Assessment of QTc-prolonging potential of BX471 in healthy volunteers. A 'thorough QTc study' following ICH E14 using various QT correction methods

AIMS

Within the framework of the clinical development of BX471, this study was intended to provide experience in conducting ‘thorough QT_c studies’ according to ICH E14. A broad range of QT correction methods and analysis strategies was employed.

METHODS

A double-blind, placebo- and positive-controlled, single-centre, three-way cross-over study was conducted in 74 healthy volunteers. Electrocardiograms were read by blinded experts. QT correction methods included Bazett''s (QT_cB), Fridericia''s (QT_cF) and several regression-based corrections.

RESULTS

There was a significant QT_cF prolongation of 10.26 ms by the positive control compared with placebo [95% confidence interval (7.83, 12.70)]. BX471 at therapeutic doses did not cause substantial QT_c prolongation [QT_cF estimate 2.93 ms, 95% confidence interval (1.00, 4.86); QT_cB estimate 3.30 ms, 95% confidence interval (0.85, 5.74)]. Regression-based QT correction methods yielded similar results to Fridericia''s correction [e.g. using a linear regression across the study population, QT_c estimate 2.39 ms, 95% confidence interval (0.55, 4.23)]. Differences between the various regression-based correction methods were small. Results were not affected by whether the QT corrections were performed per ECG or per beat.

CONCLUSIONS

BX471 does not cause meaningful QT_c prolongation. Three QT correction methods may be sufficient in future studies: Bazett''s (required by regulatory authorities), Fridericia''s (as the most reliable fixed formula) and a regression-based correction (individually or population-based), each performed per ECG (i.e. applied to the means of several beats of one ECG recording).     

Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects

Aims

Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QT_c) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QT_c.

Methods

Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction.

Results

Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml⁻¹, 399 ± 11.9 pg ml⁻¹ and 627 ± 21.2 pg ml⁻¹). QT_cP, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QT_cP (ΔΔQT_cP) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml⁻¹ (ΔΔQT_cP^avg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQT_cP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin.

Conclusions

These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QT_c and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.     

Sertindole: efficacy and safety in schizophrenia

The most commonly prescribed class of medications in the United States for chronic severe pain is opioid analgesics. Due to their low cost and widespread availability, the synthetic opioids are popular choices among clinicians and patients. However, there is an increasingly recognized risk of QT prolongation with several drugs in this class, and recently propoxyphene (Darvon) was withdrawn from the market by the Food and Drug Administration (FDA) due to, in part, the risk of QT prolongation and ventricular arrhythmias Updated Epidemiological Review of Propoxyphene Safety. [FDA Alert]. Rockville, MD: U.S. Food and Drug Administration; 2010. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM234383.pdf on 5 May 2012.     

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/RR^1/3) 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.     

The effect of sertindole on QTD and TPTE

Nielsen J, Andersen MP, Graff C, Kanters JK, Hardahl T, Dybbro J, Struijk JJ, Meyer JM, Toft E. The effect of sertindole on QTD and TPTE. Objective: Recent research suggests that other surrogate markers than QTc, including QTc dispersion and Tpeak‐Tend, may better correlate with cardiac arrhythmia risk. While sertindole significantly prolongs the QTc interval, the effects on other markers of arrhythmia risk, such as QTc dispersion and Tpeak‐Tend are unknown. Method: Digital 12‐lead ECG was recorded at baseline and at steady‐state in 37 patients switched to sertindole. ECG was analysed for Fridericia‐corrected QT duration (QTcF), QT dispersion and Tpeak‐Tend. Results: From a baseline QTcF of 407 ± 22 ms, mean QTcF prolongation during sertindole treatment was 20 ± 23 ms, P < 0.01. No effect on QTc dispersion was found (?1 ± 11 ms; P = 0.41). No increased duration of the Tpeak‐Tend interval from baseline was found (+7 ± 21 ms; P = 0.05). Conclusion: These findings might be related to the absence of confirmed Torsade de Pointes (TdP) cases related to sertindole exposure, despite sertindole’s QTc prolonging effects.     

Systematic decrements in QTc between the first and second day of contiguous daily ECG recordings under controlled conditions

Background: Many thorough QT (TQT) studies use a baseline day and double delta analysis to account for potential diurnal variation in QTc. However, little is known about systematic changes in the QTc across contiguous days when normal volunteers are brought into a controlled inpatient environment. Methods: Two separate crossover TQT studies included 2 days of no treatment lead‐in days with ECG collection preceding periods of drug treatment . In the first study, there were two pairs of such contiguous days with 10 replicate electrocardiograms (ECGs) collected at six time points, and in the second study, there were four pairs of contiguous days with nine replicate ECGs collected at five time points. These lead‐in day pairs provided the opportunity to evaluate any systematic changes across contiguous first and second days of an inpatient environment. Within‐patient consistency of change across pairs of days as well as within day, diurnal variation could also be evaluated. Results: Modest (4.2 ms [range 1.9–6.5 ms]) but consistent decreases (significant [P < 0.05] for all 32 comparisons) were observed (probability: ≤5.4 × 10^?16). Although group behavior with respect to QTc was consistent, individual subjects demonstrated substantial variability across pairs of days. Evidence of diurnal variation was weak and inconsistent. Magnitude of any diurnal variation was less than magnitude of change across days. Conclusions: Subjects show a systematic decrease in QTc from first day to second day of inpatient status and do not demonstrate a significant diurnal pattern. The magnitude of this systematic change is sufficient to influence QTc study interpretation. (PACE 2011; 34:1116–1127)     

抗精神病药致首发精神疾病QTc 间期变化的相关 因素分析

目的 调查抗精神病药致首发精神疾病QTc间期延长的影响因素.方法 对服用稳定剂量抗精神病药治疗1月的309例首发精神疾病患者进行回顾性调查,收集人口学资料、空腹血糖、血压、血脂等生化指标、心电图资料,以QTc≥440ms作为QTc间期延长的标准,分析QTc间期延长的状况及其相关因素.结果 QTc间期延长的发生率为10.6%.药物治疗组QTc间期均值大于基线期,差异有统计学意义(P<0.05);药物联合电休克治疗组以及药物联合脑电治疗组QTc间期与基线期相比,差异无统计学意义(P>0.05).单一抗精神病药治疗组QTc间期与基线期差异无统计学意义(P>0.05);而抗精神病药联用以及抗精神病药联用抗抑郁药/心境稳定剂组QTc间期均值大于基线期,差异有统计学意义(P<0.05).抗精神病药等效氯丙嗪剂量<1000mg/d组别QTc间期与基线期相比差异有统计学意义(P<0.05).抗精神病药剂量与QTc间期没有相关性.女性是QTc间期延长的风险因素(OR=3.26,95%CI=1.050~10.094),其他因素未进入回归方程.结论 首发精神疾病患者抗精神病药治疗期间QTc间期延长存在性别差异,女性发生QTc间期延长的风险是男性的3.26倍.药物联用延长的QTc间期并未达到异常值.抗精神病药剂量与QTc间期没有相关性.除了性别因素外,其他指标不是QTc间期延长的风险因素.     

老年人睡眠质量及睡眠时长与动态心电图校正的QT间期的关联分析

背景　睡眠对于维持人体健康至关重要,睡眠质量和睡眠时长与多种疾病发生相关。既往职业人群研究表明,睡眠剥夺与QT间期延长相关。但关于一般人群中睡眠质量、睡眠时长与校正的QT间期（QTc）关联的研究较少。目的　探讨中国老年人群睡眠质量及睡眠时长与QTc的关联。方法　选取2017年11-12月如皋市长寿和衰老队列（RuLAS）的睡眠和心电图数据,并根据匹兹堡睡眠质量指数量表（PSQI）评分将老年人分为睡眠正常组（n=776）、睡眠质量轻度下降组（n=214例）、睡眠质量下降组（n=152例）;通过静息心电图（ECG）仪的解读程序收集ECG参数〔QTc、心率（HR）、P波、QRS间期、PR间期、V5导联的R波（RV5）、V1导联的S波（SV1）〕。采用多重线性回归分析探讨PSQI评分与QTc的影响因素。结果　老年人PSQI评分为（4.6±2.6）分,夜间睡眠时长为（9.2±1.8）h。3组间性别、受教育程度、饮酒情况、糖尿病患病情况、认知功能评分、体力活动评分、QTc、RV5比较,差异均有统计学意义（P<0.05）。校正多种混杂因素后,多重线性回归分析显示,PSQI评分〔β=1.63,95%CI（0.23,3.04）,P=0.023〕,≤6 h〔β=21.22,95%CI（6.28,36.16）,P=0.005〕的睡眠时长、>10 h〔β=8.81,95%CI（0.24,17.39）,P=0.044〕的睡眠时长是QTc的影响因素。结论　中国老年人群睡眠质量差、睡眠时长过长或过短与QTc相关,提示睡眠质量及时长可能是QTc的影响因素之一,改善睡眠可能预防QTc延长,从而预防心源性死亡。