Mean QTc Prolongation Research Articles

Association between escitalopram dose personalisation based on quantification of drug plasma levels and the outcome of escitalopram treatment

IntroductionGiven the negative impact of anxiety and depression on society and the shortage of new antidepressants, it is of paramount importance to make the best use of available treatment options. Therapeutic drug monitoring (TDM) in escitalopram treatment can potentially be clinically useful, as underexposed patients show reduced efficacy of escitalopram treatment and as adverse drug reactions (ADRs) of escitalopram are dose-dependent.ObjectivesThis prospective cohort study aimed to investigate whether escitalopram treatment efficacy or safety are associated with escitalopram dose adjustment based on TDM readouts.Methods89 included patients aged between 15 and 65 years who suffered from depression were enrolled in the study before starting treatment with escitalopram. Patients were assessed one day before starting treatment with the recommended dose of 10 mg/day escitalopram (baseline, visit 0) and at follow-up after four and eight weeks. Dose adjustment at four-week follow-up was based on the measured escitalopram plasma level two weeks after treatment initiation; patients who required dose increase to 15 or 20 mg/day comprised comparator group, patients who did not required dose increase comprised control group, while patients who did not reach optimal exposure at eight-week follow-up were characterized as non-compliers. Treatment efficacy was approximated by the relative change on the Hamilton Depression Rating Scale (HAMD), while safety was approximated based on the changes on the Scandinavian UKU side effect rating scale and ECG readouts. Changes in HAMD, UKU score and QTc interval were compared between groups by one-way ANOVA or chi-square tests.ResultsCompared to baseline, significant reductions in HAMD scores of 36% (95%CI, 30%-43%) and 53% (95%CI, 47%-60%) were observed at four- and eight-week follow-up, respectively; however, there were no significant differences between groups (p > 0.1). In the groups adjusted to 15 and 20 mg, 15/26 and 19/33 patients, respectively, reported adverse effects, compared with 6/17 patients in the control group and 6/13 in the non-complier group (p>0.1). A significant mean QTc prolongation of 6.40 ms (95%CI, 3.27-9.53) was observed between the baseline and eight-week follow-up (p=0.0013), without significant differences in QTc interval prolongation between groups (p > 0.1).ConclusionsEscitalopram dose adjustment resulted in optimal drug exposure and solid treatment response in the majority of patients; however, no differences in efficacy were found between the patients who required dose adjustments, the ones who did not, and the ones who ultimately did not achieve optimal exposure. In addition, the selective increase of the dose to the patients who did not reach optimal drug exposure on the recommended dose of 10 mg/day did not lead to significant increase in adverse drug reactions and QTc prolongation.Disclosure of InterestNone Declared

Electrocardiographic proarrhythmic changes in pregnancy of women with CHD.

Pregnancy-related physiological adaptations result in increased heart rate as well as electrocardiographic changes such as a mean QTc prolongation of 27 ms. Pregnant women with CHD are at increased risk for cardiovascular complications. The aim of this study was to identify risk factors for abnormally prolonged QTc interval-a risk factor for ventricular arrhythmias-in pregnant women with CHD. Retrospective longitudinal single-centre study. Pre-pregnancy demographic and electrocardiographic risk factors for abnormal QTc duration during pregnancy of (a) > 460 ms and (b) >27 ms increase were analyzed. Eighty-three pregnancies in 63 women were included, of which three had documented arrhythmias. All five Modified World Health Organization Classification of Maternal Cardiovascular Risk (mWHO) classeswere represented, with 15 pregnancies (18.1%) in mWHO class I, 26 (31.3%) in mWHO II, 28 (33.7%) in mWHO II-III, 11 (13.3%) in mWHO III, and three pregnancies (3.6%) in mWHO class IV. Heart rate and QTc interval increased, while QRS duration and PR interval shortened during pregnancy. QTc duration of > 460 ms was associated with increased pre-pregnancy QTc interval, QRS duration, and weight, as well as body mass index. QTc increase of > 27 ms was associated with increased heart rate prior to pregnancy. No significant associations of electrocardiographic changes with mWHO class or CHD type were identified. Increased QTc in pregnant women with CHD was associated with being overweight or having higher heart rate, QRS, or QTc duration prior to pregnancy. These patients should be monitored closely for arrhythmias during pregnancy.

Virtual clinical QT exposure-response studies – A translational computational approach

Background and purposeA 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. Experimental approachFull 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. Key resultsComputationally 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. Conclusion and implicationsComputational 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.

Cardiac Corrected QT Interval Changes Among Patients Treated for COVID-19 Infection During the Early Phase of the Pandemic

Critical illness, a marked inflammatory response, and viruses such as SARS-CoV-2 may prolong corrected QT interval (QTc). To evaluate baseline QTc interval on 12-lead electrocardiograms (ECGs) and ensuing changes among patients with and without COVID-19. This cohort study included 3050 patients aged 18 years and older who underwent SARS-CoV-2 testing and had ECGs at Columbia University Irving Medical Center from March 1 through May 1, 2020. Patients were analyzed by treatment group over 5 days, as follows: hydroxychloroquine with azithromycin, hydroxychloroquine alone, azithromycin alone, and neither hydroxychloroquine nor azithromycin. ECGs were manually analyzed by electrophysiologists masked to COVID-19 status. Multivariable modeling evaluated clinical associations with QTc prolongation from baseline. COVID-19, hydroxychloroquine, azithromycin. Mean QTc prolongation, percentage of patients with QTc of 500 milliseconds or greater. A total of 965 patients had more than 2 ECGs and were included in the study, with 561 (58.1%) men, 198 (26.2%) Black patients, and 191 (19.8%) aged 80 years and older. There were 733 patients (76.0%) with COVID-19 and 232 patients (24.0%) without COVID-19. COVID-19 infection was associated with significant mean QTc prolongation from baseline by both 5-day and 2-day multivariable models (5-day, patients with COVID-19: 20.81 [95% CI, 15.29 to 26.33] milliseconds; P < .001; patients without COVID-19: -2.01 [95% CI, -17.31 to 21.32] milliseconds; P = .93; 2-day, patients with COVID-19: 17.40 [95% CI, 12.65 to 22.16] milliseconds; P < .001; patients without COVID-19: 0.11 [95% CI, -12.60 to 12.81] milliseconds; P = .99). COVID-19 infection was independently associated with a modeled mean 27.32 (95% CI, 4.63-43.21) millisecond increase in QTc at 5 days compared with COVID-19-negative status (mean QTc, with COVID-19: 450.45 [95% CI, 441.6 to 459.3] milliseconds; without COVID-19: 423.13 [95% CI, 403.25 to 443.01] milliseconds; P = .01). More patients with COVID-19 not receiving hydroxychloroquine and azithromycin had QTc of 500 milliseconds or greater compared with patients without COVID-19 (34 of 136 [25.0%] vs 17 of 158 [10.8%], P = .002). Multivariable analysis revealed that age 80 years and older compared with those younger than 50 years (mean difference in QTc, 11.91 [SE, 4.69; 95% CI, 2.73 to 21.09]; P = .01), severe chronic kidney disease compared with no chronic kidney disease (mean difference in QTc, 12.20 [SE, 5.26; 95% CI, 1.89 to 22.51; P = .02]), elevated high-sensitivity troponin levels (mean difference in QTc, 5.05 [SE, 1.19; 95% CI, 2.72 to 7.38]; P < .001), and elevated lactate dehydrogenase levels (mean difference in QTc, 5.31 [SE, 2.68; 95% CI, 0.06 to 10.57]; P = .04) were associated with QTc prolongation. Torsades de pointes occurred in 1 patient (0.1%) with COVID-19. In this cohort study, COVID-19 infection was independently associated with significant mean QTc prolongation at days 5 and 2 of hospitalization compared with day 0. More patients with COVID-19 had QTc of 500 milliseconds or greater compared with patients without COVID-19.

Pooled Multicenter Analysis of Cardiovascular Safety and Population Pharmacokinetic Properties of Piperaquine in African Patients with Uncomplicated Falciparum Malaria.

Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicenter trial from 10 sites in Africa. A linear relationship described the QTc-prolonging effect of piperaquine, estimating a 5.90-ms mean QTc prolongation per 100-ng/ml increase in piperaquine concentration. The effect of piperaquine on absolute QTc interval estimated a mean maximum QTc interval of 456 ms (50% effective concentration of 209 ng/ml). Simulations from the pharmacokinetic-pharmacodynamic models predicted 1.98 to 2.46% risk of having QTc prolongation of >60 ms in all treatment settings. Although piperaquine administration resulted in QTc prolongation, no cardiovascular adverse events were found in these patients. Thus, the use of dihydroartemisinin-piperaquine should not be limited by this concern. (This study has been registered at ClinicalTrials.gov under identifier NCT02199951.).

Chloroquine-induced QTc prolongation in COVID-19 patients.

BackgroundIn the battle against the SARS-CoV‑2 pandemic, chloroquine has emerged as a new potential therapeutic option for the treatment of infected patients. A safety consideration for the application of chloroquine is its QTc-prolonging potential. Thus far, no data are available on the QTc-prolonging potential of chloroquine in COVID-19 patients.ObjectiveTo assess the degree of chloroquine-induced QTc prolongation in hospitalised COVID-19 patients.MethodsA baseline electrocardiogram (ECG) and ECGs recorded during chloroquine treatment were retrospectively collected in patients suspected of having COVID-19. The QTc interval was calculated by computerised and manual interpretation. Baseline and follow-up QTc intervals were compared using the paired samples t-test.ResultsA total of 95 patients had a baseline ECG recording and at least one ECG recording during chloroquine therapy. Chloroquine treatment resulted in a mean QTc prolongation of 35 ms (95% CI 28–43 ms) using computerised interpretation and 34 ms (95% CI 25–43 ms) using manual interpretation. No torsade de pointes was observed during chloroquine treatment. After manual review, 22 patients (23%) had a QTc interval exceeding 500 ms during chloroquine treatment. None of these patients had a prolonged QTc interval prior to the initiation of chloroquine treatment.ConclusionsChloroquine significantly prolongs the QTc interval in a clinically relevant matter. This highlights the need for ECG monitoring when prescribing chloroquine to COVID-19 patients.

P.1.g.046 - ECG alterations associated with psychotropic drug use in clinical settings: clinical and genetic predictors

Background QTc prolongation is a potentially life-threatening side effect of some antidepressants and antipsychotics, and a number of other electrocardiogram (ECG) alterations were associated with psychotropic drugs. Poor knowledge is available about the genetic risk factors of QTc prolongation during treatment with these drugs. Polymorphisms in the α1-subunit of cardiac L-type calcium channel (CACNA1C) were associated with several types of arrhythmic diseases (including Long QT syndrome), but no data are available in regard to their possible effect on QTc duration during psychotropic drugs use. The present study primarily aimed to investigate QTc variation in relation to the prescription of psychotropic drugs stratified according to their cardiovascular risk [3]. The possible modulating effect of polymorphisms in the α1-subunit of cardiac L-type calcium channel (CACNA1C) gene was considered. As secondary aim, we investigated other ECG alterations possibly associated with psychotropic drugs. Methods 213 patients with a diagnosis of mood, anxiety or psychotic disorder who required a pharmacological treatment with antidepressant and/or antipsychotic drugs were included. A cross-sectional sample (n=145) had one standard ECG at baseline while a prospective sample (n=68) had a baseline and follow-up ECG. 13 SNPs in the CACNA1C gene were genotyped in both samples. An independent prospective sample was available from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Patients having a baseline and follow-up ECG were selected (n=515) and CACNA1C polymorphisms were extracted from imputed genome-wide data. In the prospective samples changes in ECG intervals (QTc, PR, QRS, RR, and QR) between baseline and follow-up were analyzed in relation to the number of psychotropic drugs stratified according to their cardiovascular risk (from moderate-high to none). In the cross-sectional sample ECG parameters were compared among groups taking psychotropic drugs with different cardiovascular risk. The effect of genotypes on these associations was tested. Results There was no evidence of mean QTc prolongation or increased risk of QTc prolongation ≥ 20 ms in association with risk drugs. The prescription of drugs with cardiovascular risk was less common in older subjects (p=0.04) or with cardiovascular comorbidities (p=0.02). Other factors (gender, ethnicity, baseline QTc, kidney function) affected QTc. rs1006737 modulated QTc duration/changes in the original prospective sample (p=0.04) and in cross-sectional sample (p=0.002) and four polymorphisms in linkage disequilibrium with it modulated QTc changes in the CATIE. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples. Discussion A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not found. A number of other factors may influence QTc. CACNA1C rs1006737 may modulate the risk of QTc prolongation in patients treated with risk drugs. Finally, high resting heart rate, even within the accepted normal range, should not be overlooked in patients treated with psychotropic drugs since it was independently associated with increased risk of all-causes mortality.

Eeffect Of Sex And Formulation on Single-Dose of Pharmacodynamics of Aripiprazole

Aripiprazole is a third-generation antipsychotic agent that possesses a unique mechanism of action. Orthostatic hypotension, QT prolongation, bradycardia and syncope are some of adverse events associated with aripiprazole. The objective of this study was to determinate the effects of aripiprazole on blood pressure and electrocardiogram on single-dose studies in healthy volunteers. A total of 180 healthy volunteers participating in six crossover bioequivalence clinical trials were included after giving informed consent (102 men and 78 women). They received a single aripiprazole 10 mg tablet or orodispersable tablet twice. Blood pressure and heart rate were measured lying down on the days of admission before taking the medication, 30 minutes, 2, 4, 6 and 8 hours after the dose. Electrocardiogram was performed before the administration of the drug, and 4 and 8 hours after. Mean blood pressure [systolic blood pressure (SBP)/diastolic blood pressure (DBP)] at baseline, 30 minutes, 2, 4, 6 and 8 hours were 116/65, 110/63, 107/59, 109/59, 111/59 and 117/59 mm Hg, respectively. A decrease between 5 and 9 mm Hg in SBP and 2 and 6 mm Hg in DBP were showed at all times after administration of drug (P < 0.05) and in all subjects, but no differences were apparent in heart rate or between males and females. Moreover, the differences between tablet and orodispersable was only showed at 4 hours (P < 0.05) post-dose. Mean QTc prolongation was 8 ms at 4 and 8 hours after dosing (P < 0.05). Our data show that a single dose of aripiprazole produces a small decrease in blood pressure and a small increase in QTc, but there was no change in heart rate. There were no differences between females and males.

Kcne3 deletion initiates extracardiac arrhythmogenesis in mice

Mutations in the human KCNE3 potassium channel ancillary subunit gene are associated with life-threatening ventricular arrhythmias. Most genes underlying inherited cardiac arrhythmias, including KCNE3, are not exclusively expressed in the heart, suggesting potentially complex disease etiologies. Here we investigated mechanisms of KCNE3-linked arrhythmogenesis in Kcne3(-/-) mice using real-time qPCR, echo- and electrocardiography, ventricular myocyte patch-clamp, coronary artery ligation/reperfusion, blood analysis, cardiac synaptosome exocytosis, microarray and pathway analysis, and multitissue histology. Kcne3 transcript was undetectable in adult mouse atria, ventricles, and adrenal glands, but Kcne3(-/-) mice exhibited 2.3-fold elevated serum aldosterone (P=0.003) and differentially expressed gene networks consistent with an adrenal-targeted autoimmune response. Furthermore, 8/8 Kcne3(-/-) mice vs. 0/8 Kcne3(+/+) mice exhibited an activated-lymphocyte adrenal infiltration (P=0.0002). Kcne3 deletion also caused aldosterone-dependent ventricular repolarization delay (19.6% mean QTc prolongation in females; P<0.05) and aldosterone-dependent predisposition to postischemia arrhythmogenesis. Thus, 5/11 Kcne3(-/-) mice vs. 0/10 Kcne3(+/+) mice exhibited sustained ventricular tachycardia during reperfusion (P<0.05). Kcne3 deletion is therefore arrhythmogenic by a novel mechanism in which secondary hyperaldosteronism, associated with an adrenal-specific lymphocyte infiltration, impairs ventricular repolarization. The findings highlight the importance of considering extracardiac pathogenesis when investigating arrhythmogenic mechanisms, even in inherited, monogenic channelopathies.

Effects of Injectable HPβCD-Diclofenac on the Human Delayed Rectifier Potassium Channel Current In Vitro and on Proarrhythmic QTc In Vivo

BackgroundNovel formulations and administration routes of established drugs may result in higher maximum concentrations or total exposures and potentially cause previously unrecognized adverse events. ObjectiveThis study evaluated the proarrhythmic potential of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-β-cyclodextrin (HPβCD), on ventricular electrical conduction in preclinical and clinical models. MethodsWe assessed the effects of diclofenac, HPβCD, and HPβCD-diclofenac on the human delayed rectifier potassium channel (IKr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-à-go-go–related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18–49 years; 55.75% male) received HPβCD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin). ResultsIn vitro, diclofenac produced no statistically significant effect on IKr. Significant, non–dose-dependent effects were observed in the presence of HPβCD or HPβCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPβCD in this in vitro model. In vivo, neither HPβCD-diclofenac dose resulted in QTc prolongation ≥2 ms (≥5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HPβCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms. ConclusionsThe findings from the present study suggest that HPβCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.

Dose-Dependent Effects of Methadone on QT interval in Patients under Methadone Maintenance Treatment

Background: The role of methadone in QTc prolongation, Torsades de Pointes (TdP) arrhythmia and sudden cardiac death has been debated. Because of widespread use of methadone in methadone maintenance treatment (MMT) centers, we aimed to study dose-related effects of methadone on QTc prolongation. Methods: In a comparative observational study, 90 patients who were under MMT were evaluated. Patients were divided into three groups according to methadone daily dose (G1: 0-59 mg, G2: 60-109 mg, G3: 110-150 mg). Twelve-lead electrocardiograms (ECG) were performed at baseline and two months later, after reaching the maximum daily dose of methadone. The QTc were calculated for each patient. Comparison of mean QTc and mean QTc prolongation between baseline and follow up ECGs were analyzed. Results: In total, mean (SD) age was 32.4 (8.5). TdP was not detected in any patients. Mean QTc was 405.2 (17.0) and 418.5 (23.1) msec before and two months after MMT respectively. There was a significant difference between mean QTc in each group before and after treatment (P<0.001). In total, mean QTc prolongation was 13.5 (8.1). Univariate analysis showed that there was a significant difference in means of QTc prolongation between G1 and the other two groups (P=0.001), but not between G2 and G3. This indicates that patients receiving methadone over 60 mg/day are at a risk of greater QTc prolongation. Conclusion: Methadone can cause QTc prolongation in different doses. However, the extent of this effect is dose dependent. Daily dose of less than 60 mg methadone is a safer cardiac dose. Nevertheless, it is not possible to administer this low dose for all opioid addict patients. Therefore, it is necessary to closely monitor patients under MMT, especially those receiving higher methadone doses, with constant scheduled ECGs before and during treatment.

Systematic Assessment of Potential Cardiac Effects of the Novel Histone Deacetylase (HDAC) Inhibitor Romidepsin.

Abstract 3709Poster Board III-645 BackgroundRomidepsin is an anti-neoplastic agent that has been identified as a novel pan-HDAC inhibitor with single-agent activity in cutaneous T-cell lymphoma (CTCL) in 2 studies (GPI-04-0001 and NCI 1312). In the GPI study the overall response rate (ORR) was 34% including 6 complete clinical responses (CCRs) in 96 pts with CTCL and the median duration of response (DOR) was 14.9 months (mo). In the NCI study, the ORR was 35% including 4 CCR in 71 pts and the median DOR was 11 mo. NCI 1312 has also reported single-agent activity in patients with peripheral T-cell lymphoma with an ORR of 31% including 4 CRs in the 48 pts analyzed. HDAC inhibitors have variably been reported to have cardiovascular effects, in particular, QTc prolongation. To systemically and rigorously evaluate the potential cardiac effects of romidepsin, a cardiac safety monitoring plan was developed after discussions with the FDA Division of Oncology Drug Products. Subsequently, a romidepsin QTc Clinical/Statisitcal Analysis Plan was developed following the ICH E14 Guidelines, to provide a comprehensive evaluation of the cardiac effects of romidepsin. MethodsAn analysis of romidepsin cardiac safety, including review and analysis of ECG findings, was performed. The primary objective of these analyses was to evaluate the effect of romidepsin on the change from baseline on the corrected QT interval of the ECG using the Fridericia QT correction method (QTcF) during Cycle 1 Day 1 exposure to study drug. A total of 4909 ECGs from 110 patients in 3 clinical studies, GPI study, NCI study, and Study GPI-06-0005 (a Phase 1 PK study) were evaluated. The 110 patients comprised 103 patients with T-cell lymphoma and 7 patients with advanced cancer treated with romidepsin at 14 mg/m2 as a 4-hour infusion on Days 1, 8, and 15 of a 28-day cycle. Using a nonlinear mixed effects model the pharmacodynamics of romidepsin was characterized for exposure-QTc effects. ResultsIn an analysis of ECG data, a mean increase of 5.0 msec (90% CI upper bound 7.7 msec) in QTcF interval was measured following infusion of romidepsin; this value includes a contribution to QTc prolongation by pre-dose antiemetics. Data from the NCI study showed that the QTcF change persisted to 24 hours, with a return to baseline by 48 hours, whereas in the smaller GPI-06-0005 study, QTcF peaked 2 hours post infusion and there was no QTcF effect seen at 24 hours. Categorical analyses showed no patients with a change from baseline >60 msec or an absolute QTcF >480 msec. No cardiac events of Torsade de Pointes were reported. Per the ICH E14 guidance,56 a threshold for regulatory concern for mean QTc prolongation is 5 msec with an upper bound of the 95% CI of 10 msec. Prolongations of >60 msec over baseline or a value >500 msec are also considered cautionary. Treatment-emergent morphological changes on ECG (minor ST-segment depression, T-wave flattening, biphasic T-waves, and T-wave inversion) have been observed during treatment with romidepsin; however the overall frequency of these minor, asymptomatic changes was similar to the frequency of pre-exposure abnormalities on each dosing day, suggesting a high degree of background noise in these data. Furthermore, there was no association between these ECG findings and any clinical, functional, or laboratory findings of cardiac abnormalities.Categorical Analysis of QTc Change on Cycle 1, Day 1CategoryStudyGPI Study N=87 n (%)NCI Study N=41 n (%)GPI-06-0005 N=7 n (%)Total N=135 n (%)QTcF change from baseline1No increase31 (36)10 (24)2 (29)43 (32)1-29 msec increase46 (53)27 (66)4 (57)77 (57)30-60 msec increase2 (2)4 (10)1 (14)7 (5)>60 msec increase0000QTcF not available8 (9)008 (6)QTcF absolute value:>450 msec2 (2)2 (5)04 (3)>480 msec0000>500 msec00001For GPI studies, baseline values are those post co-med, or if missing post co-med, then pre-comed baseline is used. ConclusionsThe findings from the romidepsin studies show that the observed QTc changes were below the threshold levels of concern outlined in ICH E14. Pharmacodynamic modeling showed no evidence of a relationship between the plasma concentration of romidepsin and changes in the QTc interval. Since hypokalemia and hypomagnesemia are associated with ECG abnormalities, supplementation with potassium and magnesium to achieve normal levels prior to romidepsin administration is recommended. Disclosures:Cabell:Gloucester Pharmaceuticals: Consultancy. Whittaker:Gloucester Pharmaceuticals: Research Funding. Nichols:Gloucester Pharmaceuticals: Employment, Equity Ownership. Nix:Gloucester Pharmaceuticals: Employment. Burris:Gloucester Pharmaceutcals: Research Funding.

Sertindole causes distinct electrocardiographic T-wave morphology changes

Sertindole's propensity to prolong the QT interval relates to blockade of the KCNH2 (HERG) encoded Ikr potassium channel, but there has been limited detailed data on T-wave morphology changes. Digital 12-lead ECG was recorded at baseline and at steady-state in 37 patients switched to sertindole. ECG was analyzed for quantitative T-wave morphology changes and Fridericia-corrected QT duration (QTcF). Prominent T-wave morphology changes occurred during sertindole treatment and in some cases without concomitant prolongation of the QTcF interval. Four patients developed notched T-waves during sertindole treatment. Mean QTc prolongation was 19 ms. The mean effect size was higher for T-wave morphology combination score (MCS) (ES=1.92; 95% CI: 1.35-2.49) compared to the mean effect size for QTcF (ES=0.88; 95% CI: 0.52-1.24). The use of T-wave morphology analysis may become clinically relevant, particularly if shown to be associated with drug-induced arrhythmia risk.

Effect of Domperidone on QT Interval in Neonates

To determine whether oral domperidone is associated with QT interval prolongation and ventricular arrhythmia and to identify factors that can influence these effects. An electrocardiogram was performed before and after oral administration of domperidone in 31 neonates or infants classified into 3 groups according to gestational age. Oral domperidone is associated with QTc prolongation except in infants with a gestational age less than 32 weeks of amenorrhea (P < .005). Mean QTc prolongation was 14 msec. On univariate analysis, oral domperidone-induced QTc prolongation was correlated with gestational age, birth weight, and elevated serum potassium. On multivariate analysis, after adjustment for gestational age, serum potassium was the only factor independently associated with interval QT prolongation during treatment. No ventricular arrhythmias were observed. This study shows a significant association between oral domperidone therapy and QTc prolongation. Two risk factors were identified: advanced gestational age and serum potassium at the upper limit of normal. It is recommended that measurement of the QT interval be done before and after oral domperidone therapy.

Electrocardiographic Changes in Children and Adolescents Treated With Ziprasidone: A Prospective Study

To assess the electrocardiographic safety profile of low-dose ziprasidone (< or =40 mg/day) among pediatric outpatients treated for up to 6 months. This was a prospective, open-label trial involving 20 subjects with a mean age of 13.2 +/- 3.0 years. Subjects received a mean ziprasidone dose of 30 +/- 13 mg/day and were followed for 4.6 +/- 2.0 months, receiving a median of nine electrocardiograms each (range 2-11; total, 176). There were statistically significant changes from baseline to peak values in heart rate, PR, and QTc intervals, but not in QRS complex width. The mean QTc prolongation was 28 +/- 26 milliseconds and not related to dose (r = 0.16, p = .07). The peak QTc of three subjects reached or exceeded 450 milliseconds; one subject experienced a 114-millisecond prolongation. There was poor agreement (kappa = 0.25) between automated and manual identification of long QTc intervals (> or =440 milliseconds). These preliminary findings, occurring at doses low by current treatment standards, suggest that close electrocardiographic monitoring is warranted when prescribing ziprasidone to children, particularly at higher doses or when combined with other QTc-prolonging agents.

Rate dependence of sotalol-induced prolongation of ventricular repolarization during exercise in humans.

Studies in animals have shown that drug-induced action potential prolongation with class III antiarrhythmic agents increases with slow pacing rates. We studied the physiological rate dependence of sotalol effects on ventricular repolarization, measured as QT interval duration on the surface electrocardiogram at rest and during a maximal exercise test, in 10 normal volunteers. In a randomized, crossover study, three dosages of sotalol (160 mg/24 hr, 320 mg/24 hr, and 640 mg/24 hr) were administered during 4 days to each subject. In a control period, no drug was administered. During each period, 50-100 QT intervals were measured over a wide range of RR intervals recorded at rest and during the course of a maximal exercise test. Plasma sotalol concentration and beta-adrenoceptor blockade (percent reduction in peak exercise heart rate from control) were also measured. The QT-versus-RR relation was fitted to several formulas, and the overall best fit was used to calculate QT interval duration normalized for a heart rate of 60 beats/min (QTc) and to analyze the rate dependence of QT prolongation with sotalol. Sotalol-induced beta-adrenoceptor blockade and QTc prolongation were dose and concentration dependent. Sotalol reduced peak exercise heart rate by 13.8 +/- 7% at the dosage of 320 mg/24 hr and by 25.4 +/- 8% at the dosage of 640 mg/24 hr (both p less than 0.01). Sotalol prolonged QTc interval by 5.8 +/- 3.7% and 11.8 +/- 3% at these respective dosages (both p less than 0.01). The concentration of sotalol required to produce minimal (mean QTc prolongation, 5.6%; confidence interval, 0-11.2%) QTc prolongation (680 ng/ml) tended to be lower than that required for minimal (mean percent reduction in maximal exercise heart rate, 13.9%; confidence interval, 0-27.8%) beta-blockade (840 ng/ml). QT prolongation with sotalol increased with increasing RR intervals (i.e., decreasing heart rate) at all dosages. QT prolongation became statistically significant for RR of 800 msec or more at all dosages and for RR intervals of 600 msec or more at the dosage of 640 mg/24 hr. This rate dependence altered the relation between QT interval duration and sotalol plasma concentrations. These results suggest that sotalol prolongs QTc interval in humans at dosages and concentrations similar to those required to produce beta-adrenoceptor blockade, QT prolongation with sotalol is more pronounced when heart rate decreases and is not apparent during exercise-induced tachycardia, and the relation between QT prolongation with sotalol and plasma concentrations of the drug depends on the heart rate at which measurements are made.