Hnatkova Katerina, Kowalski Donna, Keirns James J, van Gelderen E Marcel, Malik Marek
Imperial College, London, England.
Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Global Development Inc., Northbrook, IL, USA.
J Electrocardiol. 2015 Mar-Apr;48(2):194-202. doi: 10.1016/j.jelectrocard.2015.01.006. Epub 2015 Jan 8.
Detection of QTc decreases after meal intake was proposed as a possible proof of assay sensitivity in studies of drug-induced QTc changes. However, day-to-day reproducibility of QTc decreases after meal intake has not been established.
Holter recordings were available from 4 different baseline drug-free days of a thorough QT study in 157 females and 164 males. During each of the baselines, subjects were fasting in the morning and were served standardized lunch. Heart rates and QTc intervals were measured during repeated time-points throughout each study day. Two investigations were performed. In the first investigation, 3 heart rate and QTc measurements 1, 2, and 3h after lunch were averaged in each subject and corrected for the morning fasting baseline. Reproducibility of heart rate and QTc changes after the meal on different days X and Y was assessed by normalized repeatability coefficients 2*|MX-MY|/|MX+MY|, where MX and MY are measurements in the same subject on days X and Y, respectively. These were compared for heart rate and QTc changes after meal for different pairs of baseline days. In the second investigation, 36 females and 41 males were considered who received moxifloxacin during the source thorough QT study. The QTc increases after moxifloxacin were expressed by averaging 3 time-point values and corrected for placebo QTc values measured 25days apart. In the same subjects, QTc readings after lunch were also corrected for fasting baseline readings 25days apart. QTc responses to moxifloxacin and to meal intake were compared.
Repeatability of QTc decreases after meal was significantly (p<0.0000001) poorer than that of heart rate increases after meal. Of the subjects receiving moxifloxacin during the study, 6% did not show QTc prolongation on moxifloxacin while 39% have not shown QTc shortening after lunch (p<0.00001).
The reproducibility of QTc changes after meal is limited. The power of proving QTc assay sensitivity by the detection of QTc changes after meal is poorer than the power of the standard moxifloxacin-based assay sensitivity.
在药物诱导的QTc变化研究中，进食后QTc降低的检测被认为是检测方法敏感性的一个可能证据。然而，进食后QTc降低的每日可重复性尚未得到证实。
在一项针对157名女性和164名男性的全面QT研究中，有来自4个不同无药物基线日的动态心电图记录。在每个基线期，受试者早晨禁食，然后食用标准化午餐。在每个研究日的多个重复时间点测量心率和QTc间期。进行了两项研究。在第一项研究中，对每位受试者午餐后1、2和3小时的3次心率和QTc测量值进行平均，并根据早晨禁食基线进行校正。通过标准化重复性系数2*|MX-MY|/|MX+MY|评估不同日期X和Y餐后心率和QTc变化的可重复性，其中MX和MY分别是同一受试者在X和Y日的测量值。比较不同基线日配对餐后心率和QTc变化的重复性系数。在第二项研究中，纳入了在源全面QT研究期间接受莫西沙星治疗的36名女性和41名男性。莫西沙星后的QTc增加通过平均3个时间点的值来表示，并根据相隔25天测量的安慰剂QTc值进行校正。在同一受试者中，午餐后的QTc读数也根据相隔25天的禁食基线读数进行校正。比较QTc对莫西沙星和进食的反应。
餐后QTc降低的可重复性显著（p<0.0000001）低于餐后心率增加的可重复性。在研究期间接受莫西沙星治疗的受试者中，6%在服用莫西沙星时未出现QTc延长，而39%在午餐后未出现QTc缩短（p<0.00001）。
餐后QTc变化的可重复性有限。通过检测餐后QTc变化来证明QTc检测方法敏感性的能力低于基于标准莫西沙星的检测方法敏感性。
