Fridericia's Correction Research Articles

Normal electrocardiographic QT interval in race-fit Standardbred horses at rest and its rate dependence during exercise

ObjectivesCardiac repolarization, measured as QT and Tpeak to Tend (TpTe) intervals on the ECG, is important, as irregularities caused by diseases, ventricular hypertrophy, drugs and genetic defects can trigger arrhythmias which predispose human patients to syncope and sudden cardiac death. In horses, repolarization is not well described and therefore QT analysis cannot yet be used diagnostically. Therefore, we sought to describe reference values for the normal QT and TpTe intervals in Standardbreds and to determine the best method for heart rate (HR) correction. Animals30 Standardbreds. MethodsQT and TpTe intervals were measured during rest and exercise and plotted against HR converted to Rpeak to Rpeak interval (RR). Data were fitted with relevant regression models. Intra- and inter-observer agreement was assessed using Bland–Altman analyses. ResultsData were best described by a piecewise linear model (r2 > 0.97). Average prediction error of this model was smaller than for both Bazett and Fridericia corrections. Coefficient of repeatability of intra- and inter-observer variability was 8.76 ms and 5.64 ms respectively and coefficient of variation was 1.77% and 2.76% respectively. TpTe increased with RR in stallions. ConclusionsThe QT interval in Standardbred horses shortens with decreasing RR interval (increasing HR) as in humans, but in a markedly different order as it clearly follows a piecewise linear model. The equine QT interval can be measured easily and there is small intra- and inter-observer variability. This model of the equine QT interval provides clinicians with a method that could support a diagnosis of repolarization disturbances in horses.

Tigecycline does not prolong corrected QT intervals in healthy subjects.

We evaluated the effect of tigecycline (50-mg and 200-mg doses) on corrected QT (QTc) intervals and assessed safety and tolerability in a randomized, placebo-controlled, four-period crossover study of 48 (44 male) healthy volunteers aged 22 to 53 years. Fed subjects received tigecycline (50 mg or 200 mg) or placebo in a blinded fashion or an open-label oral dose of moxifloxacin (400 mg) after 1 liter of intravenous fluid. Serial electrocardiograms were recorded before, and for 96 h after, dosing. Blood samples for tigecycline pharmacokinetics were collected after each recording. QTc intervals were corrected using Fridericia's correction (QTcF). Pharmacokinetic parameters were calculated using noncompartmental methods with potential relationships examined using linear mixed-effects modeling. Adverse events were recorded. The upper limits of the 90% confidence interval for the mean difference between both tigecycline doses and placebo for all time-matched QTcF interval changes from baseline were <5 ms. The tigecycline concentrations initially declined rapidly and then more slowly. In the group given 50 mg of tigecycline, the pharmacokinetic parameters and means were as follows: maximum concentration of drug in serum (C(max)), 432 ng/ml; area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞), 2,366 ng · h/ml; clearance (CL), 21.1 liters/h; volume of distribution at steady state (V(ss)), 610 liters; and terminal half-life (t(1/2)), 22.1 h. Proportional or similar values were found for the group given 200 mg of tigecycline. Linear mixed-effects modeling failed to show an effect on QTcF values by tigecycline concentrations (P = 0.755). Tigecycline does not prolong the QTc interval in healthy subjects. This study has been registered at ClinicalTrials.gov under registration no. NCT01287793.

Phase I study to assess the pharmacokinetics and the effect on cardiac repolarization of amrubicin and amrubicinol in patients with advanced solid tumors

To evaluate the pharmacokinetics and cardiac repolarization effect (measured by QT/QTc interval) of amrubicin and its active metabolite amrubicinol in non-Japanese patients with advanced solid tumors. Patients received amrubicin 40 mg/m(2)/day as a 5-min infusion on days 1-3 of a 21-day cycle. During cycle 1, serial blood and plasma samples were collected on days 1-9 and time-matched triplicate electrocardiograms on the "off-drug" visit (1-5 days prior to start of treatment) and days 1-9. Twenty-four patients were treated. Amrubicinol reached peak concentration 2-4 h after amrubicin administration and had a terminal half-life of 53 h. Distribution of amrubicinol into erythrocytes was fivefold greater than into plasma. The molar ratio of amrubicinol to amrubicin in blood was 0.67 on day 3. The presence of an NQO1 polymorphism did not alter drug exposure. The upper bound of the one-sided 95 % confidence interval for the time-matched, baseline-adjusted change from the off-drug day in QTcI (individual correction) was <10 ms at all times and was only >10 ms (10.20 ms) at a single time point for QTcF (Fridericia correction). No relationship was observed between blood amrubicin or amrubicinol concentrations and QTcF changes. All QTcF measurements were <480 ms, and none increased by >60 ms from baseline. Data suggest that amrubicinol is an important active metabolite in humans and that both compounds were not associated with clinically relevant QTc interval prolongation at the dose regimen studied.

A Thorough QTc Study of 3 Doses of Iloperidone Including Metabolic Inhibition Via CYP2D6 and/or CYP3A4 and a Comparison to Quetiapine and Ziprasidone

The potential for iloperidone, a D2/5-HT2A antipsychotic, to affect the heart rate-corrected QT interval (QTc) was assessed in the absence and presence of metabolic inhibitors in a randomized, open-label, multicenter study. QT interval prolongation by medications, including both conventional and atypical antipsychotic drugs, can predispose patients to cardiac arrhythmias and result in sudden death. Adults with schizophrenia or schizoaffective disorder and normal electrocardiograms at baseline (N = 188) were randomized 1:1:1:1:1 to iloperidone, 8 mg twice daily (BID), 12 mg BID, 24 mg once daily (QD); quetiapine, 375 mg BID; or ziprasidone, 80 mg BID during period 1 (no metabolic inhibitors present). Iloperidone BID produced mean changes in QTc Fridericia correction (QTcF) interval (8.5-9.0 milliseconds [ms]) similar to those produced by ziprasidone (9.6 ms) and higher than those produced by quetiapine (1.3 ms). Iloperidone, 24 mg QD, produced a mean QTcF change of 15.4 ms. Coadministration of metabolic inhibitors with iloperidone during periods 2 (paroxetine) and 3 (paroxetine and ketoconazole) resulted in greater increases in the QTc interval. Increased QTc was observed in individuals with specific cytochrome P450 2D6 polymorphisms. Up to 10% of patients on iloperidone experienced QTc intervals of 60 ms or longer in the presence of metabolic inhibition and QD dosing. However, no patients experienced QTc changes of clinical concern (QTc ≥ 500 ms). The most common adverse events with iloperidone were headache, anxiety, and dyspepsia. The only cardiovascular adverse events with iloperidone were non-concentration-dependent tachycardia that was mild in most patients and did not lead to further sequelae. Pharmacogenetics and recommendations are discussed.

Losmapimod concentration–QT relationship in healthy volunteers: meta-analysis of data from six clinical trials

The objective of this work was to describe the losmapimod concentration-QT relationship using meta-analysis of data from clinical trials with healthy volunteers and to evaluate the covariates that have significant impact on the QT prolongation. Losmapimod plasma concentration and QT interval data were collected from six early clinical studies with healthy volunteers. The electrocardiograms (ECGs) were collected at baseline and at a number of post-dose time points (losmapimod or placebo). The population pharmacokinetic/pharmacodynamic (PK/PD) modelling approach was applied to investigate the relationship between losmapimod concentration and QT prolongation. The dataset for analysis comprised 190 healthy adults who took at least one dose of losmapimod or placebo. Of the 2,494 QT observations collected, 1,532 observations had matched QT and losmapimod plasma concentration data. Population PK/PD analyses indicated that the model with the individual heart rate correction factor (α) fitted the data better than those using fixed α (0.33 for Fridericia's correction or 0.5 for Bazett's correction) and that there was no relationship between losmapimod concentration and QT interval. Female volunteers had about a 3 % higher QT interval at baseline than the male volunteers. No other covariates had a significant effect on the QT interval. It is appropriate to apply population PK/PD analysis to investigate the effect of drug concentration on QT prolongation. Our meta-analysis of healthy volunteer data indicated no relationship between systemic losmapimod concentration and QT interval in healthy volunteers.

Effects of Trastuzumab Emtansine (T-DM1) on QT Interval and Safety of Pertuzumab Plus T-DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in development for human epidermal growth factor receptor 2 (HER2)-positive cancer. Drugs in development are generally tested for their effects on QT interval, prolongation of which is associated with the potentially fatal arrhythmia torsades de pointes. In addition, an association between left ventricular dysfunction and other HER2-directed agents has been documented. This multicenter, phase 2 study, TDM4688g, assessed the safety and pharmacokinetic characteristics of T-DM1 (3.6 mg/kg every 3 weeks) in patients with previously treated HER2-positive metastatic breast cancer, and the safety of pertuzumab plus T-DM1, an anti-HER2 extracellular domain antibody, in patients with early disease progression on T-DM1 alone. The primary end point was the change in QTc interval from baseline to each postbaseline time point, adjusted for heart rate using Fridericia's correction. T-DM1 had no clinically relevant effect on QTc interval. The observed upper limit of the one-sided 95% confidence interval was below the 10-millisecond threshold of safety concern. The safety and efficacy of single-agent T-DM1 was consistent with that observed in previous studies. Pertuzumab plus T-DM1 was generally well tolerated with no new safety signals. These results support further investigation of T-DM1 as a single agent and with pertuzumab.

Measurement and Rate Correction of the QT Interval

Measurement and Rate Correction of the QT Interval

A randomized, crossover, placebo‐ and moxifloxacin‐controlled study to evaluate the effects of bosutinib (SKI‐606), a dual Src/Abl tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects

Effects of therapeutic and supratherapeutic concentrations of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, on the corrected QT interval (QTc) in 60 healthy adults were assessed, according to ICH-E14 guidelines, in this 2-part, randomized, single-dose, double-blind, crossover, placebo- and open-label moxifloxacin-controlled study. Subjects received placebo, moxifloxacin and bosutinib 500 mg with food (therapeutic) in Part 1. In Part 2, subjects received placebo and bosutinib 500 mg plus ketoconazole (supratherapeutic). ANOVA compared baseline-adjusted QTc for bosutinib with placebo; and bosutinib plus ketoconazole with placebo plus ketoconazole. Primary endpoint was population-specific QT correction (QTcN). Secondary endpoints were Bazett QT correction (QTcB), Fridericia's formula QT correction (QTcF) and individual QT correction (QTcI). Upper bounds for 90% confidence intervals were <10 msec for the mean change in QTcN from placebo at all postdose time points, suggesting that mean therapeutic exposures (C(max) , 114 ng/mL; AUC, 2,330 ng · h/mL) and mean supratherapeutic exposures (C(max) , 326 ng/mL; AUC, 15,200 ng · h/mL) were not associated with QTc changes. Similar results were obtained for QTcB, QTcF and QTcI. No clinically relevant pharmacokinetic/pharmacodynamic relationship was observed between bosutinib concentrations and QTc. No subjects had QTcB, QTcF, QTcI or QTcN >450 msec or change from baseline >30 msec. In summary, therapeutic and supratherapeutic bosutinib exposures are not associated with QTc prolongation in healthy adults.

Exposure-QTc Response Analysis of Class 1 Selective Histone Deacetylase Inhibitor Romidepsin

Abstract 2680 Background:Romidepsin is a class 1 selective histone deacetylase (HDAC) inhibitor approved in the United States for patients with relapsed/refractory cutaneous and peripheral T-cell lymphomas. Potential cardiac class effects of HDAC inhibitors have been variably reported. We have previously reported that detailed electrocardiogram (ECG) analyses from 110 patients across 3 clinical studies showed clinically insignificant, transient ECG changes that were not associated with functional cardiovascular changes. The primary objective of the study described herein was to further evaluate the potential of romidepsin to prolong QT and assess any possible relationship between romidepsin plasma concentration and heart rate-corrected QT interval duration (QTc). Methods:Patients from GPI-06–0005, an exploratory phase 1 study of adult patients with advanced malignancies treated with 1-hour or 4-hour intravenous (IV) romidepsin infusion, received ECG assessments on Day 1 of cycles 1 and 2: baseline (both pre- and post-antiemetic premedication) and at each pharmacokinetic (PK) sampling time (0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after initiation of romidepsin dosing). Patients either received a 4-hour IV infusion at 14 mg/m2 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles or for 1 cycle followed by 8–12 mg/m2 infused over 1 hour for 5 cycles. Post-antiemetic baseline was included to isolate the effects of romidepsin as antiemetics alone may increase the QTc interval. All ECGs were read by a central ECG laboratory and overread by a cardiologist for verification of interval measurements. Standard analyses as defined in the International Conference on Harmonization E14 Guidance, Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs were used. Nonlinear mixed effect modeling was used to analyze the exposure-response relationship of romidepsin and QTc. Results:ECG data were available for 26 patients who received romidepsin at 14 mg/m2 over a 4-hour IV infusion (approved dosing regimen). Fourteen of these patients also received 8–12 mg/m2 romidepsin over a 1-hour IV infusion; 3 patients received 8 mg/m2, 6 received 10 mg/m2, and 5 received 12 mg/m2. The majority of the 26 patients were female (62%) and White (89%); median age was 61.7 years (range, 44–82 years). Patients who received romidepsin at 12 mg/m2 as a 1-hour infusion had a median plasma Cmax up to 2.5-fold higher than that observed with the approved dosing regimen. The time courses of mean QTcF (Fridericia correction), QTcI (individual correction) and ΔQTcF, as well as median romidepsin plasma concentration were examined. No marked trend was evident, except for some evidence of a modest change in QTcF that was temporally dissociated from the pharmacokinetic profile. However, no consistent pattern of pharmacodynamic counterclockwise hysteresis was noted across or within patients. Exposure-response modeling demonstrated no statistically significant effect of romidepsin concentration on QTc. As shown in the Figure comparing change in QTcF relative to baseline pre-antiemetic administration or post-antiemetic administration, there was a slight mean decrease from post-antiemetic baseline in QTcF at each time point following romidepsin administration, and a mean increase relative to pre-antiemetic baseline. Mean changes in QTcF from the post-antiemetic, pre-romidepsin baseline for the 14 mg/m2 4-hour infusion were negative for all assessments. The maximum upper bound of the 90% confidence interval (CI) for the change from post-antiemetic, pre-romidepsin baseline was 5.59 ms noted at the 6-hour time point; mean change in QTcF at this time was –0.11 ms. No patients in this study developed a QTcF > 450 ms in the 24-hour period following the start of infusion. No trends were observed across lower dose levels (8-, 10-, and 12-mg/m2) for the 1-hour romidepsin infusions. Conclusions:No concentration-dependent effects of romidepsin on the duration of QTc interval were identified, including at romidepsin exposures up to more than 2.5-fold higher than the approved and clinically used dosing of 14 mg/m2 as a 4-hour IV infusion. [Display omitted] Disclosures:Godfrey:Geron Corporation: Consultancy; Neurocrine Biosciences: Consultancy; Agios: Consultancy; Adnexus: Consultancy; Lundbeck, Inc.: Consultancy; Vertex Pharmaceuticals: Equity Ownership; Anoixis Corporation: Employment; Celgene: Consultancy. Off Label Use: Dosing in studies is off label. Cabell:Celgene: Consultancy. Balser:Celgene: Contracted Consultancy. Wolfson:Celgene: Contracted Consultancy. Nichols:Celgene: Employment, Equity Ownership.

A thorough QT study to evaluate the effects of singledose exenatide 10 μg on cardiac repolarization in healthy subjects

This was a singledose, randomized, positive- and placebo-controlled, double-dummy, double-blinded, 3-period crossover thorough QT study of exenatide, a glucagon-like peptide-1 receptor agonist for the treatment of Type 2 diabetes that enhances insulin secretion in a glucose- dependent fashion. Healthy subjects (n = 70) underwent an initial tolerability screening, receiving subcutaneous exenatide 10 μg daily for 3 consecutive days. Subjects who passed tolerability screening (n = 62) received exenatide 10 μg, placebo, and moxifloxacin (400 mg orally; positive control) separated by washout periods of approximately 5 days. Twelve-lead electrocardiograms and blood samples for plasma exenatide, glucose, and insulin were collected. QT intervals were heart rate-corrected using Fridericia's correction (QTcF) and an individual correction (QTcI) and were analyzed as change from predose (ΔQTcF, or ΔQTcI). The relationships between the QTc interval and plasma exenatide, glucose, and insulin concentrations were also explored. Based on ΔQTcF and ΔQTcI assessments, exenatide 10 μg did not show a clinically significant prolongation of QT compared with placebo; the upper bound of the 2-sided 90% confidence interval (CI) for the largest mean difference from placebo was < 10 msec with both corrections. A positive slope was observed between plasma exenatide and ΔΔQTcF (0.02 (95% CI 0.01, 0.03), p < 0.001); no significant slope was observed between plasma exenatide concentrations and ΔΔQTcI (0.01 (95% CI 0.00, 0.02), p = 0.064). The plasma exenatide versus QTc analyses may be confounded by exenatide's glucose-lowering effect. A negative slope was observed between plasma glucose and [delta]QTcF (-1.5 (95% CI -2.2, -0.7), p < 0.001) and between plasma glucose and ΔQTcI (-1.6 (95% CI -2.3, -0.9), p < 0.0001). Plasma insulin and ΔQTcF were not correlated. This study demonstrated that single-dose exenatide 10 μg was not associated with clinically meaningful prolongation of the QTc interval.

Seizure-related cardiac repolarization abnormalities are associated with ictal hypoxemia

Cardiac arrhythmias and respiratory disturbances have been proposed as likely causes for sudden unexpected death in epilepsy. Oxygen desaturation occurs in one-third of patients with localization-related epilepsy (LRE) undergoing inpatient video-electroencephalography (EEG) telemetry (VET) as part of their presurgical workup. Ictal-related oxygen desaturation is accompanied by hypercapnia. Both abnormal lengthening and shortening of the corrected QT interval (QTc) on electrocardiography (ECG) have been reported with seizures. QTc abnormalities are associated with increased risk of sudden cardiac death. We hypothesized that there may be an association between ictal hypoxemia and cardiac repolarization abnormalities. VET data from patients with refractory LRE were analyzed. Consecutive patients having at least one seizure with accompanying oxygen desaturation below 90% and artifact-free ECG data were selected. ECG during the 1 min prior to seizure onset (PRE) and during the ictal/postictal period with accompanying oxygen desaturation below 90% (DESAT) was analyzed. Consecutive QT and RR intervals were measured. In the same patients, DESAT seizures were compared with seizures without accompanying oxygen desaturation below 90% (NODESAT). For NODESAT seizures, QT and RR intervals for 2 min after seizure onset were measured. Thirty-seven DESAT seizures were analyzed in 17 patients with localization-related epilepsy. A total of 2,448 QT and RR intervals were analyzed during PRE. During DESAT, 1,554 QT and RR intervals were analyzed. Twelve of the 17 patients had at least one NODESAT seizure. A total of 19 NODESAT seizures were analyzed, including 1,558 QT and RR intervals during PRE and 3,408 QT and RR intervals during NODESAT. The odds ratio for an abnormally prolonged (>457 ms) QTcH (Hodges correction method) during DESAT relative to PRE was 10.64 (p < 0.0001). The odds ratio for an abnormally shortened (<372 ms) QTcH during DESAT relative to PRE was 1.65 (p < 0.0001). Seizure-related shortening and prolongation of QTc during DESAT were also observed when Fridericia correction of the QT was applied. During DESAT seizures, the mean range of QT values (QTr) (61.14 ms) was significantly different from that during PRE (44.43 ms) (p = 0.01). There was a significant association between DESAT QTr and oxygen saturation nadir (p = 0.025) and between DESAT QTr and duration of oxygen desaturation (p < 0.0001). Both QTcH prolongation and shortening also occurred with NODESAT seizures. A seizure-associated prolonged QTcH was more likely during DESAT than NODESAT, with an odds ratio of 4.30 (p < 0.0001). A seizure-associated shortened QTcH was more likely during DESAT than NODESAT with an odds ratio of 2.13 (p < 0.0001). We have shown that the likelihood of abnormal QTcH prolongation is increased 4.3-fold with seizures that are associated with oxygen desaturation when compared with seizures that are not accompanied with oxygen desaturation. The likelihood of abnormally shortened QTcH increases with seizures that are accompanied by oxygen desaturation with an odds ratio of 2.13 compared with that in seizures without desaturations. There is a significant association between the depth and duration of oxygen desaturation and QTr increase. These findings may be related to the pathophysiology of SUDEP.

A Supratherapeutic Dose of the Janus Kinase Inhibitor Tasocitinib (CP-690,550) Does Not Prolong QTc Interval in Healthy Participants

Tasocitinib (CP-690,550), a selective inhibitor of the Janus kinase (JAK) family, is being developed for the treatment of several autoimmune diseases and prevention of allograft rejection. The aim of this study was to characterize the effect of tasocitinib on QT interval. Sixty male and female healthy adults were enrolled in a single-dose, randomized, 3-period, crossover study of a supratherapeutic dose of tasocitinib (100 mg), placebo, and moxifloxacin 400 mg. Triplicate electrocardiograms were performed at predose baseline and serially over 24 hours postdose in each treatment period. The upper limits of the 2-sided 90% confidence intervals (CIs) for the difference in QTc interval, corrected using Fridericia correction (QTcF), between tasocitinib and placebo were less than 5 ms at all time points. Concentration-QTcF analysis showed that the predicted mean change (90% CI) in QTcF at the observed mean C(max) was -0.12 (-1.18, 0.94) ms. For moxifloxacin, mean (90% CI) estimates of the change in QTcF from placebo were 11.3 (9.4, 13.1) and 12.5 (10.7, 14.4) ms at 2 and 4 hours, respectively, thereby establishing study sensitivity. A single supratherapeutic dose of tasocitinib 100 mg was well tolerated and not associated with QTc prolongation.

Cardiac safety of a granisetron transdermal system in the treatment of chemotherapy-induced nausea and vomiting.

e19601 Background: Granisetron, a 5-HT3 antagonist, is widely used as an antiemetic. However, 5-HT3 antagonists may have cardiac effects, as shown by the withdrawal of IV dolesetron for treatment of chemotherapy-induced nausea and vomiting (CINV) in the US owing to risk of cardiac effects. Such effects are a concern, as chemotherapy and radiotherapy can cause acute dysrhythmias and longer-term cardiac damage. Granisetron Transdermal System (GTDS, Sancuso) is approved in the US for prevention of CINV in patients receiving up to 5 days of moderately or highly emetogenic (MEC, HEC) consecutive chemotherapy. GTDS is applied 24–48 hours prior to chemotherapy and can be left in place up to 7 days. Because of the novel delivery and altered pharmacokinetic profile of granisetron in the GTDS compared with IV or oral delivery, cardiac safety was investigated in a phase III clinical trial and a phase I QTc cardiac safety study. Methods: In a randomized, double-blind, phase III trial of GTDS vs oral granisetron in multiday MEC and HEC regimens, patients had sequential 12-lead ECG readings at baseline, at start of chemotherapy (coinciding with the estimated granisetron maximum plasma concentration [Cmax]), and at 120 hours post treatment. In a blinded placebo-controlled phase I QTc study, healthy subjects received GTDS, placebo, or active control. The primary end point was time-matched, placebo-corrected change from baseline in QTc based on the Fridericia correction (ddQTcF), allowing exclusion ≥10 ms increases at the 95% CI level, tested at 3 or more time points around the granisetron Cmax. Results: In the phase III trial, there were no clinically relevant changes in repolarization intervals, ECG morphology, or heart rate in the GTDS group (n=273). In the phase I QTc study, mixed-effects modeling showed a maximum ddQTcF in the GTDS group (n=60) of 1.9 ms on day 3 and 2.5 ms on day 5, excluding any change ≥10 ms at the 95% CI level. Conclusions: In a phase III trial in patients receiving chemotherapy and GTDS, no cardiac safety issues emerged. This finding was supported by a phase I QTc study of GTDS in healthy subjects that showed no significant QTc prolongation at standard regulatory and clinical thresholds.

Increased Short-Term Variability of the QT Interval in Professional Soccer Players: Possible Implications for Arrhythmia Prediction

BackgroundSudden cardiac death in competitive athletes is rare but it is significantly more frequent than in the normal population. The exact cause is seldom established and is mostly attributed to ventricular fibrillation. Myocardial hypertrophy and slow heart rate, both characteristic changes in top athletes in response to physical conditioning, could be associated with increased propensity for ventricular arrhythmias. We investigated conventional ECG parameters and temporal short-term beat-to-beat variability of repolarization (STVQT), a presumptive novel parameter for arrhythmia prediction, in professional soccer players.MethodsFive-minute 12-lead electrocardiograms were recorded from professional soccer players (n = 76, all males, age 22.0±0.61 years) and age-matched healthy volunteers who do not participate in competitive sports (n = 76, all males, age 22.0±0.54 years). The ECGs were digitized and evaluated off-line. The temporal instability of beat-to-beat heart rate and repolarization were characterized by the calculation of short-term variability of the RR and QT intervals.ResultsHeart rate was significantly lower in professional soccer players at rest (61±1.2 vs. 72±1.5/min in controls). The QT interval was prolonged in players at rest (419±3.1 vs. 390±3.6 in controls, p<0.001). QTc was significantly longer in players compared to controls calculated with Fridericia and Hodges correction formulas. Importantly, STVQT was significantly higher in players both at rest and immediately after the game compared to controls (4.8±0.14 and 4.3±0.14 vs. 3.5±0.10 ms, both p<0.001, respectively).ConclusionsSTVQT is significantly higher in professional soccer players compared to age-matched controls, however, further studies are needed to relate this finding to increased arrhythmia propensity in this population.

Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome

A prolonged QT interval corrected for heart rate (QTc) is a major risk factor in patients with long QT syndrome (LQTS). However, heart rate-related risk in this genetic disorder differs among genotypes. This study hypothesized that risk assessment in LQTS patients should incorporate genotype-specific QT correction for heart rate. The independent contribution of 4 repolarization measures (the absolute QT interval, and Bazett's, Fridericia's, and Framingham's correction formulas) to the risk of aborted cardiac arrest or sudden cardiac death during adolescence, before and after further adjustment for the RR interval, was assessed in 727 LQTS type 1 and 582 LQTS type 2 patients. Improved QT/RR correction was calculated using a Cox model, dividing the coefficient on log(RR) by that on log(QT). Multivariate analysis demonstrated that in LQTS type 1 patients 100-ms increments in the absolute QT interval were associated with a 3.3-fold increase in the risk of life-threatening cardiac events (P = .020), and 100-ms decrements in the RR interval were associated with a further 1.9-fold increase in the risk (P = .007), whereas in LQTS type 2 patients, resting heart rate was not a significant risk factor (hazard ratio 1.11; P = .51; P value for heart rate × genotype interaction = .036). Accordingly, analysis of an improved QT correction formula showed that patients with the LQTS type 1 genotype required a greater degree of QT correction for heart rate (improved QTc = QT/RR⁰·⁸) than LQTS type 2 patients (improved QTc = QT/RR⁰·²). Our findings suggest that risk stratification for life-threatening cardiac events in LQTS patients can be improved by incorporating genotype-specific QT correction for heart rate.

Single Therapeutic and Supratherapeutic Doses of Laropiprant, a Selective Prostaglandin D2 Receptor 1 Antagonist, Do Not Prolong the QTcF Interval in Healthy Volunteers

Laropiprant (LRPT), a prostaglandin D(2) receptor-1 antagonist shown to reduce niacin-induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This study evaluated the effects of LRPT (50 mg and 600 mg, respectively) on the QT interval with Fridericia's correction (QTcF). QTcF measurements were made over a 24-hour period following administration of single-dose moxifloxacin 400 mg, LRPT 50 mg, LRPT 600 mg, or placebo. The primary hypothesis was supported if the 90% confidence intervals (CIs) for the least squares (LS) mean differences between placebo and LRPT in change from baseline in QTcF interval were <10 milliseconds at every time point. The upper limits of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for LRPT 50 mg and 600 mg were <5 milliseconds at every time point. The lower limits of the 90% CIs for placebo-adjusted LS mean changes from baseline in QTcF intervals for moxifloxacin exceeded 0 milliseconds at every time point, demonstrating the sensitivity of this assay to detect increases in the QTcF interval. In conclusion, single doses of LRPT 50 mg and 600 mg do not prolong the QTcF interval relative to placebo and are generally well tolerated.

Cardiovascular Safety of Degarelix: Results From a 12-Month, Comparative, Randomized, Open Label, Parallel Group Phase III Trial in Patients With Prostate Cancer

We assessed the cardiovascular safety profile of degarelix, a new gonadotropin-releasing hormone antagonist. This is the first report to our knowledge on cardiovascular safety data from a completed 1-year randomized controlled trial of leuprolide acetate vs degarelix. Outcomes considered in these analyses included the QT interval by central reading and analysis, and cardiovascular adverse events. On multivariate analyses relationships between selected baseline factors and cardiovascular events were evaluated. There were no significant differences between treatment groups for mean change in Fridericia's correction of QT during the trial. Markedly abnormal Fridericia's correction of QT values (500 milliseconds or greater) were observed in only a small number of subjects by treatment group, that is 2 (less than 1%) in the pooled degarelix group and 2 (1%) in the leuprolide group. Supraventricular arrhythmias were the most common type of arrhythmias, affecting 2% of subjects in the pooled degarelix group and 4% in the leuprolide group. Other arrhythmias occurred in 1% or less of subjects by treatment group. The most frequently reported cardiac disorder was ischemic heart disease, which occurred in 4% of subjects treated with degarelix and 10% of those on leuprolide. Cox proportional hazard ratio estimates for selected baseline covariates showed a significantly increased risk of cardiovascular events by age (p=0.0459) and systolic blood pressure (p=0.0061). In men with prostate cancer degarelix and leuprolide have similar cardiovascular safety profiles. These observations suggest that the cardiovascular events associated with both agents result from hypogonadism rather than a direct drug effect.

A thorough QT/QTc study of multiple doses of tapentadol immediate release in healthy subjects

This randomized, double-blind, placebo- and positive-controlled 4-way crossover study evaluated the effects of tapentadol immediate release (IR) on the QT/QTc interval. Healthy subjects received tapentadol IR 100 mg or 150 mg, or placebo, every 6 h on Days 1 and 2, with a >= 7-day washout between treatments. Moxifloxacin 400 mg was the positive control. Serial triplicate 12-lead electrocardiograms (ECGs) were performed; the Fridericia correction (QTcF) was the primary correction method. Serial blood sampling was performed for pharmacokinetic analyses. Of the 75 subjects who were randomized, 68 received at least 1 dose of study medication, and 59 completed the study. Upper limits of the 90% confidence intervals (CIs) for the difference in mean DeltaQTcF between tapentadol IR 100 or 150 mg and placebo were < 10 ms (non-inferiority criterion) for all time points. The lower limit of the 90% CI for mean DeltaQTcF between moxifloxacin and placebo exceeded 5 ms from 1 to 6 h after dosing, establishing assay sensitivity. No subject had a postdose QTc interval > 480 ms, change from baseline > 60 ms, or clinically relevant change in heart rate or other ECG variables. Steady-state concentrations were reached within 18 to 24 h. Common adverse events were vertigo (central nervous system (CNS) origin), headache, somnolence, nausea, vomiting, and feeling drunk. Therapeutic and supratherapeutic doses of tapentadol do not affect the QT/QTc interval.

Thorough cardiac QTc interval conductance assessment of a novel oral tranexamic acid treatment for heavy menstrual bleeding

Objective: To assess the effect of a novel oral tranexamic acid treatment on cardiac repolarization in a randomized, double-blind, positive- and placebo-controlled, four-treatment single-dose cross-over inpatient study.Methods: QTc interval and drug exposure relationship analyses were performed using triplicate digital electrocardiographs (ECGs) collected from 12-lead Holter monitors from healthy females (n = 48) with plasma drug concentrations and pharmacokinetics simultaneously evaluated over 24 h post-dose. Therapeutic (1.3 g) and supratherapeutic (3.9 g) tranexamic acid modified immediate-release doses, a positive-control 0.4 g moxifloxacin dose, and a placebo-control were administered at each period.Results: All post-dose, time-matched, baseline-adjusted, mean QTcF (Fridericia's heart rate correction, QT/RR1/3) treatment-placebo differences (ΔΔQTcF), were less than 5 milliseconds (ms) for the 1.3 g and 3.9 g tranexamic acid doses. Upper limits of the 95% confidence interval (CI) for all tranexamic acid-placebo ΔΔQTcF doses were < 10 ms for all time points. Lower limits of the 95% CI for the positive-control (moxifloxacin-placebo) ΔΔQTcF were > 5 ms at multiple time points demonstrating assay sensitivity. No correlation between tranexamic acid plasma concentrations and adjusted QTc intervals was observed. A positive linear relationship was observed for moxifloxacin (p < 0.01).Conclusion: Cardiac repolarization is not influenced by tranexamic acid at the doses studied.

Pharmacokinetics, bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphate

The pharmacokinetics, bioavailability and effects on electrocardiographic (ECG) parameters of fludarabine phosphate (2F-ara-AMP) were evaluated in adult patients with B-cell chronic lymphocytic leukemia. Patients received single doses of intravenous (IV) (25 mg/m(2), n=14) or oral (40 mg/m(2), n=42) 2F-ara-AMP. Plasma concentrations of drug and metabolites and digital 12-lead ECGs were monitored for 23 h after dosing. The dephosphorylated product fludarabine (2F-ara-A) was the principal metabolite present in the systemic circulation. Mean (+/-SD) elimination half-life did not differ significantly between IV and oral dosage groups (11.3+/-4.0 vs 9.7+/-2.0 h, p=0.053). Renal excretion was a major clearance pathway, along with transformation to a hypoxanthine metabolite 2F-ara-Hx. Estimated mean oral bioavailability of 2F-ara-A was 58%. Compared to the time-matched drug-free baseline Fridericia correction of the QT interval (QTcF), the mean QTcF change following 2F-ara-AMP did not differ from zero, and a treatment effect of >+10 and >+15 ms could be excluded following oral and IV 2F-ara-AMP, respectively. Similarly, heart rate, PR interval and QRS duration did not change following 2F-ara-AMP treatment. Thus the 25 mg/m(2) IV and 40 mg/m(2) oral doses of 2F-ara-AMP produce similar systemic exposure, and do not prolong QTcF, indicating low risk of drug induced Torsades de Pointes.