 0.0001), compared with amiodarone. In Protocol 3, 812 dronedarone users and 2436 propafenone users were analysed. There were no differences between two drugs for primary and secondary outcomes. Conclusion The use of dronedarone with NOACs was associated with cardiovascular benefits in an Asian population, compared with non-dronedarone AADs and amiodarone. [ABSTRACT FROM AUTHOR]

Introduction: Understanding symptom patterns in atrial fibrillation (AF) can help in disease management. We report on the application of natural language processing (NLP) to electronic medical records (EMRs) to capture symptom reports in patients with newly diagnosed (incident) AF. Methods and Results: This observational retrospective study included adult patients with an index diagnosis of incident AF during January 1, 2016 through June 30, 2018, in the Optum datasets. The baseline and follow‐up periods were 1 year before/after the index date, respectively. The primary objective was identification of the following predefined symptom reports: dyspnea or shortness of breath; syncope, presyncope, lightheadedness, or dizziness; chest pain; fatigue; and palpitations. In an exploratory analysis, the incidence rates of symptom reports and cardiovascular hospitalization were assessed in propensity‐matched patient cohorts with incident AF receiving first‐line dronedarone or sotalol. Among 30 447 patients with an index AF diagnosis, the NLP algorithm identified at least 1 predefined symptom in 9734 (31.9%) patients. The incidence rate of symptom reports was highest at 0–3 months post‐diagnosis and lower at >3–6 and >6–12 months (pre‐defined timepoints). Across all time periods, the most common symptoms were dyspnea or shortness of breath, followed by syncope, presyncope, lightheadedness, or dizziness. Similar temporal patterns of symptom reports were observed among patients with prescriptions for dronedarone or sotalol as first‐line treatment. Conclusion: This study illustrates that NLP can be applied to EMR data to characterize symptom reports in patients with incident AF, and the potential for these methods to inform comparative effectiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: Basal-like breast cancers comprise the majority of triple-negative breast cancers (TNBC) and lack effective treatment options that have a sustained response. Part of the reason that they are hard to eliminate is that they exhibit high levels of genomic instability and cellular diversity. Most basal-like tumors have high levels of Phosphoinositide 3-Kinase (PI3K) pathway activity. A key driver of this pathway is PIK3CA. Many compounds have been made to target PIK3CA and have become standard-of-care in some estrogen-dependent patients; however, in TNBC patients, PI3K inhibitors (PI3Ki) as single agents thus far have shown limited duration at tolerable doses. The goal of this study was to identify and/or repurpose drugs that, when combined with PI3Ki, yield a significant inhibition of tumor growth. When treated in conjunction with the PI3Ki BYL-719, which is clinically prescribed as alpelisib, 20 potent drug combinations were identified and formed a basis toward clinical studies with these molecules. Basal-like triple-negative breast cancer (TNBC) tumor cells are difficult to eliminate due to resistance mechanisms that promote survival. While this breast cancer subtype has low PIK3CA mutation rates when compared to estrogen receptor-positive (ER+) breast cancers, most basal-like TNBCs have an overactive PI3K pathway due to gene amplification or high gene expression. BYL-719 is a PIK3CA inhibitor that has been found to have low drug-drug interactions, which increases the likelihood that it could be useful for combinatorial therapy. Alpelisib (BYL-719) with fulvestrant was recently approved for treating ER+ breast cancer patients whose cancer had developed resistance to ER-targeting therapy. In these studies, a set of basal-like patient-derived xenograft (PDX) models was transcriptionally defined with bulk and single-cell RNA-sequencing and clinically actionable mutation profiles defined with Oncomine mutational profiling. This information was overlaid onto therapeutic drug screening results. BYL-719-based, synergistic two-drug combinations were identified with 20 different compounds, including everolimus, afatinib, and dronedarone, which were also found to be effective at minimizing tumor growth. These data support the use of these drug combinations towards cancers with activating PIK3CA mutations/gene amplifications or PTEN deficient/PI3K overactive pathways. [ABSTRACT FROM AUTHOR]

Aims This post hoc analysis of the ATHENA trial (NCT00174785) assessed the effect of dronedarone on the estimated burden of atrial fibrillation (AF)/atrial flutter (AFL) progression to presumed permanent AF/AFL, and regression to sinus rhythm (SR), compared with placebo. Methods and results The burden of AF/AFL was estimated by a modified Rosendaal method using available electrocardiograms (ECG). Cumulative incidence of permanent AF/AFL (defined as ≥6 months of AF/AFL until end of study) or permanent SR (defined as ≥6 months of SR until end of study) were calculated using Kaplan–Meier estimates. A log-rank test was used to assess statistical significance. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were estimated using a Cox model, adjusted for treatment group. Of the 4439 patients included in this analysis, 2208 received dronedarone, and 2231 placebo. Baseline and clinical characteristics were well balanced between groups. Overall, 304 (13.8%) dronedarone-treated patients progressed to permanent AF/AFL compared with 455 (20.4%) treated with placebo (P < 0.0001). Compared with those receiving placebo, patients receiving dronedarone had a lower cumulative incidence of permanent AF/AFL (log-rank P < 0.001; HR: 0.65; 95% CI: 0.56–0.75), a higher cumulative incidence of permanent SR (log-rank P < 0.001; HR: 1.19; 95% CI: 1.09–1.29), and a lower estimated AF/AFL burden over time (P < 0.01 from Day 14 to Month 21). Conclusion These results suggest that dronedarone could be a useful antiarrhythmic drug for early rhythm control due to less AF/AFL progression and more regression to SR vs. placebo, potentially reflecting reverse remodeling. Clinical trial registration NCT00174785 [ABSTRACT FROM AUTHOR]

Patients with atrial fibrillation may require rhythm control therapy in addition to anticoagulation therapy for the prevention of stroke. Since 2012, the European Society of Cardiology and European Heart Rhythm Association guidelines have recommended non-vitamin K antagonist oral anticoagulants, including rivaroxaban, for the prevention of stroke in patients with atrial fibrillation. During the same period, these guidelines have also recommended dronedarone or amiodarone as second-line rhythm control agents in certain patients with atrial fibrillation and no contraindications. Amiodarone and dronedarone both strongly inhibit P -glycoprotein, while dronedarone is a moderate and amiodarone a weak inhibitor of cytochrome P450 3A4 (CYP3A4). Based on these data and evidence from physiologically based pharmacokinetic modelling, amiodarone and dronedarone are expected to have similar effects on rivaroxaban exposure resulting from P -glycoprotein and CYP3A4 inhibition. However, the rivaroxaban label recommends against the concomitant use of dronedarone, but not amiodarone, citing a lack of evidence on the concomitant use of rivaroxaban and dronedarone as the reason for the different recommendations. In this report, we discuss evidence from clinical studies and physiologically based pharmacokinetic modelling on the potential for increased rivaroxaban exposure resulting from drug–drug interaction between rivaroxaban and dronedarone or amiodarone. The current evidence supports the same clinical status and concomitant use of either amiodarone or dronedarone with rivaroxaban, which could be considered in future recommendations. [ABSTRACT FROM AUTHOR]

Dronedarone (DRN) is a clinically used drug to mitigate arrhythmias with multichannel block properties, including the sodium channel Na v 1.5. Extracellular acidification is known to change the pharmacological properties of several antiarrhythmic drugs. Here, we explore how modification in extracellular pH (pHe) shapes the pharmacological profile of DRN upon Na v 1.5 sodium current (I Na) and in the ex vivo heart preparation. Embryonic human kidney cells (HEK293T/17) were used to transiently express the human isoform of Na v 1.5 α-subunit. Patch-Clamp technique was employed to study I Na. Neurotoxin-II (ATX-II) was used to induce the late sodium current (I NaLate). Additionally, ex vivo Wistar male rat preparations in the Langendorff system were utilized to study electrocardiogram (ECG) waves. DRN preferentially binds to the closed state inactivation mode of Na v 1.5 at pHe 7.0. The recovery from I Na inactivation was delayed in the presence of DRN in both pHe 7.0 and 7.4, and the use-dependent properties were distinct at pHe 7.0 and 7.4. However, the potency of DRN upon the peak I Na , the voltage dependence for activation, and the steady-state inactivation curves were not altered in both pHe tested. Also, the pHe did not change the ability of DRN to block I NaLate. Lastly, DRN in a concentration and pH dependent manner modulated the QRS complex, QT and RR interval in clinically relevant concentration. Thus, the pharmacological properties of DRN upon Na v 1.5 and ex vivo heart preparation partially depend on the pHe. The pHe changed the biological effect of DRN in the heart electrical function in relevant clinical concentration. [ABSTRACT FROM AUTHOR]

Dronedarone (DRN), an antiarrhythmic drug, exhibits potent pharmacological effects in the management of cardiac arrhythmias. Despite its therapeutic potential, DRN faces formulation challenges due to its low aqueous solubility. Hence, the present study is dedicated to the examination of amorphous solid dispersions (ASDs) as a strategic approach for enhancing the solubility of DRN. Initially, the glass forming ability (GFA) of API was assessed alongside its thermal degradation profile, and it was revealed that DRN is a stable glass former (GFA III compound) that remains thermally stable up to approximately 200 °C. Subsequently, five commonly used ASD matrix/carriers, i.e., hydroxypropyl methylcellulose (HPMC), povidone (PVP), copovidone (PVP/VA), Soluplus® (SOL), and Eudragit® E PO (EPO), were screened for the formation of a DRN-based ASD using film casting and solvent shift methods, along with miscibility evaluation measurements. SOL proved to be the most promising matrix/carrier among the others, and, hence, was used to prepare DRN ASDs via the melt-quench method. The physicochemical characterization of the prepared systems (via pXRD) revealed the complete amorphization of the API within the matrix/carrier, while the system was physically stable for at least three months after its preparation. In vitro release studies for the ASDs, conducted under non-sink conditions, revealed the sustained supersaturation of the drug for at least 8 h. Finally, the use of attenuated total reflectance (ATR) FTIR spectroscopy showed the formation of a strong molecular interaction between the drug molecules and SOL.

Aims: Age and sex may impact the efficacy of antiarrhythmic drugs on cardiovascular outcomes and arrhythmia recurrences in patients with atrial fibrillation (AF). We report on a post hoc analysis of the ATHENA study (NCT00174785), which examined cardiovascular outcomes in patients with non-permanent AF treated with dronedarone vs. placebo.Methods and Results: Efficacy and safety of dronedarone were assessed in patients according to age and sex. Baseline characteristics were comparable across subgroups, except for cardiovascular comorbidities, which were more frequent with increasing age. Dronedarone significantly reduced the risk of cardiovascular hospitalization or death due to any cause among patients 65-74 [n = 1830; hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.60-0.83; P < 0.0001] and ≥75 (n = 1925; HR 0.75, 95% CI 0.65-0.88; P = 0.0002) years old and among males (n = 2459; HR 0.74, 95% CI 0.64-0.84; P < 0.00001) and females (n = 2169; HR 0.77, 95% CI 0.67-0.89; P = 0.0002); outcomes were similar for time to AF/AFL recurrence. Among patients aged <65 years (n = 873), cardiovascular hospitalization or death due to any cause with dronedarone vs. placebo was associated with an HR of 0.89 (95% CI 0.71-1.11; P = 0.3). The incidence of all treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation was comparable among males and females, and increased with increasing age.Conclusions: These results support the use of dronedarone for the improvement of clinical outcomes among patients aged ≥65 years and regardless of sex. [ABSTRACT FROM AUTHOR]

The concurrent administration of dronedarone and oral anti-coagulants is common because both are used in managing atrial fibrillation (AF). Dronedarone is a moderate inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein (P-gp). Apixaban and rivaroxaban are P-gp and CYP3A4 substrates. This study aims to investigate the impact of exposure and bleeding risk of apixaban or rivaroxaban when co-administered with dronedarone using physiologically based pharmacokinetic/pharmacodynamic analysis. Modeling and simulation were conducted using Simcyp® Simulator. The parameters required for dronedarone modeling were collected from the literature. The developed dronedarone physiologically based pharmacokinetic (PBPK) model was verified using reported drug-drug interactions (DDIs) between dronedarone and CYP3A4 and P-gp substrates. The model was applied to evaluate the DDI potential of dronedarone on the exposure of apixaban 5 mg every 12 h or rivaroxaban 20 mg every 24 h in geriatric and renally impaired populations. DDIs precipitating major bleeding risks were assessed using exposure-response analyses derived from literature. The model accurately described the pharmacokinetics of orally administered dronedarone in healthy subjects and accurately predicted DDIs between dronedarone and four CYP3A4 and P-gp substrates with fold errors <1.5. Dronedarone co-administration led to a 1.29 (90 % confidence interval (CI): 1.14–1.50) to 1.31 (90 % CI: 1.12–1.46)-fold increase in the area under concentration-time curve for rivaroxaban and 1.33 (90 % CI: 1.15–1.68) to 1.46 (90 % CI: 1.24–1.92)-fold increase for apixaban. The PD model indicated that dronedarone co-administration might potentiate the mean major bleeding risk of apixaban with a 1.45 to 1.95-fold increase. However, the mean major bleeding risk of rivaroxaban was increased by <1.5-fold in patients with normal or impaired renal function. Dronedarone co-administration increased the exposure of rivaroxaban and apixaban and might potentiate major bleeding risks. Reduced apixaban and rivaroxaban dosing regimens are recommended when dronedarone is co-administered to patients with AF. [ABSTRACT FROM AUTHOR]

Cytochrome P4502J2 (CYP2J2) metabolizes arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs). Dronedarone, an antiarrhythmic drug prescribed for treatment of atrial fibrillation (AF) induces cardiac adverse effects (AEs) with poorly understood mechanisms. We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly, disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable via EET enrichment. In this study, we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac AEs. We first synthesized a deuterated analogue of dronedarone (termed poyendarone) and demonstrated that it neither inactivates CYP2J2, disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity in vitro. Our patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by deuteration. Next, we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat (BTB) variability reflective of proarrhythmic phenotype. In contrast, poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 activity. Importantly, poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF, while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic risk. Our findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs. Dronedarone irreversibly inactivates CYP2J2, depletes EETs, exacerbates mitochondrial toxicity and drug-induced proarrhythmia in cardiomyocytes (upper panel). Poyendarone lacks CYP2J2 inactivation, preserves EETs, exhibits negligible mitochondrial toxicity and mitigates drug-induced proarrhythmia (lower panel). [Display omitted] [ABSTRACT FROM AUTHOR]

Background: While there are several completed clinical trials that address treatment strategies in patients with symptomatic and recurrent atrial fibrillation (AF), there are no randomized clinical trials that address first-line rhythm control of new-onset AF. Recent data suggest that early initiation of rhythm control within 1 year can improve outcomes., Methods: In this open-label pragmatic clinical trial nested within the Get With The Guidelines Atrial Fibrillation registry, approximately 3,000 patients with first-detected AF will be enrolled at approximately 200 sites. Participants will be randomized (1:1) to treatment with dronedarone in addition to usual care versus usual care alone. The primary endpoint will be time to first cardiovascular (CV) hospitalization or death from any cause through 12 months from randomization. Secondary endpoints will include a WIN ratio (all-cause death, ischemic stroke or systemic embolism, heart failure hospitalization, acute coronary hospitalization), CV hospitalization, and all-cause mortality. Patient reported outcomes will be analyzed based on change in Atrial Fibrillation Effect on Quality of Life (AFEQT) and change in Mayo AF-Specific Symptom Inventory (MAFSI) from baseline to 12 months., Conclusion: CHANGE AFIB will determine if treatment with dronedarone in addition to usual care is superior to usual care alone for the prevention of CV hospitalization or death from any cause in patients with first-detected AF. The trial will also determine whether initiation of rhythm control at the time of first-detected AF affects CV events or improves patient reported outcomes., Clinicaltrials: GOV #: - NCT05130268., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The goal of this study was to develop a bilosomal gel formulation to enhance transdermal permeability of dronedarone hyrdrochloride (DRN) which suffers from poor oral absorption and limited bioavailability. To overcome this obstacle, bilosomes were successfully prepared using 23 full-factorial design. Span®40, cholesterol, sodium deoxycholate (bile salt), clove oil (permeability enhancer), and either Tween® 60 or Tween® 80 (edge activator) were used in bilosome preparation by ethanol injection method. In this design, independent variables were X1, edge activator type; X2, edge activator amount (mg); and X3, permeability enhancer concentration (% w/v). Optimal formula (B2) of the highest desirability of (0.776) demonstrated minimum vesicle size (VS) of 312.4 ± 24.42 nm, maximum absolute value of zeta potential (ZP) − 36.17 ± 2.57 mV, maximum entrapment efficiency (EE %) of 80.95 ± 3.01%, maximum deformability Index (DI) of 8.24 ± 1.26 g and maximum drug flux after 12 h (J12) of 21.23 ± 1.54 µg/cm2 h upon ex vivo permeation study. After 12 h, 70.29 ± 6.46% of DRN was released from B2. TEM identification of B2 showed spherical shaped nanosized vesicles which were physically stable for 3 months at different temperatures. B2 was incorporated into carboxymethylcellulose gel base for easiness of dermal application. B2 gel demonstrated good physical properties, non-Newtonian psuedoplastic flow, and enhanced release (57.0 ± 8.68% of DRN compared to only 13.3 ± 1.2% released from drug suspension after 12 h) and enhanced skin permeation. [ABSTRACT FROM AUTHOR]

To summarize healthcare resource utilization (HCRU) in patients with newly diagnosed (incident) paroxysmal or persistent atrial fibrillation (AF). This retrospective, observational cohort study assessed HCRU among patients with incident paroxysmal or persistent AF using data from 1 January 2015 to 30 September 2019 in the IBM MarketScan® Research Databases. A total of 50,796 patients were identified in the overall incident AF cohort. Rates of all-cause inpatient hospital stays, all-cause emergency room visits, and all-cause outpatient visits in the overall incident cohort were 46.8, 114.7, and 2,752.7 events per 100 patient-years (PY), respectively. Rates of cardiovascular-related inpatient stays for the overall population were 11.3 events per 100 PY. During follow-up, 50.4% of the overall cohort filled prescriptions for direct-acting oral anticoagulants and 5.0% had catheter ablation. Advances in anticoagulation and ablation have been realized since previously published HCRU analyses of patients with atrial fibrillation. This update suggests that HCRU among patients with incident AF in the US remains high with some subgroups of patients receiving more specialized care. [ABSTRACT FROM AUTHOR]

Aims: Limited therapeutic options are available for the management of atrial fibrillation/flutter (AF/AFL) with concomitant heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF). Dronedarone reduces the risk of cardiovascular events in patients with AF, but sparse data are available examining its role in patients with AF complicated by HFpEF and HFmrEF. Methods and results: ATHENA was an international, multicentre trial that randomized 4628 patients with paroxysmal or persistent AF/AFL and cardiovascular risk factors to dronedarone 400 mg twice daily versus placebo. We evaluated patients with (i) symptomatic HFpEF and HFmrEF (defined as left ventricular ejection fraction [LVEF] >40%, evidence of structural heart disease, and New York Heart Association class II/III or diuretic use), (ii) HF with reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVEF ≤40%), and (iii) those without HF. We assessed effects of dronedarone versus placebo on death or cardiovascular hospitalization (primary endpoint), other key efficacy endpoints, and safety. Overall, 534 (12%) had HFpEF or HFmrEF, 422 (9%) had HFrEF or left ventricular dysfunction, and 3672 (79%) did not have HF. Patients with HFpEF and HFmrEF had a mean age of 73 ± 9 years, 37% were women, and had a mean LVEF of 57 ± 9%. Over a mean follow‐up of 21 ± 5 months, dronedarone consistently reduced risk of death or cardiovascular hospitalization (hazard ratio 0.76; 95% confidence interval 0.69–0.84) without heterogeneity based on HF status (pinteraction >0.10). This risk reduction in the primary endpoint was consistent across the range of LVEF (as a continuous function) in HF without heterogeneity (pinteraction = 0.71). Rates of death, cardiovascular hospitalization, and HF hospitalization each directionally favoured dronedarone versus placebo in HFpEF and HFmrEF, but these treatment effects were not statistically significant in this subgroup. Conclusions: Dronedarone is associated with reduced cardiovascular events in patients with paroxysmal or persistent AF/AFL and HF across the spectrum of LVEF, including among those with HFpEF and HFmrEF. These data support a rationale for a future dedicated and powered clinical trial to affirm the net clinical benefit of dronedarone in this population. [ABSTRACT FROM AUTHOR]

Trichomonas vaginalis is a protozoan that causes human trichomoniasis, the most common non-viral sexually transmitted infection (STI) affecting approximately 278 million people worldwide. The current treatment for trichomoniasis is based on 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, known as metronidazole (MTZ). Although effective in clearing the parasite infection, MTZ is related to provoking severe side effects, and it is not recommended during pregnancy. In addition, some strains present resistance to 5'-nitroimidazoles, making urgent the development of alternative drugs for trichomoniasis. Amiodarone, an antiarrhythmic drug, exerts a significant anti-parasite effect, mainly due to its interference with calcium homeostasis and the biosynthesis of sterols. Therefore, we decided to test the effect of amiodarone and two other related compounds (amioder and dronedarone) on T. vaginalis. Our observations show that amiodarone stimulated, rather than inhibited, parasite growth, induced cell aggregation, and glycogen accumulation. Furthermore, the other two compounds displayed anti-parasite activity with IC50 of 3.15 and 11 µM, respectively, and the apoptosis-like process killed the cells. In addition, cells exhibited morphological changes, including an effect on hydrogenosomes structure. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether co-administration of antiarrhythmic dronedarone and anticoagulant rivaroxaban would increase the risks of hemorrhage after atrial fibrillation (AF) ablation. Methods: A total of 100 patients with AF who underwent radiofrequency catheter ablation (CA) in the Department of Cardiology, the Affiliated Hospital of Qingdao University from 2019–12 to 2020–11 were included. Patients were divided into an oral dronedarone and rivaroxaban group (D-R group, N = 50) and an oral amiodarone and rivaroxaban group (A-R group, N = 50) according to the postoperative antiarrhythmic and anticoagulation strategies. Patients in 2 groups were given propensity score matching (PSM) to obtain a sample with balanced inter-group covariates. A retrospective observational study was conducted. After 3 months of follow-up, the incidence of clinically relevant non-major bleeding (CRNMB), major hemorrhages, and early AF recurrence was observed. Results: After PSM, 41 patients were included in each group. With similarly distributed baseline characteristics and ablation characteristics after PSM, the CRNMB rate after AF ablation was significantly higher in the D-R group than in the A-R group (26.8% versus 7.3%, P = 0.02), and no major hemorrhages were detected in both groups. No significant difference was observed in the sinus rhythm maintenance rate between the D-R group and the A-R group (26.8% vs. 22.0%, P = 0.43). Conclusions: Compared to co-administration of amiodarone and rivaroxaban, co-administration of dronedarone and rivaroxaban increases the risk of CRNMB but it does not increase the risk of major hemorrhages in blanking period after AF ablation. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the effectiveness and safety of dronedarone compared with other commonly used antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrences.Methods and Results: An international observational cohort study in Germany, Spain, Italy, and the USA enrolling patients with AF receiving AAD therapy. Patients with New York Heart Association (NYHA) Class IV heart failure were excluded. Participants were followed for up to 18 months, regardless of discontinuation or subsequent AAD switches. Atrial fibrillation recurrence was captured by hospitalization, emergency room visit, or electrocardiogram-based documentation of AF. Confounding bias was controlled for in the analysis of AF recurrence using multivariate models of 19 variables for adjustment. A total of 1009 participants [mean age 67.2 (10.8) years, male to female ratio 1.3] were recruited from 170 centres, 693 (69%) of which were from across Europe and the remaining 316 (31%) from the USA. At the time of enrolment, participants were taking dronedarone (51%) or other AADs (49%) [flecainide or propafenone (42%), sotalol (11%), and amiodarone (47%)]. No significant differences in the risk of first confirmed AF recurrence with dronedarone vs. other AADs [crude hazard ratio (HR) 1.10 (95% confidence interval 0.85-1.42); adjusted HR 1.16 (0.87-1.55)] were found, irrespective of whether univariate or multivariate models were used. Reported safety events were in accordance with the known safety profile of dronedarone.Conclusion: In this population of patients from either Europe or the USA receiving dronedarone or another AAD, the effectiveness of dronedarone was comparable to that observed for other AADs in preventing first AF recurrence. [ABSTRACT FROM AUTHOR]

While current guidelines recommend amiodarone and dronedarone for rhythm control in patients with atrial fibrillation (AF) and coronary artery disease (CAD), there was no comparative study of antiarrhythmic drugs (AADs) on the cardiovascular outcomes in general practice. This study included patients with AF and CAD who received their first prescription of amiodarone, class Ic AADs (flecainide, propafenone), dronedarone or sotalol between January 2016 and December 2020. The primary outcome was a composite of hospitalization for heart failure (HHF), stroke, acute myocardial infarction (AMI), and cardiovascular death. We used Cox proportional regression models, including with inverse probability of treatment weighting (IPTW), to estimate the relationship between AADs and cardiovascular outcomes. Among the AF cohort consisting of 8752 patients, 1996 individuals had CAD, including 477 who took dronedarone and 1519 who took other AADs. After a median follow-up of 38 months, 46.3% of patients who took dronedarone and 54.4% of patients who took other AADs experienced cardiovascular events. Compared to dronedarone, the use of other AADs was associated with increased cardiovascular events after adjusting for covariates (hazard ratio [HR] 1.531, 95% confidence interval [CI] 1.112–2.141, p = 0.023) and IPTW (HR 1.491, 95% CI 1.174–1.992, p = 0.012). The secondary analysis showed that amiodarone and class Ic drugs were associated with an increased risk of HHF. The low number of subjects in the sotalol group limits data interpretation. For patients with AF and CAD, dronedarone was associated with better cardiovascular outcomes than other AADs. Amiodarone and class Ic AADs were associated with a higher risk of cardiovascular events, particularly HHF. [Display omitted] • In this study cohort in Taiwan, 53.5% of patients with AF and CAD took amiodarone as first-line AAD, 23.9% took dronedarone, 19.7% took class Ic drugs and 2.9% took sotalol. • For patients with AF and CAD, dronedarone was associated with better cardiovascular outcomes than other AADs. • Amiodarone and class Ic AADs were associated with a higher risk of cardiovascular events, particularly hospitalization for heart failure (HHF). • Our study suggested that dronedarone is the preferred first-line choice for rhythm control in patients with AF and CAD. [ABSTRACT FROM AUTHOR]

Deuteration is a chemical modification strategy that has recently gained traction in drug development. The replacement of one or more hydrogen atom(s) in a drug molecule with its heavier stable isotope deuterium can enhance its metabolic stability and pharmacokinetic properties. However, it remains uninterrogated if rational deuteration at bioactivation "hot-spots" could attenuate its associated toxicological consequences. Here, our preliminary screening with benzofuran antiarrhythmic agents first revealed that dronedarone and its major metabolite N-desbutyldronedarone elicited a greater loss of viability and cytotoxicity in human hepatoma G2 (HepG2) cells as compared with amiodarone and its corresponding metabolite N-desethylamiodarone. A comparison of dronedarone and its in-house synthesized deuterated analogue (termed poyendarone) demonstrated that deuteration could attenuate its in vitro toxicity in HepG2 cells by modulating the extent of mitochondrial dysfunction, reducing the dissipation of mitochondrial membrane potential, and evoking a distinct apoptotic kinetic signature. Furthermore, although pretreatment with the CYP3A inducer rifampicin or the substitution of glucose with galactose in the growth media significantly augmented the loss of cell viability elicited by dronedarone and poyendarone, a lower loss of cell viability was consistently observed in poyendarone across all concentrations. Taken together, our preliminary investigations suggested that the rational deuteration of dronedarone at its benzofuran ring reduces aberrant cytochrome P450 3A4/5-mediated bioactivation, which attenuated its mitochondrial toxicity in human hepatic HepG2 cells. [ABSTRACT FROM AUTHOR]

Background: In this post hoc analysis, we assessed patient characteristics as predictors of dronedarone trough concentrations and characterized the relationship of trough concentrations of dronedarone with its efficacy and safety. Hypothesis: Dronedarone is recommended as a 400 mg twice daily dose taken orally with meals. We hypothesize that drug concentration/bioavailability of dronedarone, measured as above‐ and below‐median trough concentrations, does not impact the efficacy outcomes. Methods: Average trough concentrations (Ctrough_avg) across multiple timepoints were calculated for each patient, and patient Ctrough_avg values were categorized as below‐median or above‐median concentrations. The effect of patient baseline characteristics on dronedarone Ctrough_avg was assessed in the below‐median versus above‐median groups. The effect of dronedarone in each Ctrough_avg group versus placebo on risk of first atrial fibrillation/atrial flutter (AF/AFL) recurrence and safety was also evaluated. Results: Overall, 1795 plasma samples were available from 507 dronedarone‐treated patients. An above‐median Ctrough_avg was associated with age ≥75 years, female sex, lower weight, higher pacemaker use, and higher oral anticoagulant use. The risk of adjudicated first AF/AFL recurrence was significantly lower with dronedarone versus placebo in the below‐median (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.56–0.91; p =.0054) and above‐median groups (HR: 0.63; 95% CI: 0.50–0.81; p =.0002). No difference in risk of AF/AFL recurrence was observed between the above‐ and below‐median groups. Safety and tolerability of dronedarone were similar between groups. Conclusion: Significant reduction in AF/AFL recurrence was observed in patients treated with dronedarone versus placebo, regardless of dronedarone concentrations above or below the median value. [ABSTRACT FROM AUTHOR]

Background: The use of antiarrhythmic drugs (AADs) in patients with chronic kidney disease (CKD) is complex because impaired renal clearance can cause increased drug levels, and risk of intolerance or adverse events. Due to the propensity for CKD to occur alongside atrial fibrillation/atrial flutter (AF/AFL), it is essential that AAD safety and efficacy are assessed for patients with CKD. Hypothesis: Dronedarone, an approved AAD, may present a suitable therapeutic option for patients with AF/AFL and concomitant CKD. Methods: EURIDIS‐ADONIS (EURIDIS, NCT00259428; ADONIS, NCT00259376) were identically designed, multicenter, double‐blind, parallel‐group trials investigating AF/AFL control with dronedarone 400 mg twice daily versus placebo (randomized 2:1). In this post hoc analysis, the primary endpoint was time to first AF/AFL. Patients were stratified according to renal function using the CKD‐Epidemiology Collaboration equation and divided into estimated glomerular filtration rate (eGFR) subgroups of 30–44, 45–59, 60–89, and ≥90 ml/min. Time‐to‐events between treatment groups were compared using log‐rank testing and Cox regression. Results: At baseline, most (86%) patients demonstrated a mild or mild‐to‐moderate eGFR decrease. Median time to first AF/AFL recurrence was significantly longer with dronedarone versus placebo for all eGFR subgroups except the 30 to 44 ml/min group, where the trend was similar but statistical power may have been limited by the small population. eGFR stratification had no significant effect on serious adverse events, deaths, or treatment discontinuations. Conclusions: This analysis suggests that dronedarone could be an effective therapeutic option for AF with an acceptable safety profile in patients with impaired renal function. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) recurrence after catheter ablation is associated with worse outcomes and quality of life. Left atrial (LA) structural remodeling provides the essential substrate for AF perpetuation. Baseline extent and the progression of LA fibrosis after ablation are strong predictors of postprocedural AF recurrence. Dronedarone is an antiarrhythmic drug proven to efficiently maintain sinus rhythm. Objective: We sought to investigate the effect of the antiarrhythmic drug Dronedarone in decreasing LA fibrosis progression and AF recurrence after ablation of AF patients. Methods: EDORA (NCT04704050) is a multicenter, prospective, randomized controlled clinical trial. Patients with persistent or paroxysmal AF undergoing AF ablation will be randomized into Dronedarone versus placebo/standard of care. The co‐primary outcomes are the recurrence of atrial arrhythmias (AA) within 13 months of follow‐up after ablation and the progression of left atrial fibrosis postablation. All patients will receive a late‐gadolinium enhancement magnetic resonance imaging at baseline, 3‐ and 12‐month follow‐up for the quantification of LA fibrosis and ablation‐related scarring. AA recurrence and burden will be assessed using a 30‐day ECG patch every 3 months with daily ECG recordings in between. Quality of life improvement is assessed using the AFEQT and AFSS questionnaires. Conclusion: EDORA will be the first trial to assess the progression of LA structural remodeling after ablation and its association with Dronedarone treatment and ablation success in a randomized controlled fashion. The trial will provide insight into the pathophysiology of AF recurrence after ablation and may provide potential therapeutic targets to optimize procedural outcomes. [ABSTRACT FROM AUTHOR]