Sotalol Concentration Research Articles

CAVIN1-Mediated hERG Dynamics: A Novel Mechanism Underlying the Interindividual Variability in Drug-Induced Long QT.

Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (IKr) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT. We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate CAVIN1 expression. Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and IKr significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. IKr reduction was caused by a rapid translocation of hERG channel from the membrane to the cytoskeleton-associated fractions upon sotalol application. CAVIN1, essential for caveolae biogenesis, was 2× more highly expressed in HS iPS-CMs, and its knockdown by small interfering RNA reduced their sensitivity to sotalol. CAVIN1 overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. We found that treatment with sotalol promoted translocation of the hERG channel from the plasma membrane to the cytoskeleton fractions in a process dependent on CAVIN1 (caveolae associated protein 1) expression. CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated the translocation of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers, such as E4031, vandetanib, and clarithromycin. Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1.

Abstract 16208: Population Pharmacokinetics of Intravenously and Orally Administered Sotalol in Patients With Cardiac Arrhythmias

Introduction: Recently, an intravenous (IV) formulation of sotalol was approved to provide a loading dose before initiating oral sotalol therapy to reduce hospitalization days. However, the population pharmacokinetics (PK) of sotalol after administration of an IV loading dose regimen in patients with atrial fibrillation were not characterized. Understanding the PK of IV sotalol loading dose in patients with atrial fibrillation is required to ensure safety and optimal therapeutic outcomes. Hypothesis: The population PK model of IV and orally administered sotalol can be developed using data from two clinical PK studies with reasonable empirical Bayes estimates (EBEs) of PK parameters absorption rate constant (Ka), clearance (CL), and volume of distribution (Vd). Methods: The PK dataset of sotalol was from: 1) Relative bioavailability study with IV and oral sotalol PK data by sponsor AltaThera Inc., 2) Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) registry study. Population PK was evaluated using NONMEM® 7.5, Perl-speaks-NONMEM (PsN®) version 5.3.0. Results: 545 sotalol concentrations in 25 patients were analyzed. A one-compartment model with a first-order elimination rate best described the data (Figure 1). The data correlated QTc interval levels within the observed sotalol concentration range (1.2 to 1900 ng/mL) were below 500 ms. In the final model, the EBE’s of sotalol PK parameters were, Ka - 1.44 hr -1 , CL 0.46 - L/h/kg, and the Vd -5.6 L/kg. Further PK/PD studies are needed to establish the correlation between sotalol PK and safety in this population. Conclusions: The PK of sotalol after IV and oral doses were adequately described using a population PK modeling approach. The QTc levels correlated to the plasma concentrations in this study were within the safety limit of 500 ms. This population PK model could be used to correlate the PK with safety (QTc interval prolongation) further to optimize the sotalol IV and oral dosing regimen.

Transplacental Therapeutic Drug Monitoring in Pregnant Women with Fetal Tachyarrhythmia Using HPLC-MS/MS.

Fetal arrhythmia develops in 0.1-5% of pregnancies and may cause fetal heart failure and fetal hydrops, thus increasing fetal, neonatal, and infant mortality. The timely initiation of transplacental antiarrhythmic therapy (ART) promotes the conversion of fetal tachycardia to sinus rhythm and the regression of the concomitant non-immune fetal hydrops. The optimal treatment regimen search for the fetus with tachyarrhythmia is still of high value. Polymorphisms of these genes determines the individual features of the drug pharmacokinetics. The aim of this study was to study the pharmacokinetics of transplacental anti-arrhythmic drugs in the fetal therapy of arrhythmias using HPLC-MS/MS, as well as to assess the effect of the multidrug-resistance gene ABCB1 3435C > T polymorphism on the efficacy and maternal/fetal complications of digoxin treatment. The predisposition to a decrease in the bioavailability of the digoxin in patients with a homozygous variant of the CC polymorphism showed a probable association with the development of ART side effects. A pronounced decrease in heart rate in women with the 3435TT allele of the ABCB1 gene was found. The homozygous TT variant in the fetus showed a probable association with an earlier response to ART and rhythm disruptions on the digoxin dosage reduction. high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) methods for digoxin and sotalol therapeutic drug monitoring in blood plasma, amniotic fluid, and urine were developed. The digoxin and sotalol concentrations were determined in the plasma blood, urine, and amniotic fluid of 30 pregnant women at four time points (from the beginning of the transplacental antiarrhythmic therapy to delivery) and the plasma cord blood of 30 newborns. A high degree of correlation between the level of digoxin and sotalol in maternal and cord blood was found. The ratio of digoxin and sotalol in cord blood to maternal blood was 0.35 (0.27 and 0.46) and 1.0 (0.97 and 1.07), accordingly. The digoxin concentration in the blood of the fetus at the moment of the first rhythm recovery episode, 0.58 (0.46, 0.8) ng/mL, was below the therapeutic interval. This confirms the almost complete transplacental transfer of sotalol and the significant limitation in the case of digoxin. Previously, ABCB1/P-glycoprotein had been shown to limit fetal exposure to drugs. Further studies (including multicenter ones) to clarify the genetic features of the transplacental pharmacokinetics of antiarrhythmic drugs are needed.

Prediction of drug pro-arrhythmic cardiotoxicity using a semi-physiologically based pharmacokinetic model linked to cardiac ionic currents inhibition

Drug-induced torsades de pointes (TdP) risks are responsible for the withdrawal of many drugs from the market. Nowadays, assessments of drug-induced TdP risks are mainly based on maximum effective free therapeutic plasma concentration (EFTPCmax) and cardiac ionic current inhibitions using the human ventricular myocytes model (Tor-ORd model). Myocytes are targets of drug-induced TdP. The TdP risks may be directly linked to myocyte drug concentrations. We aimed to develop a semi-physiologically based pharmacokinetic (Semi-PBPK) model linked to cardiac ionic current inhibition (pharmacodynamics, PD) (Semi-PBPK-PD) to simultaneously predict myocyte drug concentrations and their TdP risks in humans. Alterations in action potential duration (ΔAPD90) were simulated using the Tor-ORd model and ionic current inhibition parameters based on myocyte or plasma drug concentrations. The predicted ΔAPD90 values were translated into in vivo alterations in QT interval(ΔQTc) induced by moxifloxacin, dofetilide, or sotalol. Myocyte drug concentrations of moxifloxacin, dofetilide, and sotalol gave better predictions of ΔQTc than plasma. Following validating the developed semi-PBPK-PD model, TdP risks of 37 drugs were assessed using ΔAPD90 and early afterdepolarization occurrence, which were estimated based on 10 × EFTPCmax and 10 × EFTMCmax (maximum effective free therapeutic myocyte concentration). 10 × EFTMCmax gave more sensitive and accurate predictions of pro-arrhythmic cardiotoxicity and the predicted TdP risks were also closer to clinic practice than 10 × EFTPCmax. In conclusion, pharmacokinetics and TdP risks of 37 drugs were successfully predicted using the semi-PBPK-PD model. Myocyte drug concentrations gave better predictions of ΔQTc and TdP risks than plasma.

Abstract 13067: Recapitulating Long QT Syndrome Phenotype in Induced Pluripotent Stem Cells-Derived Cardiomyocytes Using CRISPR/Cas9 Technology

Introduction: Long QT syndrome (LQTS) is an inherited arrhythmia syndrome with a hallmark of QT prolongation secondary to delayed repolarization of cardiomyocytes (CM) on 12-lead ECG. Hypothesis: Studying LQTS in an induced pluripotent stem cell (iPSC)-derived CM model allows for patient-specific phenotype characterization in vitro . We report such a strategy (fig. A) in a patient with LQT type 3 (ECG QTc 503 msec) who harbored a heterozygous pathogenic variant in SCN5A (c.1231G>A), and in a healthy control for comparison (ECG QTc 388 msec). Methods: IPSCs were generated from patient and control dermal fibroblasts using a non-integrational Sendai reprogramming method. The patient’s SCN5A (c.1231G>A) variant was edited into the healthy control using CRISPR/Cas9 technology. CM were subsequently differentiated and beating CM clusters were seeded onto Maestro CytoView multi-electrode array plates. Serial corrected field potential duration (FPD) measurements (n=12), equivalent to QTc values on ECG, were recorded on days 24 to 39 of CM differentiation per sample. CM were exposed to varying concentrations of Nifedipine and Sotalol through cell culture media exchange. Paired t-tests (non-parametric) were utilized for p<0.05. Results: Reprogrammed iPSCs displayed pluripotency characteristics (fig.B). IPSC-derived CMs had confirmed cardiac lineage (fig. C). Prolonged FPD values, corrected for beating rate, were observed in both the LQT3 patient-derived iPSC-CMs (p<0.0001) and the genetically induced LQT3 iPSC-CMs (p<0.0001) compared to control (fig. D & E). Nifedipine and sotalol altered FPD in a dose-dependent response (fig. F & G). Conclusions: An iPSC-derived CM model reliably recapitulates the phenotype of LQTS. Induced LQT3 iPSC-CMs genetically edited from a healthy control accurately recapitulate the LQT3 disease phenotype. Drug effects on CM repolarization were demonstrable in the iPSC-CM model.

SUCCESSFUL MANAGEMENT OF SOTALOL OVERDOSE IN THE ICU: UTILIZATION OF EARLY TEMPORARY IV PACING AND HEMODYALISIS

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Sotalol is a non-selective beta blocker with class III antiarrhythmic properties, a bioavailability of 90-100%, negligible protein binding, low lipid solubility, and 80-90% renal excretion. Sotalol toxicity is a medical emergency associated with hemodynamic instability and fatal arrhythmias. There are no standardized management guidelines with literature suggesting the use of IV glucagon, calcium, bicarbonate, high dose insulin infusion, lipid emulsion therapy and hemodialysis (HD). We report a case of Sotalol toxicity with significant cardiac instability successfully managed with conventional therapy in conjunction with early utilization of temporary pacing and HD. CASE PRESENTATION: 29-year-old female with history of thyroidectomy and drug abuse presented to the emergency department at 15:00 after ingesting 60 tablets of Sotalol 80mg in a suicide attempt. IV Glucagon and calcium were administered on scene. On arrival, she was bradycardic, hypotensive, with a QTc of 495 and serum sotalol concentration (SCC) of 11374ng/ml. Dextrose 10% and insulin infusion at 25units/hr were started for stabilization, up-titration was limited due to glucose disturbance. At 17:00 she required an Epinephrine infusion at 0.04mcg/hr for hemodynamic support, bicarbonate infusion, IV Mg, calcium gluconate and atropine. At 18:34 QTc increased to 683, patient was taken for prompt placement of temporary pacer with a set rate of 45bpm. Nephrology was consulted for emergent HD despite a normal kidney function to help with drug clearance. HD was initiated at 00:30 but was stopped after 2.5 hours due to hypotension and Torsades de Pointes (TdP). Insulin and Epinephrine drips were increased to 45units/hr and 0.24mcg/hr, pacing was increased to 50bpm, 2g of IV Mg were given with subsequent resolution of TdP. At 5:30, she had another episode of NSVT for which she received IV Mg. She required up to 0.5mcg/hr of Epinephrine for stabilization. On day 2 SSC was reduced to 6916ng/mL. At 1600, recurrent NSVT was noted, over-ride pacing was set at 90bpm, she underwent an additional 4 hours of HD. On day 3 she had a 3rd session 4-hour-HD with a post SCC of 401ng/mL. Temporary Pacer was removed on day 4. She had no recurrent arrhythmias and was successfully weaned off insulin and epinephrine drips. Repeat Sotalol levels remained <120ng/mL. DISCUSSION: Large dose Sotalol overdose is rarely encountered and carries significant risk to patients due to its QT prolonging effect associated with TdP, ventricular arrhythmias, and cases reporting asystole requiring cardiopulmonary resuscitation. Our patient was successfully managed without major complications or end-organ damage with early utilization of a temporary pacemaker and HD in addition to conventional therapy. CONCLUSIONS: It is plausible that early external pacing and HD played a role in avoiding adverse outcomes and should be considered in future cases of sotalol toxicity. REFERENCE #1: Anderson JL, Askins JC, Gilbert EM, et al. Multicenter trial of sotalol for suppression of frequent, complex ventricular arrhythmias: a double-blind, randomized, placebo-controlled evaluation of two doses. J Am Coll Cardiol. 1986;8(4):752-762. doi:10.1016/s0735-1097(86)80414-4 DISCLOSURES: No relevant relationships by Anil Kumar Ananthaneni, source=Web Response No relevant relationships by Cory Markham, source=Web Response No relevant relationships by Malak Modi, source=Web Response No relevant relationships by Nasim Motayar, source=Web Response No relevant relationships by Axel Rodriguez Rosa, source=Web Response

Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice

BackgroundDue to blocking β-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice.Materials and methodsAs a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography–mass spectrometry.ResultsSotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80–100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study.ConclusionSotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

Abstract 12650: A Faster and Safe Way for Dose Escalation of Sotalol Therapy in Patients With Atrial Fibrillation or Flutter

Sotalol is frequently employed to prevent the recurrence of highly symptomatic atrial fibrillation or flutter, but recurrence is not unusual and may require dose escalation. Sotalol can cause QTc prolongation proportional to blood concentration and at times may cause Torsade de Pointes ventricular tachycardia (TdP). Because the risk of TdP, dose escalation of oral sotalol therapy is mandated by FDA to be in-hospital for a minimum of 3 days under ECG monitoring with facilities and personnel able to provide cardiac resuscitation. With oral administration (bid), 3 days are needed to reach the new maximal steady-state blood concentrations (Cmax ss) and thus maximal QTc . Three hospital days in a telemetry bed is costly of time and resources. IV sotalol makes it possible to reduce the escalation time from 3 days to 1 day. The IV to oral dose escalation has been developed by model informed drug development. Serum sotalol concentrations and corresponding QTc were obtained from a bioequivalence study in healthy volunteers who received a single dose of oral and IV sotalol. NONMEM software package was used for population pharmacokinetic modeling and simulation. First Order Conditional Estimation method with Interaction (FOCE-INTER) was used for computation. We chose to administer IV sotalol over 1 hour to obtain the new Cmax ss target in a timeframe convenient for medical staff to supervise. Simulation for dose escalation from 80 to 120 mg bid is shown in the Figure; 75 mg IV sotalol is administered over 1 hour followed by 120 mg oral sotalol at 5 hours from start of infusion, then a second oral dose of 120 mg at 12 hours. One can target escalation from 120 to 160 mg by loading 90 mg IV over 1 hr followed by 160 mg oral dosing. Sotalol concentration will peak in 2-4 hours following each oral administration, thus in 21 hour there will be 3 sotalol peak concentrations. This permits evaluation of QTc response and risk of TdP all within a 1 day admission.

Abstract 12649: A Faster and Safe Way to Initiate Sotalol Therapy for Patients With Atrial Fibrillation or Flutter

Sotalol drug therapy is frequently employed to prevent the recurrence of highly symptomatic atrial fibrillation or flutter (AF, AFb). Sotalol can cause QTc prolongation that is proportional to blood concentration. Excessive concentration can cause Torsade de Pointes ventricular tachycardia (TdP). Because the risk of TdP, initiation of oral sotalol therapy is mandated by FDA to be in-hospital for a minimum of three days under ECG monitoring with facilities and personnel able to provide cardiac resuscitation. With oral administration (bid), 3 days are needed to reach maximal steady-state blood concentrations (Cmax ss) and thus maximal QTc prolongation. Three hospital days in a telemetry bed is costly and considerable expenditure of time and resources. Availability of IV sotalol makes it possible to reduce the loading time from 3 days to 1 day. The IV to oral loading regimen has been developed by model informed drug development. Serum sotalol concentrations and corresponding QTc were obtained from a previously performed bioequivalence study in healthy volunteers who received a single dose of oral and IV sotalol. NONMEM software package was used for population pharmacokinetic modeling and simulation. First Order Conditional Estimation method with Interaction (FOCE-INTER) was used for computation. We chose to administer IV sotalol over 1 hour to obtain Cmax ss target in a timeframe convenient for medical staff to supervise. The simulation for loading to the Cmax target produced by 80 mg PO bid is shown in the Figure; 60 mg IV sotalol is administered over 1 hour followed by 80 mg oral sotalol at 5 hours from start of infusion end then a second oral dose of 80 mg at 12 hours. One can target 120 mg maintenance dose by loading 90 mg IV over 1 hr followed by 120 mg oral dosing. Sotalol concentration will peak in 2-4 hours following each oral administration, thus in 21 hour there will be 3 sotalol peak concentrations. This permits evaluation of QTc response and risk of TdP all within a 1 day admission.

Model-Informed Development of Sotalol Loading and Dose Escalation Employing an Intravenous Infusion.

BackgroundSotalol is often employed to prevent recurrence of symptomatic atrial flutter/atrial fibrillation. Because sotalol can prolong the QT interval excessively causing ventricular arrhythmias, a 3-day in-hospital loading or dose escalation period is mandated with oral administration in the product label for patient safety. In patients with normal renal function, 3 days (five oral doses) are required to obtain steady state maximum sotalol concentration, which results in maximum QT prolongation. The aim of this study is to develop an intravenous to oral loading regime for sotalol therapy that reduces the 3-day in-hospital initiation or dose escalation with oral administration to 1 day without compromising patient safety.MethodsUsing model-informed drug development techniques, simulations were developed for initiation and dose escalation of sotalol therapy by employing an intravenous loading dose followed by oral sotalol administrations.ResultsIn patients with normal renal function, an initial 1-h loading dose of intravenous sotalol followed by two oral doses in 24 h has been developed permitting attainment of three maximum serum concentrations reflecting maximum QT prolongation in a 1-day observation period. Dosing regimens for patients with impaired renal function are also developed.ConclusionsIn patients with normal renal function, using an intravenous loading dose followed by oral administrations permits safe initiation or dose escalation of sotalol in 1 day instead of the 3-day dosing regimen with oral administration.

2525 Development of human cell-based screening assays to detect subject-specific drug-response variability

OBJECTIVES/SPECIFIC AIMS: The goals of this study are to develop a human-based screening assay for testing individual drug reactions and investigate the mechanism underlying susceptibility to develop diLQT. METHODS/STUDY POPULATION: We derived iPSC-CMs from 10 subjects with a high sensitivity to Sotalol (high-S group) and 10 subjects with no changes in QT interval after administration of the same drug (low-S group). Multielectrode array (MEA) was used to measure field potential duration, a surrogate to the QT interval in the electrocardiogram, in iPSC-CMs under basal conditions and in response to increasing concentrations of Sotalol. Transcriptomic profiling of iPSC-CMs from high-S Versus low-S groups was performed using RNA-sequencing. A parameter sensitivity analysis was performed on the Paci et al. iPSC-CM mathematical model to further support the lead hits identified via RNA-sequencing. RESULTS/ANTICIPATED RESULTS: Cardiac differentiation resulted in the generation of iPSC-CMs with appropriate cardiac channel expression and response to a hERG blocker E4031. MEA recordings showed a significantly higher response to Sotalol in iPSC-CMs from high-S compared with low-S subjects. Transcriptomic profiling identified upregulation or downregulation of genes (DLG2, KCNE4, PTRF, HTR2C, CAMKV) involved in downstream regulation of cardiac repolarization and calcium handling machinery as underlying high sensitivity to Sotalol. In silico parameter sensitivity analysis corroborated transcriptomic profiling of select genes; upregulated KCNE4 and downregulated CAMKV were predicted to positively and negatively correlate with iPSC-CM action potential duration when exposed to Sotalol, respectively. DISCUSSION/SIGNIFICANCE OF IMPACT: Our findings suggest subject-specific iPSCs can be used to model functional abnormalities observed in diLQTS and offer novel insights into iPSC-based screening assays for toxic drug reactions. Success of this study may help identify key components underlying diLQT susceptibility to ultimately develop novel therapeutic agents.

Pharmacokinetics and electrophysiological effects of sotalol hydrochloride in horses.

Arrhythmias in horses may require long-term anti-arrhythmic therapy. Unfortunately, oral anti-arrhythmic drugs for use in horses are currently scarce. In human patients and small animals, sotalol, a β-blocker with class III anti-arrhythmic properties, is often used for long-term treatment. To determine the pharmacokinetics of sotalol at multiple oral dosages in unfasted horses, as well as the effects on electro- and echocardiographic measurements, right atrial and ventricular monophasic action potential (MAP) and effective refractory period (ERP). Placebo controlled, double-blinded experiment. Six healthy, unfasted Warmblood horses were given either 0, 2, 3 or 4 mg/kg bodyweight (bwt) sotalol orally (PO) twice daily (bid) for 9 days in a randomised cross-over design. Echocardiography and surface electrocardiography were performed and plasma concentrations of sotalol and right atrial and right ventricular MAPs and ERPs were determined at steady-state conditions. Statistical analysis was performed using a repeated measures univariate analysis with post hoc Bonferroni corrections. Calculated mean steady-state plasma concentrations determined by nonlinear mixed-effect modelling were 287 (range 234-339), 409 (359-458) and 543 (439-646) ng/mL for 2, 3 and 4 mg/kg bwt sotalol PO bid respectively. Sotalol significantly increased the QT interval and ERPs, but, despite increasing plasma concentrations, higher dosages did not result in a progressive increase in QT interval or ERPs. Echocardiographic and other electrocardiographic measurements did not change significantly. MAP durations at 90% repolarisation were not significantly different during sotalol treatment. Besides transient local sweating, no side effects were noted. Study size and ad libitum feeding of hay. Sotalol at a dose of 2, 3 and 4 mg/kg bwt PO bid increases the QT interval and ERP and might be a useful drug for long-term anti-arrhythmic therapy in horses.

Extemporaneous sotalol hydrochloride oral solutions for use in paediatric cardiology: formulation and stability study

ObjectivesSotalol hydrochloride (SOT) is an antiarrhythmic β-blocker which is highly effective for the treatment of supraventricular tachycardia in children. However, a licensed paediatric dosage form with sotalol is not currently...

Quantification of ventricular repolarization heterogeneity during sotalol administration using the V-index

Drug-induced alterations of repolarization heterogeneity are checked to prevent the risk of lethal arrhythmias. Before drugs approval, FDA mandates a “thorough QT study.” In the last 14 years, the test avoided the withdrawal from the market of related drugs. However, it is questioned if the low specificity of the test might have hindered molecules from being commercialized. Research of alternative indices, linked with the physiology, is therefore supported by regulatory agencies. A new measure of ventricular repolarization heterogeneity (V-index) was recently proposed; it is based on a stochastic model that links the electrical potential of the myocytes with the surface ECG and it provides an estimate of the heterogeneity of the repolarization times. After being tested on synthetic signals, the metric is now undergoing a validation procedure. In this work, we performed a retrospective study to assess the metric as a function of the sotalol concentration. Since sotalol leads to an increased dispersion of the repolarization times, due to the block of the beta-adrenergic receptors, it provides a good test bench for the V-index. Briefly, 12-lead digital ECG recordings of 38 healthy subjects were collected in three consecutive days. At the first day no drugs were administrated. A 160-mg dose of sotalol was injected at the second day and 320-mg dose at the third one. The serum concentration of the drug was assessed at predefined intervals during the second and the third days. The QT interval and the V-index were computed at the same instants to support a proper comparison. The goals were as follows: evaluation of i) sensitivity of the metric to the effects of the drug and ii) time evolution of the metric as a function of serum concentration. All measures were collected during rest conditions and only on stable beats. A beat was defined stable whether its RR value was within of an interval of 20 ms around the local mean. The metric showed a different mean value in presence of sotalol (baseline: 26.17 ± 9.23 ms vs single-drug dose: 36.00 ± 14.51 ms; p b 0.001 paired t-test). The cross-correlation among QT and V-index showed a high level of similarity (N0.9, p b 0.001). The results confirmed a study performed on the same data set using only the QT interval (Extramiana et al. 2010, Ann Noninvasive Electrocardiol). Further studies are still necessary, but the research showed that quantification of repolarization heterogeneity through the V-index is effective. Moreover, being directly linked to a physiological model, the Vindex could offer additional insights in risk stratification.

Gender Differences in Cardiac Repolarization Following Intravenous Sotalol Administration

Females are more susceptible to drug-induced torsade de pointes (TdP), which is associated with excessive prolongation of the heart rate-corrected QT interval (QTc). Sotalol prolongs the cardiac action potential that can be observed as QT prolongation and can induce TdP. The aim of this study was to assess gender differences in sotalol-induced QTc prolongation. A total of 15 healthy volunteers, 9 female and 6 male (age: 32 ± 8 years) received 75 mg intravenous sotalol over 2.5 hours at a constant infusion rate. A 12-lead electrocardiograph (ECG) was recorded at baseline, 0.5, 1, 2, 3, 4, and 5 hours following the start of the infusion, and blood samples were collected simultaneously. QTc was calculated by the Fridericia and Framingham formulas. The 2 formulas resulted in virtually identical QTc intervals. The data analysis included repeated measures of analysis of variance (ANOVA), univariate analysis, and linear regression analysis. The longest average QTc intervals were observed at 2 hours of sotalol infusion in both genders. Compared to baseline, the increase was very significant in females (411 ± 13 vs 438 ± 13 ms, P < .001), while it was less significant in males (395 ± 23 vs 413 ± 27 ms, P < .05). The magnitude of individual changes from baseline were greater in females than in males (34 ± 8 vs 21 ± 12 ms, P < .05). In each gender, QTc and serum sotalol concentration strongly correlated (r = .93, P < .001). An upward shift of the regression line in females indicates a longer QTc at any concentration level. Males had greater body weight and body surface area than females (P < .05) but neither correlated with QTc or predicted QTc prolongation. The univariate analysis indicated that the single predictor for the greater QTc prolongation was female gender. Females had greater QTc prolongation than males following sotalol administration. This enhanced response to drug action may explain the higher incidence of drug-induced TdP seen in females.

QT Prolongation and Serum Sotalol Concentration Are Highly Correlated following Intravenous and Oral Sotalol

Objectives: The aim of this study was to evaluate the correlation between QT interval (QT) and serum sotalol concentration following a single low dose of oral and intravenous sotalol. Methods: Fifteen healthy volunteers received 75 mg intravenous sotalol over 2.5 h and 80 mg oral sotalol in a random order. Serum sotalol concentrations and 12-lead electrocardiograms were obtained simultaneously at baseline and 7 times following dosings. Rate-corrected QT (QTc) was calculated by the Bazett, Fridericia and Framingham formulas. Linear regression analysis was performed between sotalol concentrations and QT measurements. Results: Significant QT prolongation was seen at very low sotalol doses and serum concentrations. QTc intervals calculated by the Framingham and Fridericia formulas showed the strongest and virtually identical correlations with serum sotalol concentration (r ≧ 0.97, p < 0.001) following oral and intravenous administrations. The equation QTc = 0.0342 (sotalol concentration) + 398 closely predicted actual QTc at any sotalol concentration. Conclusions: A strong correlation was observed between serum sotalol concentration and QTc prolongation across the entire concentration range. Low-dose sotalol caused significant QT prolongation. At similar concentrations, intravenous and oral sotalol caused similar QT and QTc effects. Knowing the QT effect can be used to guide further dose increase.

Massive ingestion of cardiac drugs: toxicokinetic aspects of digoxin and sotalol during hemofiltration

Case. We present the case of a 75-year-old patient admitted to the emergency department after ingesting a large amount of several cardiac drugs, among which were digoxin and sotalol. Because of renal insufficiency, cardiogenic shock, and high serum digoxin levels, the patient received continuous venovenous hemofiltration (CVVH) and digoxin-specific Fab fragments. Digoxin and the digoxin-specific Fab fragments are normally cleared by the kidneys. Methods. Serum-free and total digoxin and serum sotalol concentrations were monitored for several days. Results. Less than 10% of the estimated ingested dose of digoxin was cleared by CVVH within 5 days. Conclusion. CVVH has little influence on the clearance of Fab-bound digoxin from the body. In contrast, sotalol is efficiently cleared by CVVH.

Evaluation of drug-induced QT prolongation in a halothane-anesthetized monkey model: Effects of sotalol

Introduction Cynomolgus monkeys are used in in vivo models of safety pharmacological studies to evaluate the effects of drug candidates on the cardiovascular system. Models using halothane-anesthetized animals have been used for the detection of drug-induced QT interval prolongation, but few studies with anesthetized monkeys have been reported. Methods The electrophysiological changes induced by dl-sotalol, a representative class III antiarrhythmic drug, were assessed in halothane-anesthetized monkeys ( n = 4) or conscious and unrestrained monkeys ( n = 4). Results In terms of basal characteristics, the QT interval was longer and the heart rate (HR) was lower under anesthesia than those under conscious conditions. Intravenous administration of 0.1 to 3 mg/kg dl-sotalol to anesthetized monkeys decreased the HR and prolonged the QT interval, monophasic action potential (MAP) duration and ventricular effective refractory period in a dose-dependent manner. In addition, reverse use-dependent prolongation of MAP duration was detected by electrical pacing, whereas the terminal repolarization period was hardly affected at any dose. Oral administration of 3 to 30 mg/kg dl-sotalol to conscious monkeys also decreased the HR and prolonged the QT interval in a dose-dependent manner. When compared at similar plasma concentrations of sotalol, the extent of QT interval prolongation under halothane anesthesia was equal to or greater than that under conscious conditions. Discussion The sensitivity for detection of drug-induced QT prolongation under halothane anesthesia may be satisfactory compared with that under conscious conditions. The present examinations indicated the usefulness of a model using halothane-anesthetized monkeys for evaluation of drug-induced QT interval prolongation.

Dose–response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys

The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.

Analysis of action potentials in the canine ventricular septum: No phenotypic expression of M cells

Transmural heterogeneity in the ventricular free wall, enhanced by the midmyocardial long action potential duration (APD) of M cells, plays an important role in the arrhythmogenesis of long QT syndrome. Although we observed dynamic expression of M cell phenotypes in the canine ventricular free wall, it is still unclear whether similar phenomena are present in the interventricular septum. This study evaluated transmural heterogeneity of APD in the septum. We isolated and perfused 22 canine septal preparations through the septal branch of the anterior descending coronary artery, and optically mapped 256 channels of action potentials on their cut-exposed transseptal surfaces before and after treatment with sotalol (I(Kr) blocker), anemone toxin II (ATX-II, which slows the inactivation of I(Na)), or drug-free state in 6, 9, and 22 preparations, respectively. The preparations were paced from the left ventricular endocardium at cycle lengths of 500, 1000, 2000, and 4000 ms. We observed progressively lengthening of APD across the septum from the right ventricular to the left ventricular endocardium without a midmyocardial maximum under all conditions. All action potentials had minor phase-1 notches, resembling the endocardial action potential in the ventricular free wall. Increasing cycle lengths and concentrations of sotalol and ATX-II prolonged APD without midmyocardial preference and increased the transseptal dispersion of APDs. Canine interventricular septal action potentials are similar in shape to the endocardial action potentials in the ventricular free wall, with smooth transseptal transition in APD. We found no phenotypical expression of M cells in the canine interventricular septum.