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Use of d,l-sotalol for rhythm control in patients with atrial fibrillation (AF) has raised safety concerns. Previous randomized studies are few and not designed for mortality outcome. The purpose of this study was to compare the incidences of mortality and ventricular arrhythmias in AF patients treated with d,l-sotalol for rhythm control vs matched control patients treated with cardioselective beta-blockers. This population-based cohort study included AF patients from the Swedish National Patient Registry (2006–2017) who underwent rhythm control after a second cardioversion. Incidence rates (IRs) and adjusted hazard ratios (aHRs) for mortality and a composite endpoint of cardiac arrest/death and ventricular arrhythmias were calculated for the overall cohort and a 1:1 propensity score matched cohort of d,l-sotalol vs beta-blocker treatment. Among patient treated with d,l-sotalol (n = 4987) and beta-blocker (n = 27,078) (mean follow-up 458 days), all-cause mortality was lower in patients treated with d,l-sotalol: IR 1.21; 95% confidence interval 0.95–1.52 vs 2.42 (2.26–2.60) deaths per 100 patient-years; aHR 0.66 (0.52–0.83). The difference in mortality persisted in the propensity score matched comparison (n = 4953 in each group): aHR 0.63 (0.48–0.86). No differences were observed in the composite outcome: IR in propensity cohorts 2.13 (1.78–2.52) vs 2.07 (1.73–2.53) events per 100 years; aHR 1.01 (0.78–1.29). There was no excess mortality with d,l-sotalol compared with cardioselective beta-blockers in patients undergoing rhythm control treatment for AF after a second cardioversion. Our results indicate that the risk associated with d,l-sotalol treatment for AF can be mitigated by careful patient selection and strict adherence to follow-up protocols. [Display omitted] [ABSTRACT FROM AUTHOR]

This paper is based on a presentation held at the Annual Safety Pharmacology Society meeting in September 2017, at which challenges for the clinical component of CiPA were presented. FDA has published an automated algorithm for measurement of the J-Tpeak interval on a median beat from a vector magnitude lead derived from a 12-lead ECG. CiPA proposes that J-Tpeak prolongation < 10 ms can be used for drugs with a QTc effect < 20 ms to differentiate between safe and unsafe delayed repolarization and to reduce the level of ECG monitoring in late stage clinical trials. We applied FDA's algorithm, complemented with iCOMPAS, to moxifloxacin and dolasetron data from the IQ-CSRC study with 9 subjects on active and 6 on placebo. The effect on QTcF and corrected J-Tpeak (J-Tpeak_c) was analyzed using concentration-effect modeling. There was a good correlation between QTcF and J-Tpeak_c prolongation after oral dosing of 400 mg moxifloxacin with placebo-adjusted, change-from-baseline (ΔΔ) J-Tpeak_c of ~12 ms at concentrations that caused ΔΔQTcF of ~20 ms. On dolasetron, J-Tpeak_c was highly variable, no prolongation was seen and an effect on ΔΔJ-Tpeak_c > 10 ms could be excluded across the observed plasma concentration range. In this limited analysis performed on the IQ-CSRC study waveforms using FDA's automated algorithm, J-Tpeak prolongation was observed on moxifloxacin, but not on dolasetron, despite clinical observations of proarrhythmias with both drugs. Challenges for the implementation of the J-Tpeak interval as a replacement or complement to the QTc interval, include to demonstrate that the proposed clinical algorithm using a J-Tpeak threshold of 10 ms, can be used to categorize drugs with a QT effect up to ~20 ms as having low pro-arrhythmic risk. [ABSTRACT FROM AUTHOR]

Abstract Introduction This paper is based on a presentation held at the Annual Safety Pharmacology Society meeting in September 2017, at which challenges for the clinical component of CiPA were presented. FDA has published an automated algorithm for measurement of the J-Tpeak interval on a median beat from a vector magnitude lead derived from a 12-lead ECG. CiPA proposes that J-Tpeak prolongation < 10 ms can be used for drugs with a QTc effect < 20 ms to differentiate between safe and unsafe delayed repolarization and to reduce the level of ECG monitoring in late stage clinical trials. Methods We applied FDA's algorithm, complemented with iCOMPAS, to moxifloxacin and dolasetron data from the IQ-CSRC study with 9 subjects on active and 6 on placebo. The effect on QTcF and corrected J-Tpeak (J-Tpeak_c) was analyzed using concentration-effect modeling. Results There was a good correlation between QTcF and J-Tpeak_c prolongation after oral dosing of 400 mg moxifloxacin with placebo-adjusted, change-from-baseline (ΔΔ) J-Tpeak_c of ~12 ms at concentrations that caused ΔΔQTcF of ~20 ms. On dolasetron, J-Tpeak_c was highly variable, no prolongation was seen and an effect on ΔΔJ-Tpeak_c > 10 ms could be excluded across the observed plasma concentration range. Discussion In this limited analysis performed on the IQ-CSRC study waveforms using FDA's automated algorithm, J-Tpeak prolongation was observed on moxifloxacin, but not on dolasetron, despite clinical observations of proarrhythmias with both drugs. Challenges for the implementation of the J-Tpeak interval as a replacement or complement to the QTc interval, include to demonstrate that the proposed clinical algorithm using a J-Tpeak threshold of 10 ms, can be used to categorize drugs with a QT effect up to ~20 ms as having low pro-arrhythmic risk. [ABSTRACT FROM AUTHOR]

Enzymatically-synthesized (2 R ,4 R )-monatin has, due to its pure sweet taste, been evaluated for potential use in foods. Non-clinical studies have shown that (2 R ,4 R )-monatin is well tolerated at high dietary concentrations, is not genotoxic/mutagenic, carcinogenic, or overtly toxic. In a pharmacokinetic and metabolism study involving 12 healthy males, consumption of a single oral dose (2 mg/kg) of (2 R ,4 R )-monatin resulted in a small reduction of heart rate and prolongation of the QTcF interval of 20–24 ms, corresponding to the time of peak plasma levels (t max ). These findings were evaluated in a cross-over thorough QT/QTc study with single doses of 150 mg (2 R ,4 R )-monatin, placebo and positive control (moxifloxacin) in 56 healthy males. Peak (2 R ,4 R )-monatin plasma concentration (1720 ± 538 ng/mL) was reached at 3.1 h (mean t max ). The placebo-corrected, change-from-baseline QTcF (ΔΔQTcF) reached 25 ms three hours after dosing, with ΔΔQTcF of 23 ms at two and four hours. Using exposure response (QTc) analysis, a significant slope of the relationship between (2 R ,4 R )-monatin plasma levels and ΔΔQTcF was demonstrated with a predicted mean QT effect of 0.016 ms per ng/mL. While similarly high plasma levels are unlikely to be achieved by consumption of (2 R ,4 R )-monatin in foods, QTc prolongation at this level is a significant finding. [ABSTRACT FROM AUTHOR]

The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration’s White Oak campus to discuss whether “QT assessment” can be performed as part of routine phase 1 studies. Based on these discussions, a group of experts convened to discuss how to improve the confidence in QT data from early clinical studies, for example, the First-Time-in-Human trial, through collection of serial electrocardiograms and pharmacokinetic samples and the use of exposure response analysis. Recommendations are given on how to design such “early electrocardiogram assessment,” and the limitation of not having a pharmacologic-positive control in these studies is discussed. A research path is identified toward collecting evidence to replace or provide an alternative to the dedicated TQT study. [ABSTRACT FROM AUTHOR]

Assesses the incidence of sudden death and classifies the causes of death following radiofrequency ablation of the atrioventricular (AV) junction. Sudden deaths; Cardiovascular deaths of known cause; Noncardiovascular deaths; Sudden death after radiofrequency ablation of the AV junction.

The Safety Pharmacology Society organized a scientific session at its annual conference in 2017 to discuss the challenges and opportunities of the Comprehensive In-Vitro Proarrhythmia Assay (CiPA) paradigm. Our intention was to raise awareness of this initiative with its members and also to gauge the extent to which safety pharmacologists have incorporated the CiPA testing strategy within the pharmaceutical industry. CiPA offers many potential opportunities including 1) a focus on proarrhythmic risk (as opposed to QTc prolongation), 2) providing scientific rationale to support the continued development of compounds that may have a poor selectivity over hERG whilst also blocking other inward currents and 3) reducing the extent of ECG monitoring in clinical trials with a greater influence of the non-clinical studies. Such opportunities may speed drug development and reduce costs. However, there are also challenges for CiPA implementation. For example, the mixed ion channel paradigm does not easily lend itself to a prospective drug discovery strategy although testing for such effects can be achieved with assays with good throughput. However, it should also be recognized that compounds with a mixed ion channel profile might also have properties that are undesirable to treat non-life threatening indications. All components of CiPA (nonclinical and clinical) require validation, particularly as a composite package to impact drug development and evaluation. One of the significant discussion points was that the existing regulatory guidance supports the use of components of CiPA through follow-up studies. A survey of the conference audience showed that the level of awareness of CiPA is quite high and that companies are already conducting some testing against a wider panel of cardiac ion channels beyond hERG. However, the adoption of other technologies (stem cell derived cardiac myocytes and in silico modeling) is less well developed. Taken together, the session demonstrated the potential advantages of CiPA, but also some significant challenges. [ABSTRACT FROM AUTHOR]

Abstract The Safety Pharmacology Society organized a scientific session at its annual conference in 2017 to discuss the challenges and opportunities of the Comprehensive In-Vitro Proarrhythmia Assay (CiPA) paradigm. Our intention was to raise awareness of this initiative with its members and also to gauge the extent to which safety pharmacologists have incorporated the CiPA testing strategy within the pharmaceutical industry. CiPA offers many potential opportunities including 1) a focus on proarrhythmic risk (as opposed to QTc prolongation), 2) providing scientific rationale to support the continued development of compounds that may have a poor selectivity over hERG whilst also blocking other inward currents and 3) reducing the extent of ECG monitoring in clinical trials with a greater influence of the non-clinical studies. Such opportunities may speed drug development and reduce costs. However, there are also challenges for CiPA implementation. For example, the mixed ion channel paradigm does not easily lend itself to a prospective drug discovery strategy although testing for such effects can be achieved with assays with good throughput. However, it should also be recognized that compounds with a mixed ion channel profile might also have properties that are undesirable to treat non-life threatening indications. All components of CiPA (nonclinical and clinical) require validation, particularly as a composite package to impact drug development and evaluation. One of the significant discussion points was that the existing regulatory guidance supports the use of components of CiPA through follow-up studies. A survey of the conference audience showed that the level of awareness of CiPA is quite high and that companies are already conducting some testing against a wider panel of cardiac ion channels beyond hERG. However, the adoption of other technologies (stem cell derived cardiac myocytes and in silico modeling) is less well developed. Taken together, the session demonstrated the potential advantages of CiPA, but also some significant challenges. [ABSTRACT FROM AUTHOR]

A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is to predict concentration-response relationships of QTc as a clinical endpoint. Full heart computational models reproducing human cardiac populations were created to predict the concentration-response relationship of changes in the QT interval as recommended for clinical trials. The concentration-response relationship of the QT-interval prolongation obtained from the computational cardiac population was compared against the relationship from clinical trial data for a set of well-characterized compounds: moxifloxacin, dofetilide, verapamil, and ondansetron. Computationally derived concentration–response relationships of QT interval changes for three of the four drugs had slopes within the confidence interval of clinical trials (dofetilide, moxifloxacin and verapamil) when compared to placebo-corrected concentration-ΔQT and concentration-ΔQT regressions. Moxifloxacin showed a higher intercept, outside the confidence interval of the clinical data, demonstrating that in this example, the standard linear regression does not appropriately capture the concentration-response results at very low concentrations. The concentrations corresponding to a mean QTc prolongation of 10 ms were consistently lower in the computational model than in clinical data. The critical concentration varied within an approximate ratio of 0.5 (moxifloxacin and ondansetron) and 1 times (dofetilide, verapamil) the critical concentration observed in human clinical trials. Notably, no other in silico methodology can approximate the human critical concentration values for a QT interval prolongation of 10 ms. Computational concentration-response modelling of a virtual population of high-resolution, 3-dimensional cardiac models can provide comparable information to clinical data and could be used to complement pre-clinical and clinical safety packages. It provides access to an unlimited exposure range to support trial design and can improve the understanding of pre-clinical-clinical translation. [ABSTRACT FROM AUTHOR]

OLZ/SAM is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, and is in development for the treatment of schizophrenia and bipolar I disorder. OLZ/SAM is under development with the intent to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. This thorough QT study assessed the effects of therapeutic and supratherapeutic doses of OLZ/SAM on cardiac repolarization in patients with schizophrenia. In this randomized, double-blind, placebo- and positive (moxifloxacin)-controlled, parallel-group study, 100 patients aged 18 to 60 years with stable schizophrenia were randomized 3:2 to the active arm and control arm. Subjects in the active arm received a therapeutic dose of 10/10 mg (10 mg olanzapine/10 mg samidorphan) on days 2–4, 20/20 mg on days 5–8, and a supratherapeutic dose of 30/30 mg (1.5 times and 3 times the maximum recommended daily dose of olanzapine and samidorphan, respectively) on days 9–13, and moxifloxacin-matched placebo on days 1 and 14. Subjects in the control arm received a single oral dose of moxifloxacin 400 mg and moxifloxacin-matched placebo on days 1 and 14 in a nested crossover fashion, along with OLZ/SAM-matched placebo on days 2–13. Serial electrocardiograms (ECGs) and simultaneous plasma drug concentrations were determined pre- and post-dose. The effects of OLZ/SAM on heart rate and ECG parameters (QT interval with Fridericia's correction [QTcF], PR and QRS interval, and T-wave morphology) were evaluated, and the primary endpoint was change from baseline in QTcF (ΔQTcF). The relationship between drug concentration and ΔQTcF (C-QTc) was evaluated using a linear mixed-effects model. Safety monitoring included adverse events reporting and clinical laboratory assessments. Based on primary analysis using C-QTc modeling, no clinically concerning QTc effect (ie, placebo-corrected ΔQTcF [ΔΔQTcF] ≥10 msec) was observed across the OLZ/SAM dose range tested (10/10 to 30/30 mg), up to olanzapine and samidorphan concentrations of approximately 110 and 160 ng/mL, respectively. The slope (90% confidence interval [CI]) of the C-QTc relationship was shallow and not significant for either olanzapine or samidorphan (0.03 [−0.01, 0.08] and 0.01 [−0.01, 0.04] msec per ng/mL, respectively). The predicted ΔΔQTcF (90% CI) was 2.33 (−2.72, 7.38) and 1.38 (−3.37, 6.12) msec at the observed geometric mean maximal concentration (C max) of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL) on day 13, respectively. The study's assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated at all doses; adverse events occurring in >5% of subjects treated with OLZ/SAM were somnolence, weight increased, nausea, and dizziness. This thorough QT study in patients with stable schizophrenia demonstrated that OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, does not have a clinically relevant effect on ECG parameters, including QT/QTc prolongation. • Olanzapine/samidorphan is being developed for schizophrenia and bipolar disorder. • OLZ/SAM had no QTc effect up to supratherapeutic doses of olanzapine and samidorphan. • Assay sensitivity was confirmed by the positive control, moxifloxacin. • OLZ/SAM was generally well tolerated up to supratherapeutic doses/concentrations. [ABSTRACT FROM AUTHOR]