QT Interval Data Research Articles

The Effects of Cycle Ergometer Versus Treadmill Exercise Stress Testing on QTc Interval Prolongation in Patients With Long QT Syndrome: A Systematic Review and Meta-analysis.

The safest and most effective exercise stress tests (EST) modalities for long QT syndrome (LQTS) are currently unknown. The main objective was to explore the effects of EST on the corrected QT interval (QTc) in patients with LQTS, and to compare the effects of different EST modalities (cycle ergometer vs treadmill). Systematic searches were performed in September 2022 in accordance with the PRISMA statement through PubMed, Medline, EBM Reviews, Embase, and Web of Science. A total of 1728 patients with LQTS, whether congenital or acquired, without any age restrictions (pediatric age ≤18 years and adult age >19 years), and 2437 control subjects were included in the 49 studies. The QT interval data were available for 15 studies. Our analyses showed that the QT interval prolonged in a similar manner using either a cycle ergometer or a treadmill (standardized mean difference [SMD] = 1.89 [95% CI, 1.07-2.71] vs SMD = 1.46 [95% CI, 0.78-2.14], respectively). Therefore, it seems that either modality may be used to evaluate patients with LQTS. The methodology for the measurement of the QT interval was very heterogeneous between studies, which inevitably influenced the quality of the analyses. Hence, researchers should proceed with caution when exploring and interpreting data in the field of exercise and LQTS.

Comparing the consistency of electrocardiogram interval measurements by resting ECG versus 12-lead Holter.

In clinical trials, traditionally only a limited number of 12‐lead resting electrocardiograms (ECGs) can be recorded and, thus, long intervals may elapse between assessment timepoints and valuable information may be missed during times when patients' cardiac electrical activity is not being monitored. These limitations have led to the increasing use of Holter recorders which provide continuous data registrations while reducing the burden on patients and freeing up time for clinical trial staff to perform other tasks. However, there is a shortage of data comparing the two approaches. In this study, data from a randomized, double‐blind, four‐period, crossover thorough QT study in 40 healthy subjects were used to compare continuous 12‐lead Holter recordings to standard 12‐lead resting ECGs which were recorded in parallel. Heart rate and QT interval data were estimated by averaging three consecutive heartbeats. Values exceeding the sample average by more than 5% were tagged as outliers and excluded from the analysis. Visual comparisons of the ECG waveforms of the Holter signal showed a good correlation with resting ECGs at matching timepoints. Resting ECG data revealed sex differences that Holter data did not show. Specifically, women were found to have a longer QTcF of 20 ms, while men had a lower heart rate. We found that continuous recordings provided a more accurate reflection of changes in cardiac electrical activity over 24 hr. However, manual adjudication is still required to ensure the quality and accuracy of ECG data, and that only artifacts are removed thereby avoiding loss of true signals.

The specification of zebrafish (Danio rerio) heart electrocardiogram index characteristic responses to different types of pollutants

Water quality was highly affected by common pollutants. Metals, pesticides and small molecules are ubiquitous pollutants. Advancement in engineering technology (computer-based monitoring systems) increased the efficiency of quantifying toxicity of different chemicals in an organism. The cardiovascular system reflects internal and external stress of an organism, and electrocardiogram (ECG) data reliably measure external stress. As ECG data can accurately reflect the physiological conditions of organisms, and zebrafish (Danio rerio) are considered to be good models for cardiovascular research, it is hypothesized that ECG parameters of zebrafish could indicate the toxicity of water-borne chemicals. To achieve this, we treated zebrafish with different concentrations of target chemicals (CuSO4, C10H19O6PS2 and NH4Cl) for 48 h and ECG data were measured. P-wave, R-wave, T-wave, PR-interval, QRS-complex and QT-interval data were the focus of this study. The results of self-organizing maps and Pearson correlation analysis indicate that the QRS-complex can be used as an indicator for CuSO4 stress. The QT-interval could be used to assess the C10H19O6PS2 stress. The QT-interval and P-wave can be used to evaluate the NH4Cl stress. Responses of zebrafish ECG parameters were identical with other vertebrate model, and were specific to toxicant types. It is proved that zebrafish heart ECG index could be used as a potential indicator in early detection of environmental stress.

Abstract P3-14-07: Evaluation of the effects of talazoparib on QT interval prolongation

Abstract Background: Talazoparib (TAL), an oral poly ADP-ribose polymerase inhibitor, is under investigation in multiple oncologic clinical trials and has been submitted to the US FDA for use in patients (pts) with germline BRCA-mutated, HER2-negative advanced breast cancer. International Conference on Harmonisation guidance recommends all new drugs be evaluated for effects on cardiac repolarization in a well-controlled clinical study. For drugs for which such evaluation cannot be conducted in healthy volunteers (eg, most anticancer agents), collection of robust corrected QT (QTc) interval data from a dedicated QTc study (hybrid thorough QT/QTc study) in pts is required in the registration dossier. The effect of steady-state (ss) TAL (1 mg once daily) on cardiac repolarization in pts with advanced solid tumors was evaluated in an open-label phase 1 study (NCT03042910). Methods: Continuous 12-lead electrocardiogram (ECG) recordings were collected at baseline (Day -1); time-matched pharmacokinetic (PK) samples and continuous ECG recordings were obtained on Days 1, 2, and 22 (when TAL concentrations achieved ss). On Day -1, pts had continuous 12-lead ECG recording starting at Time 0 (Day 1 dosing time) for 6 hrs. On Days 1 and 22, ECG recording started 45 min before TAL administration and continued for 6 hrs post dose and blood samples for PK were collected before dose and at 1, 2, 4, and 6 hrs post dose. On Day 2, a 30-min ECG recording and a PK sample were obtained before dose at Time 0. Continuous ECG recordings were submitted to a central laboratory; triplicate 10-sec ECGs were extracted from a 5-min extraction window beginning 15 min before each PK collection time. ECG measurements were reported via blinded manual adjudication process and included PR interval, QT interval, RR interval, and QRS complex. The QT interval was corrected for effect of heart rate using Fridericia's correction (QTcF) and Bazett's correction (QTcB). The estimate of change from time-matched baseline and its 2-sided 90% confidence interval (CI) was calculated for each nominal time point using PROC MEANS. Additionally, a prespecified PK/pharmacodynamic (PD) model was used to describe the relationship between plasma TAL concentrations ([TAL]) and QTc. The prespecified linear mixed-effects model included [TAL], time (categorical), and treatment with random pt effects on [TAL] and the intercept. If the upper bounds (UB) of 1-sided 95% CIs of time-matched ΔQTc for all ECG time points were <20 msec and the UB of 1-sided 95% CIs of the predicted ΔQTc at the mean ss maximum [TAL] was <20 msec, the effect of TAL on QTc was not of clinical relevance. Results: 37 of 38 pts enrolled received TAL and were included in the ECG and PK/PD analyses. No pts had a postbaseline absolute maximum QTcF or QTcB ≥500 msec or ΔQTc ≥60 msec. The UB of the 1-sided 95% CI for the time-matched ΔQTcF and ΔQTcB were <12 msec at all nominal ECG time points. In the PK/PD analysis, the slopes (95% CI) of QTcF-[TAL] and QTcB-[TAL] relationships were -0.14 (-0.78 to 0.50) msec/ng/mL and -0.24 (-0.88 to 0.41) msec/ng/mL, respectively, indicating that TAL did not have a concentration-dependent effect on QTcF or QTcB. Conclusion: TAL does not have a clinically relevant effect on QTc. Funding: Medivation LLC, acquired by Pfizer. Citation Format: Hoffman J, Chakrabarti J, Wainberg ZA, Plotka A, Babu S, Milillo Naraine A, Kanamori D, Moroose R, Nguyen L, Wang D. Evaluation of the effects of talazoparib on QT interval prolongation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-14-07.

Population Pharmacokinetic/Pharmacodynamics Modeling of Ibutilide in Chinese Healthy Volunteers and Patients With Atrial Fibrillation (AF) and/or Atrial Flutter (AFL)

PurposeThe goal of this study was to develop a population pharmacokinetic (PK) and PK/pharmacodynamics (PD) model for ibutilide, to evaluate the time course of its effect on QT interval in Chinese. MethodsThe population PK and PK/PD model were developed using data from 40 Chinese healthy volunteers using nonlinear mixed-effects modeling, and the final population PK/PD model was applied on 100 patients with atrial fibrillation (AF) and/or atrial flutter (AFL). FindingsThe PK parameters of ibutilide were best described by a 3-compartment model with first-order elimination. No statistically significant covariate was found for each PK model parameter. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian rhythm of QT intervals was described by 2 mixed-effect cosine functions. The QT interval data of ibutilide was well characterized by a sigmoid Emax model (E(C)=Emaxγ×Cγ/(EC50γ+Cγ)) with an effect compartment. The final PK/PD model was used to estimate individual parameters of patient data and found good predictions compared with healthy volunteers; AF and/or AFL patients had lower Emax and higher EC50. ImplicationsA population PK and PK/PD model for ibutilide in healthy volunteers was developed and could well capture ibutilide’s PK/PD characteristics. The final PK/PD model was applied on patients with AF and/or AFL successfully.

An Analysis of the Relationship Between Preclinical and Clinical QT Interval-Related Data.

There has been significant focus on drug-induced QT interval prolongation caused by block of the human ether-a-go-go-related gene (hERG)-encoded potassium channel. Regulatory guidance has been implemented to assess QT interval prolongation risk: preclinical guidance requires a candidate drug's potency as a hERG channel blocker to be defined and also its effect on QT interval in a non-rodent species; clinical guidance requires a "Thorough QT Study" during development, although some QT prolonging compounds are identified earlier via a Phase I study. Clinical, heart rate-corrected QT interval (QTc) data on 24 compounds (13 positives; 11 negatives) were compared with their effect on dog QTc and the concentration of compound causing 50% inhibition (IC50) of hERG current. Concordance was assessed by calculating sensitivity and specificity across a range of decision thresholds, thus yielding receiver operating characteristic curves of sensitivity versus (1-specificity). The area under the curve of ROC curves (for which 0.5 and 1 indicate chance and perfect concordance, respectively) was used to summarize concordance. Three aspects of preclinical data were compared with the clinical outcome (receiver operating characteristic area under the curve values shown in brackets): absolute hERG IC50 (0.78); safety margin between hERG IC50 and clinical peak free plasma exposure (0.80); safety margin between QTc effects in dogs and clinical peak free plasma exposure (0.81). Positive and negative predictive values of absolute hERG IC50 indicated that from an early drug discovery perspective, low potency compounds can be progressed on the basis of a low risk of causing a QTc increase.

Abstract P4-22-10: Evaluation of the effects of palbociclib (PAL) + letrozole (LET) on QTc

Abstract Background: PAL , an oral cyclin dependent kinase (CDK) 4/6 inhibitor, is under investigation in multiple oncologic clinical trials and is currently approved for use in multiple countries in patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC). International Conference on Harmonization guidance recommends that all new drugs be evaluated for effects on cardiac repolarization in a well-controlled clinical study. For drugs for which such evaluation cannot be conducted in healthy volunteers (eg, most non-adjuvant anticancer agents), collection of robust corrected QT (QTc) interval data from a dedicated QTc study (hybrid thorough QT/QTc study) in patients [pts] is required in the registration dossier. The phase 3 PALOMA-2 study (N=666) confirmed the superior clinical benefit of PAL+LET vs placebo (P) + LET in postmenopausal women with estrogen receptor positive/HER2– ABC who have not received any prior systemic anticancer therapies for ABC. One of the secondary objectives of the study was to evaluate the effects of PAL+LET on QTc. Methods: 12 lead (with a 10 second rhythm strip) tracings were performed in triplicate ∼2 min apart but within 10 min for all 3 ECGs. On the day preceding the initiation of treatment (Day 0), triplicate ECGs were obtained at time 0, 2, 4, 6, and 8 hrs (baseline). On Cycle 1 Day 14, when PAL concentrations were at steady-state, triplicate ECGs time-matched to baseline ECGs collected on Day 0 (±35 min) were obtained following PAL or P dosing. All ECGs were sent to a central laboratory for blinded manual adjudication and these data were used for analysis. ECG measurements included PR interval, QT interval, RR interval and QRS complex. The QT interval was corrected for the effect of heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). Approximately 60 pts were to be included for QTc evaluation to ensure 40 evaluable pts in the PAL+LET arm (2:1 randomization) of PALOMA-2 and thus, to establish noninferiority between post-baseline and baseline (ΔQTc) at all 5 QTc sampling timepoints on Cycle 1 Day 14 with 90% power. The test was based on a 1-sided difference in means t test for paired ΔQTc (α= 0.05). The difference in means between ΔQTc under the alternative hypothesis is 10 ms, assuming a noninferiority margin of 20 ms and the standard deviation of the paired differences equal to 16 ms based on PALOMA-1 study. If the upper bounds (UB) of 1-sided 95% confidence intervals (CI) of ΔQTc for all 5 QTc time points were <20 ms, the post-baseline QTc will be considered noninferior to baseline and PAL+LET effect on QTc will be concluded to be not of clinical relevance. Results: A total of 77 pts were enrolled for intensive QTc assessment in PAL+LET arm. No pts had a post-baseline absolute maximum QTcF, QTcS or QTcB ≥500 ms or a ΔQTc ≥60 ms during the intensive QTc assessment period. A random effect analysis of the mean ΔQTc data demonstrated that the UB of the 1-sided 95% CI for QTcF, QTcS, and QTcB were <8 ms at all 5 QTc sampling time points. Conclusion: PAL+LET does not have a clinically relevant effect on QTc. Sponsor: Pfizer Citation Format: Ruiz A, Gauthier E, Durairaj C, Huang X, Hoffman J, Finn RS, Moulder S, Joy AA, Ettl J, Rugo HS, Wang D. Evaluation of the effects of palbociclib (PAL) + letrozole (LET) on QTc [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-10.

Population Pharmacokinetic–Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects

PurposeThe goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. MethodsThis multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic–pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. FindingsA total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration–effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin’s pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An Emax model (E[C]=[Emax⋅C]/[EC50+C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic–pharmacodynamic link model. ImplicationsThe drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316.

A Prospective Observational Study of Patients Receiving Intravenous and Intramuscular Olanzapine in the Emergency Department

Parenteral olanzapine is an emerging therapy for a variety of conditions in the emergency department (ED). Intramuscular administration is standard; however, intravenous administration has been proposed as a safe alternative route. We investigate the safety and efficacy of both intramuscular and intravenous olanzapine in the ED when used for a variety of indications. This was a prospective observational study of patients presenting to an urban Level I trauma center ED. Trained research associates screened the ED for patients receiving parenteral olanzapine. The primary outcome of the study was incidence of respiratory depression measured with standard markers. Secondary outcomes included use of additional doses or sedatives, corrected QT interval (QTc) data, time to nadir sedation, adverse events, and physician assessment of efficacy. There were 784 patients included in the final analysis. Intravenous olanzapine was administered to 295 patients; 489 received intramuscular olanzapine. Respiratory depression occurred in 11 of 295 patients (3.7%; 95% confidence interval [CI] 1.6% to 5.9%) receiving intravenous olanzapine and 10 of 489 (2.0%; 95% CI 0.8% to 3.3%) receiving intramuscular olanzapine. Seven patients required intubation, 2 in the intravenous group and 5 in the intramuscular group. Nonrespiratory complications occurred in 8 patients, 6 of 295 (2.0%; 95% CI 0.4% to 3.6%) in the intravenous group and 2 of 489 (0.4%; 95% CI 0% to 0.96%) in the intramuscular group. Dysrhythmias were isolated to 2 episodes of bradycardia requiring only supportive care. These data suggest that, with proper monitoring, administration of olanzapine, both intramuscular and intravenous, is safe for several indications in the ED.

Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects.

A randomized, partial‐blind, repeat‐dose, 3‐period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open‐label 400‐mg dose of the positive control moxifloxacin, with a 21‐day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day ‐1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3‐fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2‐sided 90% confidence intervals for ΔΔQTcF (difference in time‐matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization.

Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance.

Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The Health and Environmental Sciences Institute Pro-Arrhythmia Working Group performed a literature search (1960–2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes.

A Retrospective Naturalistic Study of Ziprasidone for Irritability in Youth with Autism Spectrum Disorder.

The purpose of this study was to assess the impact of ziprasidone monoantipsychotic treatment targeting irritability in a naturalistic outpatient autism spectrum disorder (ASD) clinical setting. We examined the use of ziprasidone, predominantly in combination with other psychotropic agents, targeting irritability in 42 youth with ASD in a large ASD-specific treatment database. Mean age at start of treatment, treatment duration, final dose, body mass index (BMI), BMI Z score, and Clinical Global Impressions-Improvement Scale (CGI-I) score at final visit were determined, and changes with treatment were analyzed using paired t tests. Cardiac corrected QT (QTc) interval data were extracted from electrocardiograms when available. Mean age at start of treatment was 11.8 years. And final mean dose of ziprasidone was 98.7 mg/day or 1.7 mg/kg/day. Seventeen (40%) participants were considered treatment responders based on the CGI-I. No changes in QTc (although only examined in nine participants), weight, BMI, or other vital signs were noted, with ziprasidone use. The rate of treatment response was less than what has been reported for the two atypical antipsychotics, risperidone and aripiprazole, approved by the Food and Drug Administration (FDA) for the treatment of irritability in autistic disorder. The response rate with ziprasidone may be more consistent with response rates for other atypical antipsychotics, although none of these agents has been studied in larger-scale double-blind, placebo-controlled trials. The lower rate of response to ziprasidone in this open-label trial is likely influenced by the treatment-refractory nature of the population studied. The weight neutrality of ziprasidone appears favorable compared with other second generation antipsychotics in this population. The response rate to ziprasidone targeting irritability may be lower than response rates associated with FDA-approved agents for this indication. Overall, ziprasidone use appeared well tolerated in youth with ASD.

Lack of effect of perampanel on QT interval duration: Results from a thorough QT analysis and pooled partial seizure Phase III clinical trials

IntroductionPerampanel is a selective, noncompetitive AMPA receptor antagonist approved as adjunctive treatment for partial seizures. To assess potential for delayed cardiac repolarization, a Phase I thorough QT study was performed, supplemented by plasma concentration–QT data modeled from 3 pooled Phase III studies. MethodsThe Phase I thorough QT study (double-blind, combined fixed-sequence, parallel-group) quantified the effect of perampanel (6mg once daily for 7 days, followed by dose escalation to a single 8-mg dose, a single 10-mg dose, then 12mg once daily for 7 days), moxifloxacin positive control (single 400-mg dose on Day 16), and placebo on QT interval duration in healthy subjects (N=261). Electrocardiograms were recorded at baseline, Day 7 (post 6mg dose), and Day 16 (post 12mg dose). Statistical comparisons were between the highest approved perampanel dose (12mg) versus placebo, a “mid-therapeutic” dose (6mg) versus placebo, and moxifloxacin versus placebo. Acknowledging that the Phase I thorough QT study could not incorporate a true “supratherapeutic” dose due to length of titration and tolerability concerns in healthy subjects, Phase III studies of perampanel included expanded electrocardiogram safety evaluations specifically intended to support concentration–QT response modeling. The lack of effect of perampanel on the QT interval is shown from pooled analysis of 3 double-blind, placebo-controlled, 19-week, Phase III studies with perampanel doses ≤12mg (N=1038, total perampanel; and N=442, placebo) in patients with partial seizures. QT measures were corrected for heart rate using Fridericia's (QTcF; the primary endpoint) and Bazett's (QTcB) formulas. ResultsIn the Phase I thorough QT study, the positive control moxifloxacin caused peak time-matched, baseline-adjusted, placebo-corrected (ΔΔ) QTcF of 12.15ms at 4h postdose, confirming a drug effect on QTc interval and study assessment sensitivity. Mean baseline-adjusted (Δ) QTcF versus nominal time curves were comparable between perampanel 12mg and placebo, with most ΔQTcF values being slightly negative. Healthy subjects receiving perampanel 6 and 12mg doses for 7 days showed no evidence of effects on cardiac repolarization. Peak ΔΔQTcF was 2.34ms at 1.5h postdose for perampanel 6mg and 3.92ms at 0.5h postdose for perampanel 12mg. At every time point, the upper 95% confidence limit of ΔΔQTcF for perampanel 6 and 12mg was <10ms. Phase III studies revealed no clinically significant difference between patients with partial seizures treated with perampanel or placebo in QTcF and QTcB values >450ms, with no dose-dependent increases or large incremental changes from baseline of >60ms. Regression analysis of individual plasma perampanel concentrations versus corresponding QTc interval values in Phase I thorough QT and Phase III studies demonstrated no relationship between perampanel concentrations and QT interval duration. ConclusionTreatment with perampanel 6mg and 12mg for 7 days did not delay cardiac repolarization in healthy volunteers. In a population analysis of 1480 patients with partial seizures treated with perampanel doses ≤12mg or placebo, no clinically significant trends in QT interval data were noted. Based on the thorough QT study and evaluations from pooled Phase III studies, there is no evidence of prolonged QT interval duration with perampanel treatment.

On comparison of SAS codes with GLM and MIXED for the crossover studies with QT interval data

The structural complexity of crossover studies for bioequivalence test confuses analysts and leaves them a hard choice among various programs. Our study reviews PROC GLM and PROC MIXED in SAS and compares widely used SAS codes for crossover studies. PROC MIXED based on REML is more recommended since it provides best linear unbiased estimator of the random between-subject effects and its variance. Our study also considers the covariance structure within subject over period which most PK/PD studies and crossover studies ignore. The QT interval data after the administra tion of moxifloxacin for a fixed time point are analyzed for the comparison of representative SAS codes for crossover studies.

Lenalidomide at Therapeutic and Supratherapeutic Doses Does Not Prolong QTc Intervals in the Thorough QTc Study Conducted in Healthy Men

The effect of lenalidomide on the corrected QT (QTc) interval was evaluated in healthy men and extended to patients based on the lenalidomide concentration–QTc (C–QTc) relationship. A rigorous assessment of the effect of lenalidomide on QTc intervals was conducted in healthy volunteers who each received, in randomized order, a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control) and placebo. Plasma lenalidomide exposure was compared between healthy volunteers and patients with multiple myeloma or myelodysplastic syndromes. In healthy volunteers, moxifloxacin produced the expected significant prolongation in QTcI (individual correction). For lenalidomide 10 mg and 50 mg, the time-matched changes from placebo in the baseline-adjusted least-squares mean QTcI were <3 ms with the upper limit of the two-sided 90% confidence interval for the change <10 ms at all time-points. No subjects experienced QTcI >450 ms or change from baseline >60 ms after lenalidomide administration. Similar results were seen with QT interval data corrected by Fridericia and Bazett methods. The C–QTc analysis yielded no significant association between lenalidomide concentrations and QTcI changes up to 1522 ng/mL; this range was close to that observed in patients receiving lenalidomide doses up to 50 mg, including those with reduced drug clearance due to renal impairment. In conclusion, single doses of lenalidomide up to 50 mg were not associated with prolonged QTc intervals in healthy males. The C–QTc analysis further assured that lenalidomide doses up to 50 mg are not expected to prolong QTc intervals in patients.

Perioperative Torsade de Pointes

Torsade de pointes is a rare but potentially fatal arrhythmia. More than 40 cases of perioperative torsade de pointes have been reported in the literature; however, the current evidence regarding this complication is very limited. To improve our understanding, we performed a systematic review and meta-analysis of all published case reports of perioperative torsade de pointes. MEDLINE was systematically searched for cases of perioperative torsade de pointes. We included patients of all age groups and cases that occurred from the immediate preoperative period to the third postoperative day. Patient and case characteristics as well as QT interval data were extracted. Forty-six cases of perioperative torsade de pointes were identified; 29 occurred in women (67%), and 2 episodes were fatal (case fatality rate: 4%). Craniotomies and cardiac surgery accounted for 40% of all cases. Preceding events identified by the authors were hypokalemia (12/46, 26%; 99% confidence interval [CI], 9%-43%) and bradycardia (7/46, 15%; 99% CI, 2%-28%). Drugs were implicated in approximately one third of the events (14/46, 30%; 99% CI, 13%-48%). The mean corrected QT (QTc) at baseline was 457 ± 67 milliseconds (minimum 320 milliseconds; maximum 647 milliseconds; data available in 27/46 patients). At the time of the event, the mean QTc increased to 575 ± 77 milliseconds (minimum 413 milliseconds; maximum 766 milliseconds; data available in 33/46 patients). On average, QTc increased by +118 milliseconds (99% CI, 70-166 milliseconds; P < 0.001) between baseline and after the torsade de pointes event. All patients, except for 2, had a substantial prolongation of their QTc interval at the time of the event. This systematic review identified several common risk factors for perioperative torsade de pointes. Given the nearly uniform presence of a substantial QTc interval prolongation at the time of a torsade de pointes episode, increased vigilance for perioperative QTc interval prolongation may be warranted.

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.

Automated versus Manual Measurement of the QT Interval and Corrected QT Interval

The International Conference on Harmonization E14 Guideline specifies detailed assessment of QT interval or corrected QT interval prolongation when developing new drugs. We recently devised new software to precisely measure the QT interval. The QT intervals of all leads for a selected single heart beat were compared between automated measurement with the new software from Fukuda Denshi and manual measurement. With both automated and manual measurement, QT intervals obtained by the tangent method were shorter than those obtained by the differential threshold method, but the extent of correction was smaller. QT interval data obtained by the differential threshold method were more similar to values obtained by visual measurement than were data obtained by the tangent method, but the extent of correction was larger. Variability was related to the T-wave amplitude and to setting the baseline and tangent in the tangent method, while skeletal muscle potential noise affected the differential threshold method. Drift, low-amplitude recordings, and T-wave morphology were problems for both methods. Among the 12 leads, corrections were less frequent for leads II and V(3) -V(6) . We conclude that, for a thorough assessment of the QT/QTc interval, the tangent method or the differential threshold method appears to be suitable because of smaller interreader differences and better reproducibility. Correction of data should be done by readers who are experienced in measuring the QT interval. It is also important for electrocardiograms to have little noise and for a suitable heart rate and appropriate leads to be selected.

Statistical models for heart rate correction of the QT interval

The analysis of QT interval data is now an essential part of the assessment of drug safety. As the QT interval is inversely associated with heart rate, an appropriate correction must be applied in order to evaluate QT data in clinical trials. The aim is to characterize changes in QT interval at a standard heart rate, taking into account the correlation between these two variables to adjust for heart rate changes during the course of the trial. It has been shown that the relationship between the RR interval (=1/heart rate) and the QT interval is highly variable between individuals but stable over time within each individual.Many mathematical models have been developed to describe the QT-RR relationship. However, there has been less emphasis on the derivation of suitable statistical models that account for the multilevel structure of the ECG data.An important example is the interpretation of the so-called population-specific heart rate corrections, which are based on data pooled from different subjects. Often, simple regression techniques are used to quantify the population correction, disregarding the subject level and leading to biased parameter estimates. Instead, population-based corrections that account for individual intercepts should be used, in order to distinguish within-subject-effects from between-subject effects. Therefore, population-specific corrections cannot be derived solely from the cross-sectional data. The impact of the different statistical models is illustrated by data from the baseline periods of six clinical QT studies.

Benchmarking Safety Pharmacology regulatory packages and best practice

Introduction The objectives of this survey were to obtain a global information update regarding current industry perspectives that describe Safety Pharmacology programs as they relate to the ICH S7A and S7B regulatory guidelines but also to obtain a broader perspective of other practises practices in the field currently used by companies. Preliminary findings were presented at the 7th Annual Meeting of the Safety Pharmacology Society (SPS) (Edinburgh, Scotland, Sept 19–21, 2007). Methods The survey was distributed by the SPS to 125 pharmaceutical companies. Survey topics included (a) an update on ICH S7A and S7B practices, (b) frontloading Safety Pharmacology studies prior to selection of candidate drugs, (c) abuse and dependence-liability studies and (d) an extended evaluation of industry practises practices as assessed by Contract Research Organizations (CROs). Results Respondents (> 94%) include GLP core battery (CV, CNS and respiratory) studies in the drug package submitted to regulatory agencies, and ∼ 40% also submit studies on gastrointestinal and renal function. Respondents to the ICH S7B aspects indicate ∼ 98% include the hERG assay and QT interval (in vivo) data in submissions, 63% include APD in vitro data and another 23% APD in vivo and other cardiac channel data (26%). SP frontloading is performed by 78% of all responding companies. Respondents indicate that 39% of these non-GLP CV studies are conducted before lead optimization (LO) and 85% during LO and before candidate drug selection. The hERG, CNS selectivity binding screens and rodent behavioral studies are frontloaded by 100%, 90% and 74% of respondents. Responding CROs (26) were surveyed on the services offered including Irwin or Functional Observational Battery (FOB) tests (70%), respiratory studies (85%), in vivo telemeterized dogs (69%) and in vitro CV studies (50%). Only 38% of SP studies are combined with toxicology studies at the CROs. Discussion The survey results indicate that ICH S7A core battery studies are implemented by most of the responding companies with a clear trend of an enhanced submission of renal and GI studies. The impact of ICH S7B is clear since, all respondents assess cardiac repolarization using cellular hERG ( I Kr) and whole animal (QT interval) assays as a component of their safety assessment. Responses indicate a diversity of approaches for conducting abuse liability studies, which primarily use the methods of self-administration and drug discrimination. While early SP frontloading of studies seems to vary, the methods used appear to be generic to some extent and include in vitro ‘off-target’ evaluations and in vivo tests to determine the potential for CNS and cardiovascular issues.