Assessment of Dofetilide or Sotalol Tolerability in the Elderly.

Background: Dofetilide and sotalol are potassium channel antagonists that require inpatient QTc monitoring during initiation, due to increased risk of fatal arrhythmias. Elderly patients are especially subject to an increased risk of fatal arrhythmias due to polypharmacy, comorbidities, and physiologic cardiac changes with aging. This study will describe the tolerability and risk factors associated with the initiation of sotalol or dofetilide in patients ≥80 years of age. Methodology: This is a multicenter, retrospective, descriptive study of patients ≥80 years old who were initiated on either dofetilide or sotalol between May 8, 2018 and July 31, 2021 at institutions within the Mayo Clinic Health System. The percentage of patients who received nonpackage insert recommended doses was identified. Incidence of and reasons for dose reductions or discontinuations due to safety-related events or clinical concerns during the initial loading period were collected. Results: The final analysis included 104 patients. The majority of patients (75%) received nonstandard initial doses of dofetilide or sotalol based on baseline estimated creatinine clearance or QTc. Overall, 39% (N = 41) of patients experienced a dose reduction or discontinuation due to a safety-related event or concern. Patients who received nonstandard initial doses of dofetilide or sotalol had 4.7 times greater odds of experiencing a safety-related event requiring dose reduction or discontinuation. Conclusion: Following package insert dosing in elderly patients increases safety and tolerability relative to more aggressive dosing of dofetilide or sotalol.

Informing a Comprehensive Risk Assessment of Infant Drug Exposure From Human Milk: Application of a Physiologically Based Pharmacokinetic Lactation Model for Sotalol.

Characterization of infant drug exposure through human milk is important and underexplored. Because infant plasma concentrations are not frequently collected in clinical lactation studies, modeling and simulation approaches can integrate physiology, available milk concentrations, and pediatric data to inform exposure in breastfeeding infants. A physiologically based pharmacokinetic model was built for sotalol, a renally eliminated drug, to simulate infant drug exposure from human milk. Intravenous and oral adult models were built, optimized, and scaled to an oral pediatric model for a breastfeeding-relevant age group (<2 years). Model simulations captured the data that were put aside for verification. The resulting pediatric model was applied to predict the impacts of sex, infant body size, breastfeeding frequency, age, and maternal dose (240 and 433 mg) on drug exposure during breastfeeding. Simulations suggest a minimal effect of sex or frequency on total sotalol exposure. Infants in the 90th percentile in height and weight have predicted exposures ≈20% higher than infants of the same age in the 10th percentile due to increased milk intake. The simulated infant exposures increase throughout the first 2 weeks of life and are maintained at the highest concentrations in weeks 2-4, with a consistent decrease observed as infants age. Simulations suggest that breastfeeding infants will have plasma concentrations in the lower range observed in infants administered sotalol. With further validation on additional drugs, physiologically based pharmacokinetic modeling approaches could use lactation data to a greater extent and provide comprehensive information to support decisions regarding medication use during breastfeeding.

Clinical and economic outcomes associated with use of anti-arrhythmic drugs versus ablation in atrial fibrillation.

Aim: To evaluate the clinical and economic impact of antiarrhythmic drugs (AADs) compared with ablation both as individual treatments and as combination therapy without/with considering the order of treatment among patients with atrial fibrillation (AFib). Materials & methods: A budget impact model over a one-year time horizon was developed to assess the economic impact of AADs (amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotalol, and as a group) versus ablation across three scenarios: direct comparisons of individual treatments, non-temporal combinations, and temporal combinations. The economic analysis was conducted in accordance with CHEERS guidance as per current model objectives. Results are reported as costs per patient per year (PPPY). The impact of individual parameters was evaluated using one-way sensitivity analysis (OWSA). Results: In direct comparisons, ablation had the highest annual medication/procedure cost ($29,432), followed by dofetilide ($7661), dronedarone ($6451), sotalol ($4552), propafenone ($3044), flecainide ($2563), and amiodarone ($2538). Flecainide had the highest costs for long-term clinical outcomes ($22,964), followed by dofetilide ($17,462), sotalol ($15,030), amiodarone ($12,450), dronedarone ($10,424), propafenone ($7678) and ablation ($9948). In the non-temporal scenario, total costs incurred for AADs (group) + ablation ($17,278) were lower compared with ablation alone ($39,380). In the temporal scenario, AADs (group) before ablation resulted in PPPY cost savings of ($22,858) compared with AADs (group) after ablation ($19,958). Key factors in OWSA were ablation costs, the proportion of patients having reablation, and withdrawal due to adverse events. Conclusion: Utilization of AADs as individual treatment or in combination with ablation demonstrated comparable clinical benefits along with costs savings in patients with AFib.

Risk for Bleeding-Related Hospitalizations During Use of Amiodarone With Apixaban or Rivaroxaban in Patients With Atrial Fibrillation : A Retrospective Cohort Study.

BACKGROUND: Amiodarone, the most effective antiarrhythmic drug in atrial fibrillation, inhibits apixaban and rivaroxaban elimination, thus possibly increasing anticoagulant-related risk for bleeding. OBJECTIVE: For patients receiving apixaban or rivaroxaban, to compare risk for bleeding-related hospitalizations during treatment with amiodarone versus flecainide or sotalol, antiarrhythmic drugs that do not inhibit these anticoagulants' elimination. DESIGN: Retrospective cohort study. SETTING: U.S. Medicare beneficiaries aged 65 years or older. PATIENTS: Patients with atrial fibrillation began anticoagulant use between 1 January 2012 and 30 November 2018 and subsequently initiated treatment with study antiarrhythmic drugs. MEASUREMENTS: Time to event for bleeding-related hospitalizations (primary outcome) and ischemic stroke, systemic embolism, and death with or without recent (past 30 days) evidence of bleeding (secondary outcomes), adjusted with propensity score overlap weighting. RESULTS: There were 91 590 patients (mean age, 76.3 years; 52.5% female) initiating use of study anticoagulants and antiarrhythmic drugs, 54 977 with amiodarone and 36 613 with flecainide or sotalol. Risk for bleeding-related hospitalizations increased with amiodarone use (rate difference [RD], 17.5 events [95% CI, 12.0 to 23.0 events] per 1000 person-years; hazard ratio [HR], 1.44 [CI, 1.27 to 1.63]). Incidence of ischemic stroke or systemic embolism did not increase (RD, -2.1 events [CI, -4.7 to 0.4 events] per 1000 person-years; HR, 0.80 [CI, 0.62 to 1.03]). The risk for death with recent evidence of bleeding (RD, 9.1 events [CI, 5.8 to 12.3 events] per 1000 person-years; HR, 1.66 [CI, 1.35 to 2.03]) was greater than that for other deaths (RD, 5.6 events [CI, 0.5 to 10.6 events] per 1000 person-years; HR, 1.15 [CI, 1.00 to 1.31]) (HR comparison: P = 0.003). The increased incidence of bleeding-related hospitalizations for rivaroxaban (RD, 28.0 events [CI, 18.4 to 37.6 events] per 1000 person-years) was greater than that for apixaban (RD, 9.1 events [CI, 2.8 to 15.3 events] per 1000 person-years) (P = 0.001). LIMITATION: Possible residual confounding. CONCLUSION: In this retrospective cohort study, patients aged 65 years or older with atrial fibrillation treated with amiodarone during apixaban or rivaroxaban use had greater risk for bleeding-related hospitalizations than those treated with flecainide or sotalol. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

A value-based budget impact model for dronedarone compared with other rhythm control strategies.

Aim: The budgetary consequences of increasing dronedarone utilization for treatment of atrial fibrillation were evaluated from a US payer perspective. Materials & methods: A budget impact model over a 5-year time horizon was developed, including drug-related costs and risks for long-term clinical outcomes (LTCOs). Treatments included antiarrhythmic drugs (AADs; dronedarone, amiodarone, sotalol, propafenone, dofetilide, flecainide), rate control medications, and ablation. Direct comparisons and temporal and non-temporal combination scenarios investigating treatment order were analyzed as costs per patient per month (PPPM). Results: By projected year 5, costs PPPM for dronedarone versus other AADs decreased by $37.69 due to fewer LTCOs, treatment with dronedarone versus ablation or rate control medications + ablation resulted in cost savings ($359.94 and $370.54, respectively), and AADs placed before ablation decreased PPPM costs by $242 compared with ablation before AADs. Conclusion Increased dronedarone utilization demonstrated incremental cost reductions over time.

Economics and outcomes of sotalol in-patient dosing approaches in patients with atrial fibrillation.

INTRODUCTION: There exists variability in the administration of in-patient sotalol therapy for symptomatic atrial fibrillation (AF). The impact of this variability on patient in-hospital and 30-day posthospitalization costs and outcomes is not known. Also, the cost impact of intravenous sotalol, which can accelerate drug loading to therapeutic levels, is unknown. METHODS: One hundred and thirty-three AF patients admitted for oral sotalol initiation at an Intermountain Healthcare Hospital from January 2017 to December 2018 were included. Patient and dosing characteristics were described descriptively and the impact of dosing schedule was correlated with daily hospital costs/clinical outcomes during the index hospitalization and for 30 days. The Centers for Medicare and Medicaid Services reimbursement for 3-day sotalol initiation is $9263.51. Projections of cost savings were made considering a 1-day load using intravenous sotalol that costs $2500.00 to administer. RESULTS: The average age was 70.3 ± 12.3 years and 60.2% were male with comorbidities of hypertension (83%), diabetes (36%), and coronary artery disease (53%). The mean ejection fraction was 59.9 ± 7.8% and the median corrected QT interval was 453.7 ± 37.6 ms before sotalol dosing. No ventricular arrhythmias developed, but bradycardia (<60 bpm) was observed in 37.6% of patients. The average length of stay was 3.9 ± 4.6 (median: 2.2) days. Postdischarge outcomes and rehospitalization rates stratified by length of stay were similar. The cost per day was estimated at $2931.55 (1. $2931.55, 2. $5863.10, 3. $8794.65, 4. $11 726.20). CONCLUSIONS: In-patient oral sotalol dosing is markedly variable and results in the potential of both cost gain and loss to a hospital. In consideration of estimated costs, there is the potential for $871.55 cost savings compared to a 2-day oral load and $3803.10 compared to a 3-day oral load.

Assessment of Drug Proarrhythmic Potential in Electrically Paced Human Induced Pluripotent Stem Cell-Derived Ventricular Cardiomyocytes Using Multielectrode Array.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for the assessment of drug proarrhythmic potential through multielectrode array (MEA). HiPSC-CM cultures beat spontaneously with a wide range of frequencies, however, which could affect drug-induced changes in repolarization. Pacing hiPSC-CMs at a physiological heart rate more closely resembles the state of in vivo ventricular myocytes and permits the standardization of test conditions to improve consistency. In this study, we systematically investigated the time window of stable ion currents in high-purity hiPSC-derived ventricular cardiomyocytes (hiPSC-vCMs) and confirmed that these cells could be used to correctly predict the proarrhythmic risk of Comprehensive In Vitro Proarrhythmia Assay (CiPA) reference compounds. To evaluate drug proarrhythmic potentials at a physiological beating rate, we used a MEA to electrically pace hiPSC-vCMs, and we recorded regular field potential waveforms in hiPSC-vCMs treated with DMSO and 10 CiPA reference drugs. Prolongation of field potential duration was detected in cells after exposure to high- and intermediate-risk drugs; in addition, drug-induced arrhythmia-like events were observed. The results of this study provide a simple and feasible method to investigate drug proarrhythmic potentials in hiPSC-CMs at a physiological beating rate.

Assessment of Sotalol and Dofetilide Dosing at a Large Academic Medical Center.

BACKGROUND: Patients initiated on sotalol and dofetilide require inpatient monitoring and dose adjustments due to risks of corrected QT (QTc) prolongation and Torsades de pointes (TdP). Patients may receive higher initial doses than recommended due to close monitoring by specialized practitioners. The objective of this study was to describe prescribing practices of sotalol and dofetilide and to compare safety outcomes between standard and nonstandard dosing strategies. METHODS: This was a single-center retrospective analysis of adult inpatients who underwent sotalol or dofetilide initiation between June 1, 2015, and August 1, 2018. The end points of this study included the percentage of patients who received standard and nonstandard dosing, incidence of QTc prolongation (≥500 milliseconds or ≥15% from baseline), incidence of TdP, and dose reduction or medication discontinuation. RESULTS: A total of 379 patients (195 sotalol and 184 dofetilide) were included in this analysis. There were 110 (56.4%) patients in the sotalol group and 111 (58.4%) patients in the dofetilide group that received nonstandard initial dosing. Nonstandard dosing was associated with a greater incidence of QTc prolongation compared to standard dosing (57.5% vs 43.0%, P = .005). Only one patient in the nonstandard dosing group experienced TdP. Patients initiated on nonstandard dosing required dose reduction or therapy discontinuation (37.6% vs 23.4%, P = .003) more frequently. CONCLUSION: Higher than recommended initial doses of sotalol or dofetilide were associated with higher incidence of QTc prolongation and more frequent therapy modification.

Assessment of the ecotoxicity of the pharmaceuticals bisoprolol, sotalol, and ranitidine using standard and behavioral endpoints.

The pharmaceuticals bisoprolol (BIS), sotalol (SOT), and ranitidine (RAN) are among the most consumed pharmaceuticals worldwide and are frequently detected in different aquatic ecosystems. However, very few ecotoxicity data are available in the literature for them. To help fill these data gaps, toxicity tests with the algae Raphidocelis subcapitata, the macrophyte Lemna minor, the cnidarian Hydra attenuata, the crustacean Daphnia similis, and the fish Danio rerio were performed for assessing the ecotoxicity of these pharmaceuticals. Standard, as well as non-standard endpoint, was evaluated, including the locomotor behavior of D. rerio larvae. Results obtained for SOT and RAN showed that acute adverse effects are not expected to occur on aquatic organisms at the concentrations at which these pharmaceuticals are usually found in fresh surface waters. On the other hand, BIS was classified as hazardous to the environment in the acute III category. Locomotor behavior of D. rerio larvae was not affected by BIS and RAN. A disturbance on the total swimming distance at the dark cycle was observed only for larvae exposed to the highest test concentration of 500 mg L-1 of SOT. D. similis reproduction was affected by BIS with an EC10 of 3.6 (0.1-34.0) mg L-1. A risk quotient (RQ) of 0.04 was calculated for BIS in fresh surface water, considering a worst-case scenario. To the best of our knowledge, this study presents the first chronic toxicity data with BIS on non-target organisms.

Telemetered common marmosets is useful for the assessment of electrocardiogram parameters changes induced by multiple cardiac ion channel inhibitors.

The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans. QTc prolongation was observed in the marmosets dosed with sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine. PR prolongation was noted after flecainide and verapamil administration, and QRS widening occurred following treatment with flecainide and quinidine. Drugs plasma levels associated with ECG changes in marmosets were similar to those in humans, except for verapamil-induced QTc prolongation. Verapamil-induced change is suggested due to body temperature decrease. These results indicate that telemetered common marmoset is a useful animal for evaluation of the ECG effects of multiple cardiac ion channel inhibitors and the influence of body temperature change should be considered in the assessment.

The fate of sotalol in aqueous chlorination: Kinetics, mechanisms and ecotoxicity assessment.

Unmetabolized pharmaceuticals often enter the water treatment plants and exposed to various treatment processes. Among these water treatment processes, disinfection is a process which involves the application of chemical oxidation to remove pathogen. Untreated pharmaceuticals from primary and secondary treatment have the potential to be exposed to the chemical oxidation process during disinfection. This study investigated the kinetics and mechanism of the degradation of sotalol during chlorination process. Chlorination with hypochlorous acid (HOCl) as main reactive oxidant has been known as one of the most commonly used disinfection methods. The second order rate constant for the reaction between sotalol and free available chlorine (FAC) was found to decrease from 60.1 to 39.1M-1min-1 when the pH was increased from 6 to 8. This result was mainly attributed by the decreased of HOCl concentration with increasing pH. In the real water samples, the presence of the higher amount of organic content was found to reduce the efficiency of chlorination in the removal of sotalol. This result showed that sotalol competes with natural organic matter to react with HOCl during chlorination. After 24h of FAC exposure, sotalol was found to produce three stable transformation by-products. These by-products are mainly chlorinated compounds. According to the acute and chronic toxicity calculated using ECOSAR computer program, the transformation by-products are more harmful than sotalol.

Use of Antiarrhythmic Medications in Medicare Part D Patients With an Implantable Cardioverter-Defibrillator and Ventricular Tachycardia.

Ventricular tachycardia (VT) is common in cardiomyopathy patients with an implantable cardioverter-defibrillator. This analysis evaluated antiarrhythmic medication use and change in use over time in patients with VT and structural heart disease. Query of Medicare claims identified patients with an implantable cardioverter-defibrillator and VT. Patients with atrial fibrillation or supraventricular tachycardia were excluded. Two cohorts were created of patients enrolled in Medicare Part D for the 12 months before 2007 and 2012. Patients were identified through a search for antiarrhythmic medication fills with a supply covering January 1 of the cohort year. Adjusted logistic regression modeling evaluated the association between patient characteristics and antiarrhythmic medication use. The 2007 (n = 2,334) and 2012 (n = 3,892) Medicare Part D cohorts had similar demographics: median age 76 years, 64%-67% male, and 87%-89% white. Of the 2007 cohort, 1,380 (59%) patients were on a beta blocker, and 484 (20.7%) were on an antiarrhythmic medication (70% amiodarone and 20% sotalol). Between 2007 and 2012, there was a statistically significant higher use of any antiarrhythmic medication (p = 0.014), beta blockers (p <0.0001), mexiletine (p = 0.005), and ranolazine (p <0.0001), while amiodarone use remained unchanged (p = 0.53). After multivariable adjustment, male gender and renal disease were associated with higher antiarrhythmic medication use. In conclusion, although antiarrhythmic medication and beta blocker use in patients with VT increased over time, <1 in 4 patients were on an antiarrhythmic medication and only 65% of the patients were on a beta blocker.

Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.

INTRODUCTION: Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS: The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a ß-blocker), or dl-sotalol (a ß+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). RESULTS: Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both ß-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DISCUSSION: The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.

Minimal T-wave representation and its use in the assessment of drug arrhythmogenicity.

BACKGROUND: Recently, numerous models and techniques have been developed for analyzing and extracting features from the T wave which could be used as biomarkers for drug-induced abnormalities. The majority of these techniques and algorithms use features that determine readily apparent characteristics of the T wave, such as duration, area, amplitude, and slopes. METHODS: In the present work the T wave was down-sampled to a minimal rate, such that a good reconstruction was still possible. The entire T wave was then used as a feature vector to assess drug-induced repolarization effects. The ability of the samples or combinations of samples obtained from the minimal T-wave representation to correctly classify a group of subjects before and after receiving d,l-sotalol 160 mg and 320 mg was evaluated using a linear discriminant analysis (LDA). RESULTS: The results showed that a combination of eight samples from the minimal T-wave representation can be used to identify normal from abnormal repolarization significantly better compared to the heart rate-corrected QT interval (QTc). It was further indicated that the interval from the peak of the T wave to the end of the T wave (Tpe) becomes relatively shorter after IKr inhibition by d,l-sotalol and that the most pronounced repolarization changes were present in the ascending segment of the minimal T-wave representation. CONCLUSIONS: The minimal T-wave representation can potentially be used as a new tool to identify normal from abnormal repolarization in drug safety studies.

[Current status of antiarrhythmic drug use and safety assessment in Chinese patients with atrial fibrillation].

Objective: To investigate the current status of antiarrhythmic drugs (AADs) use in Chinese patients with atrial fibrillation(AF) and assess the safety of AADs in this patient cohort. Methods: From January 2011 to December 2013, a total of 4 008 AF patients treated with AADs was enrolled in this study and patients were followed up for 24 months. Detailed information of prescribed drug, the causes of drug discontinuation and side effects were recorded. Results: Amiodarone was prescribed to 64.3%(2 579 cases) and propafenone to 31.1%(1 247 cases) of the enrolled patients, only 148 patients(3.7%) were treated with sotalol and 34 patients (0.8%) were treated with moracizine. The prevalence of heart failure (4.0%(102/2 579) vs. 1.4%(17/1 247, P<0.001), coronary heart disease (13.5% (348/2 579) vs. 7.4%(93/1 247), P<0.001) and non-ischemic cardiomyopathy (3.1%(78/2 579) vs. 0.7%(9/1 247), P<0.001) was significantly higher in patients treated with amiodarone than in the patients treated with propafenone. During the follow-up period, the discontinuation rate of amiodarone, propafenone, sotalol and moracizine was 28.8%(743/2 579), 25.1%(313/1 247), 14.2%(21/148) and 32.4%(11/34) respectively. The reasons of discontinuing amiodarone were: follow physicians' decision (75.7%, 563 cases), no effect (3.0%, 22 cases), side effects (4.3%, 32 cases) and patients' own decision (17.0%, 126 cases). The side effects of amiodarone included thyroid dysfunction (56.3%, 18 cases), bradycardia (12.5%, 4 cases), interstitial pneumonitis/pulmonary interstitial fibrosis (6.2%, 2 cases) and others (gastrointestinal symptom, rash, hepatic dysfunction, etc.). Conclusions: Amiodarone and propafenone are the most common AADs used in Chinese patients with atrial fibrillation. The prescription of AADs is essentially in accordance to the guideline of AF treatment. However, the discontinuation rates of AADs are high in Chinese AF patients. Lacking of better AADs is still a major problem in AF pharmacotherapy. Clinical Trial Registry Chinese Clinical Trial Registry, ChiCTR-OCH-13003729.

Risk based in vitro performance assessment of extended release abuse deterrent formulations.

High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products.

QT interval correction assessment in the anesthetized guinea pig.

INTRODUCTION: The anesthetized guinea pig (ANES GP) has proven to be an effective small animal model to evaluate cardiac electrophysiologic effects of drug-candidate molecules during lead optimization. While heart rate (HR) corrected QT interval (QTc) is a key variable to determine test article-dependent repolarization effects, ideal correction methods are an area of constant debate given the potential influence of anesthesia, autonomic tone, species, strain and gender on the QT/HR relationship. The aim of this study was to characterize the ability of common correction formulas to normalize rate-dependent effects on the QT interval in the ketamine/xylazine ANES GP. METHODS: Atrial pacing (n=10), ivabradine or ephedrine (n=6/group) infusions were used, respectively to evaluate the effects of a wide range of HRs on the QT/HR relationship. Correction formulas (Bazett [QTcb], Fridericia [QTcf] and Van de Water [QTcVdW]) were applied and the best fit formula was determined with the aid of the slope of their QT-HR linear relationship. RESULTS: From 100 to 220bpm, QTcb underestimated the change in QT interval duration (QT/HR slope=0.35 to 0.67). However, QTcVdW was more appropriate in this HR range (QT/HR slope=-0.07 and 0.09). At higher HRs (>220bpm), QTcb performed better (QT/HR slope=-0.02 and 0.07) as compared to QTcf (QT/HR slope=-0.18 to -0.1) and QTcVdW (QT/HR slope=-0.2 to -0.17) (p<0.01). All the correction formulas identified dofetilide- and sotalol-dependent repolarization delay (n=6/group) but QTcb and QTcf demonstrated reduced sensitivity as compared to fixed cardiac pacing (p<0.01). In contrast, QTcVdW resulted in an apparent underestimation of the QT interval duration at HR levels above the basal ketamine/xylazine ANES GP HRs (>220bpm) with ephedrine (n=6). DISCUSSION: The best fit correction formula in the ANES GP was highly dependent on the HR range. In the ketamine/xylazine model, QTcVdW performed best with HR <220bpm and QTcb performed best with HR >220bpm. The QTcVdW correction formula was thus selected in the ketamine/xylazine ANES GP since HRs in this model are generally within the optimal range for this correction formula.

Long-term stability, reproducibility, and statistical sensitivity of a telemetry-instrumented dog model: A 27-month longitudinal assessment.

INTRODUCTION: ICH guidelines, as well as best-practice and ethical considerations, provide strong rationale for use of telemetry-instrumented dog colonies for cardiovascular safety assessment. However, few studies have investigated the long-term stability of cardiovascular function at baseline, reproducibility in response to pharmacologic challenge, and maintenance of statistical sensitivity to define the usable life of the colony. These questions were addressed in 3 identical studies spanning 27months and were performed in the same colony of dogs. METHODS: Telemetry-instrumented dogs (n=4) received a single dose of dl-sotalol (10mg/kg, p.o.), a ß1 adrenergic and IKr blocker, or vehicle, in 3 separate studies spanning 27months. Systemic hemodynamics, cardiovascular function, and ECG parameters were monitored for 18h post-dose; plasma drug concentrations (Cp) were measured at 1, 3, 5, and 24h post-dose. RESULTS: Baseline hemodynamic/ECG values were consistent across the 27-month study with the exception of modest age-dependent decreases in heart rate and the corresponding QT-interval. dl-Sotalol elicited highly reproducible effects in each study. Reductions in heart rate after dl-sotalol treatment ranged between -22 and -32 beats/min, and slight differences in magnitude could be ascribed to variability in dl-sotalol Cp (range=3230-5087ng/mL); dl-sotalol also reduced LV-dP/dtmax 13-22%. dl-Sotalol increased the slope of the PR-RR relationship suggesting inhibition of AV-conduction. Increases in the heart-rate corrected QT-interval were not significantly different across the 3 studies and results of a power analysis demonstrated that the detection limit for QTc values was not diminished throughout the 27month period and across a range of power assumptions despite modest, age-dependent changes in heart rate. DISCUSSION: These results demonstrate the long-term stability of a telemetry dog colony as evidenced by a stability of baseline values, consistently reproducible response to pharmacologic challenge and no diminished statistical sensitivity over time.

A simple and sensitive LC-MS/MS method for the determination of sotalol in rat plasma.

A sensitive, rapid and robust HPLC method with tandem mass spectrometry (HPLC/MS/MS) detection has been developed and validated for the quantification of sotalol in rat plasma. Plasma samples were precipitated with acetonitrile before analysis. The chromatographic separation was performed on an Atlantis hydrophilic interaction liquid chromatography Silica column (50 × 2.1 mm, 3 µm) with a gradient mobile phase of 10 mm NH4 COOH (containing 0.2% of formic acid) as buffer A and acetonitrile as mobile phase B. Sotalol (m/z 273.2 → 255.1) and atenolol (the internal standard, IS, m/z 267.2 → 190.1) were monitored under positive ionization mode with 5500 QTRAP. Retention time of sotalol and the IS were 2.69 and 3.43 min, respectively. The linear range was 5-500 nm based on the analysis of 0.1 mL of plasma. The intrabatch precision ranged from 1.2 to 6.1%, and the inter-batch precision was from 3.3 to 6.5%. The coefficient of variation of IS-normalized matrix factor was 7.6%. Experiments for stability were performed and the analyte was sufficiently stable. A run time of 6 min for each injection made it possible to analyze a high throughput of plasma samples. The assay was successfully applied to the determination of sotalol in rat plasma after a micro-dose oral administration.

Analysis of the cost-effectiveness of dronedarone versus amiodarone, propafenone, and sotalol in patients with atrial fibrillation: results for Serbia.

BACKGROUND: Recent studies have shown that dronedarone is associated with significantly fewer adverse effects and treatment discontinuations, and a trend toward reduced all-cause mortality, compared with amiodarone. Introduction of dronedarone in clinical practice is limited by its higher cost than amiodarone, propafenone, and sotalol. AIM: To estimate cost-effectiveness of dronedarone versus amiodarone, propafenone, and sotalol in patients with atrial fibrillation (AF). METHODS: We constructed a Markov model, which was then simulated by Monte Carlo simulation using 1,000 virtual patients. Costs and outcomes were estimated from the societal perspective and discounted at 3% annually. A lifetime horizon and three-month cycle length were used. The main outcome measurement was the number of years spent without stroke. Values of transition probabilities and therapy outcomes were estimated from available literature. The prices of health services and drugs were obtained from the Republic Institute for Health Insurance Tariff Book and Drug List A and from the drug developer. RESULTS: Cost-effectiveness shows that the dronedarone treatment option has the most advantageous relationship, where, for one year without a stroke, the total cost is €1,779.23. In the case of the amiodarone therapy option, for one year without a stroke €3,845.10 is needed, for propafenone €4,674.20, while for sotalol the sum is €14,973.89. Estimated annual costs for patients with first-detected AF in Serbia were €610. CONCLUSIONS: The results of our model indicate that dronedarone is a cost-effective therapy compared with amiodarone, propafenone, and sotalol in patients with AF, if the outcome measurement is the number of years spent without stroke.