Malik Marek, Hnatkova Katerina, Ford John, Madge David
St Paul's Cardiac Electrophysiology, London, England.
J Clin Pharmacol. 2008 Oct;48(10):1146-57. doi: 10.1177/0091270008323261. Epub 2008 Aug 29.
Detailed electrocardiographic (ECG) support was provided to a first-in-man, single-ascending-dose study that included 6 cohorts of 8 male volunteers each. In each cohort, 6 and 2 subjects received active compound and placebo, respectively. Long-term 12-lead ECGs were obtained on baseline day -1, dosing day 1, and day 2. Automatic QT-interval measurements were made at 63 time points (28 at baseline and 35 on treatment). Based on QT/RR distribution, 20% of measurements were visually verified. Baseline-corrected time-matched DeltaQTc values were obtained at 35 postdose time points. Placebo subjects of all cohorts were pooled. When 2 cohorts of the lowest, middle, and highest doses were pooled (12 subjects per active treatment group), the spreads of placebo-corrected DeltaDeltaQTc values were within the regulatory requirements (single-sided 95% confidence interval <10 milliseconds) at all time points. Thus, this ECG support of the first-in-man study provided data of regulatory acceptable accuracy at a small fraction of the cost of a full thorough QT study.
为一项首次人体单剂量递增研究提供了详细的心电图（ECG）支持，该研究包括6个队列，每个队列有8名男性志愿者。在每个队列中，分别有6名和2名受试者接受活性化合物和安慰剂。在基线第-1天、给药第1天和第2天获得长期12导联心电图。在63个时间点进行自动QT间期测量（基线时28个，治疗时35个）。根据QT/RR分布，20%的测量值进行了目视验证。在给药后35个时间点获得基线校正的时间匹配DeltaQTc值。将所有队列的安慰剂受试者合并。当将最低、中等和最高剂量的2个队列合并时（每个活性治疗组12名受试者），在所有时间点，安慰剂校正的DeltaDeltaQTc值的离散度均在监管要求范围内（单侧95%置信区间<10毫秒）。因此，这项首次人体研究的心电图支持以全面彻底QT研究成本的一小部分提供了监管可接受准确性的数据。
