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1.
First Clinical Study with AP30663 - a KCa 2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation.
Gal, P, Klaassen, ES, Bergmann, KR, Saghari, M, Burggraaf, J, Kemme, MJB, Sylvest, C, Sørensen, U, Bentzen, BH, Grunnet, M, et al
Clinical and translational science. 2020;(6):1336-1344
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Abstract
Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca2+ activated K+ (KCa 2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (Cmax ) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel KCa 2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.
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Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.
Darpo, B, Benson, C, Brown, R, Dota, C, Ferber, G, Ferry, J, Jarugula, V, Keirns, J, Ortemann-Renon, C, Pham, T, et al
Journal of clinical pharmacology. 2020;(1):125-139
Abstract
The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.
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Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.
Vicente, J, Zusterzeel, R, Johannesen, L, Ochoa-Jimenez, R, Mason, JW, Sanabria, C, Kemp, S, Sager, PT, Patel, V, Matta, MK, et al
Clinical pharmacology and therapeutics. 2019;(4):943-953
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Abstract
Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-Tpeak (J-Tpeak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ-Tpeak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-à-go-go related gene (hERG), prolonged ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.
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Reduction over time of QTc prolongation in patients with sotalol after cardioversion of atrial fibrillation.
Lenhoff, H, Darpö, B, Ferber, G, Rosenqvist, M, Frick, M
Heart rhythm. 2016;(3):661-8
Abstract
BACKGROUND Sotalol is recommended to prevent relapse of atrial fibrillation after cardioversion (CV). Sotalol prolongs the action potential by blocking the rapid component of the delayed rectifier potassium current, which results in corrected QT (QTc) prolongation on the electrocardiogram. Pronounced QTc prolongation may lead to proarrhythmias and sudden death. OBJECTIVE We investigated the dynamics of the QTc interval during the week after CV in patients treated with sotalol compared with patients treated with a β-blocker. METHODS Patients who underwent elective CV for persistent atrial fibrillation and maintained sinus rhythm for 1 week were included prospectively. All patients were on the highest tolerable stable dose of metoprolol or sotalol. Twelve-lead electrocardiograms were recorded 1 hour and 1 week after CV. RESULTS A total of 104 patients on sotalol and 104 on metoprolol were included; clinical characteristics between groups were comparable. One hour after CV, the QTc interval was significantly longer in sotalol-treated patients than in metoprolol-treated patients (465 ± 25 ms vs 423 ± 30 ms; P ≤ .0001). After 1 week, the QTc interval was reduced by -20.3 ± 24 ms in sotalol-treated patients (P ≤ .001); no such effect was seen in metoprolol-treated patients (-2.5 ± 18 ms; P = 0.28). The heart rate was stable during the week in both groups. In multivariate analysis of sotalol-treated patients, factors contributing to pronounced reduction in the QTc interval were longer QTc interval after CV and renal function. CONCLUSION The QTc interval is significantly reduced during the week after CV to sinus rhythm in sotalol-treated patients. This provides insight into the increased risk of proarrhythmias in the immediate time period after CV.
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Onartuzumab with or without bevacizumab in combination with weekly paclitaxel does not prolong QTc or adversely affect other ECG parameters in patients with locally recurrent or metastatic triple-negative breast cancer.
Borin, MT, Chen, M, Mocci, S, Rubets, I, Chittenden, J, Aldairy, W, Stroh, M
Cancer chemotherapy and pharmacology. 2015;(2):401-10
Abstract
PURPOSE The potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or metastatic triple-negative breast cancer. METHODS Triplicate 12-lead ECGs were recorded at screening, pre- and post-dose on day 1 of cycles 1, 2, and 4, and at the study drug discontinuation visit (SDDV). Onartuzumab serum samples were collected pre- and post-dose on day 1 of cycles 1-4 and at the SDDV. Fridericia's correction was applied to QT recordings (QTcF), and change from baseline (ΔQTcF) was calculated. Post-baseline measurements were reported as baseline-adjusted control arm (placebo plus bevacizumab plus paclitaxel)-corrected values (ΔΔQTcF). Categorical ECG findings were noted. Linear mixed effects modeling evaluated a potential concentration-ΔQTcF relationship. RESULTS Out of 185 enrolled patients, 165 patients had ECG-evaluable data for analyses. Similar ΔQTcF and ΔΔQTcF values were observed across all treatment arms, with mean increase <10 and <7 ms, respectively, across all time points. Similar changes in heart rate, PR interval, and QRS duration were noted across all treatment arms. Incidences of abnormal ECG findings of clinical interest were comparable in the onartuzumab-containing arms and the control arm. No concentration-ΔQTcF relationship was evident at onartuzumab serum concentrations up to 1,200 μg/ml. CONCLUSIONS These data suggest that onartuzumab, at the dose and exposures studied in this clinical trial, does not meaningfully affect the QTcF interval.
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Ipragliflozin does not prolong QTc interval in healthy male and female subjects: a phase I study.
Zhang, W, Smulders, R, Abeyratne, A, Dietz, A, Krauwinkel, W, Kadokura, T, Keirns, J
Clinical therapeutics. 2013;(8):1150-1161.e3
Abstract
BACKGROUND Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent's effects on the QT/QTc interval. OBJECTIVE The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects. METHODS This was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericia's correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms. RESULTS A total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms). CONCLUSIONS No clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413.
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Lack of significant effect of bilastine administered at therapeutic and supratherapeutic doses and concomitantly with ketoconazole on ventricular repolarization: results of a thorough QT study (TQTS) with QT-concentration analysis.
Tyl, B, Kabbaj, M, Azzam, S, Sologuren, A, Valiente, R, Reinbolt, E, Roupe, K, Blanco, N, Wheeler, W
Journal of clinical pharmacology. 2012;(6):893-903
Abstract
The effect of bilastine on cardiac repolarization was studied in 30 healthy participants during a multiple-dose, triple-dummy, crossover, thorough QT study that included 5 arms: placebo, active control (400 mg moxifloxacin), bilastine at therapeutic and supratherapeutic doses (20 mg and 100 mg once daily, respectively), and bilastine 20 mg administered with ketoconazole 400 mg. Time-matched, triplicate electrocardiograms (ECGs) were recorded with 13 time points extracted predose and 16 extracted over 72 hours post day 4 dosing. Four QT/RR corrections were implemented: QTcB; QTcF; a linear individual correction (QTcNi), the primary correction; and a nonlinear one (QTcNnl). Moxifloxacin was associated with a significant increase in QTcNi at all time points between 1 and 12 hours, inclusively. Bilastine administration at 20 mg and 100 mg had no clinically significant impact on QTc (maximum increase in QTcNi, 5.02 ms; upper confidence limit [UCL] of the 1-sided, 95% confidence interval, 7.87 ms). Concomitant administration of ketoconazole and bilastine 20 mg induced a clinically relevant increase in QTc (maximum increase in QTcNi, 9.3 ms; UCL, 12.16 ms). This result was most likely related to the cardiac effect of ketoconazole because for all time points, bilastine plasma concentrations were lower than those observed following the supratherapeutic dose.
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Neurally mediated syncope as a cause of syncope in patients with Brugada electrocardiogram.
Yokokawa, M, Okamura, H, Noda, T, Satomi, K, Suyama, K, Kurita, T, Aihara, N, Kamakura, S, Shimizu, W
Journal of cardiovascular electrophysiology. 2010;(2):186-92
Abstract
INTRODUCTION Patients with type 1 Brugada electrocardiogram (ECG) and an episode of syncope are diagnosed as symptomatic Brugada syndrome; however, all episodes of syncope may not be due to ventricular tachyarrhythmia. METHODS AND RESULTS Forty-six patients with type 1 Brugada ECG (all males, 51 +/- 13 years, 29 spontaneous, 17 Ic-drug induced), 20 healthy control subjects (all males, 35 +/- 11 years), and 15 patients with suspected neurally mediated syncope (NMS; 9 males, 54 +/- 22 years) underwent the head-up tilt (HUT) test. During the HUT test, 12-lead ECGs were recorded in all patients, and the heart rate variability was investigated in some patients. Sixteen (35%) of 46 patients with Brugada ECG, 2 (10%) of 20 control subjects, and 10 (67%) of 15 patients with suspected NMS showed positive responses to the HUT test. Although no significant differences were observed in HUT-positive rate among Brugada patients with documented VT (7/14; 50%), syncope (5/19; 26%) and asymptomatic patients (4/13; 31%), the HUT-positive rate was significantly higher in patients with documented VT (50%) and those with VT or no symptoms (11/27, 41%) compared to that in control subjects (10%) (P < 0.05). Augmentation of ST-segment amplitude (> or =0.05 mV) in leads V1-V3 was observed in 11 (69%) of 16 HUT-positive patients with Brugada ECG during vasovagal responses, and was associated with augmentation of parasympathetic tone following sympathetic withdrawal. CONCLUSION Thirty-five percent of patients with Brugada ECG showed vasovagal responses during the HUT test, suggesting that some Brugada patients have impaired balance of autonomic nervous system, which may relate to their syncopal episodes.
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The risk of non-sustained ventricular tachycardia after percutaneous alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy.
Klopotowski, M, Chojnowska, L, Malek, LA, Maczynska, R, Kukula, K, Demkow, M, Witkowski, A, Dabrowski, M, Karcz, M, Baranowski, R, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2010;(5):285-92
Abstract
BACKGROUND Percutaneous alcohol septal ablation (ASA) becomes an alternative option of treatment for symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM). The procedure relieves left ventricular outflow tract obstruction, but produces a myocardial scar in patients who already have a substrate for life-threatening ventricular arrhythmia. OBJECTIVES To examine the effect of ASA on the occurrence of non-sustained ventricular tachycardia (nsVT) on 24 h ambulatory Holter monitoring in HOCM patients. METHODS Sixty-one consecutive patients (34 males, mean age 48 years), who underwent ASA between 1997 and 2003 were analyzed. Holter recordings were performed in each patient before and after ablation. RESULTS Follow-up ranged from 60 to 125 months (median 116 months). The mean number of Holter recordings per patient was 2.7 (range 1-11) before and 8.3 (range 2-23) after ASA (p < 0.001). Non-sustained ventricular tachycardia occurred in 14 patients before and 27 patients after ASA (23 vs. 44%, p = 0.01). The percentage of Holter recordings with nsVT before and after ablation was similar (14.5 vs. 15.7%, p = 0.56, respectively). No difference was observed between the number of nsVT per Holter recording before and after ablation (0.21 vs. 0.24%, p = 0.65, respectively). The percentage of patients with nsVT after ASA was comparable to the proportion of patients with nsVT in a control group consisting of 705 patients with hypertrophic cardiomyopathy under follow-up at our institution (44.3 vs. 43.2%, p = 0.91). There was no significant difference in percentage of Holter recordings with nsVT with respect to sex, amount of alcohol used during ASA, peak creatine phosphokinase level, and gradient reduction at rest. CONCLUSION Alcohol septal ablation affected neither the percentage of Holter recordings with nsVT nor the number of nsVT episodes per Holter recording among HOCM patients.
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Pacemaker-based analysis of atrioventricular conduction and atrial tachyarrhythmias in patients with primary sinus node dysfunction.
Stockburger, M, Trautmann, F, Nitardy, A, Just-Teetzmann, M, Schade, S, Celebi, O, Krebs, A, Dietz, R
Pacing and clinical electrophysiology : PACE. 2009;(5):604-13
Abstract
BACKGROUND Most patients with symptomatic sinus node disease (SND) receive DDDR pacemakers (PM) in order to cover SND and atrioventricular (AV) block from the outset. But the concern about adverse effects of right ventricular pacing (RVP) is increasing. So far, data on the incidence of AV block in SND are based on clinical events. The study undertakes to assess and appraise AV block and atrial tachyarrhythmias (AT) from memory and electrograms of a dual-chamber PM set to an AAIR-DDDR switch mode (AAISafeR). METHODS A dual-chamber PM incorporating the AAISafeR mode was implanted in 58 patients (70 +/- 10 years, 28 males) with SND, but without AV block >I. AV block and AT episodes were retrieved from the PM memory and validated from electrograms. AV block episodes were classified potentially relevant while comprising AV block III or AV block I/II during exercise. RESULTS The patients experienced a median of 90 (interquartile range 7-1,084) commutations. Possibly relevant AV block occurred in 32 patients (55%). Validation revealed high-quality PM-based categorization. The RVP prevalence was 0% (0-16%). The median AT prevalence was 0.03 (0-26) min/day. RVP was the only multivariate predictor of AT (P = 0.001). CONCLUSIONS Potentially relevant AV block occurs frequently in patients with SND. Nonetheless, the RVP prevalence is kept low through the AAISafeR mode. The protection of SND patients with demand-actuated ventricular pacing appears reasonable. The AT prevalence is low in SND patients treated by the AAISafeR mode. Even low RVP proportions appear to favor AT. Prospective evaluation is needed.