Darpo B, Benson C, Dota C, Ferber G, Garnett C, Green C L, Jarugula V, Johannesen L, Keirns J, Krudys K, Liu J, Ortemann-Renon C, Riley S, Sarapa N, Smith B, Stoltz R R, Zhou M, Stockbridge N
Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden; iCardiac Technologies, Rochester, New York, USA.
Clin Pharmacol Ther. 2015 Apr;97(4):326-35. doi: 10.1002/cpt.60.
The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.
测试了五种“QT阳性”药物和一种阴性药物的QT效应，以评估暴露-反应分析是否能在一项针对健康受试者的小型研究中检测到QT效应。每种药物以两种剂量水平给予9名受试者（6名服用安慰剂）；选择阳性药物以使QTcF延长10至12毫秒和15至20毫秒。昂丹司琼、奎宁、多拉司琼、莫西沙星和多非利特的浓度/ΔQTc效应斜率显著为正。对于较低剂量，不能排除超过10毫秒的效应，即预测平均ΔΔQTcF效应的置信区间上限高于10毫秒。对于阴性药物左西替利嗪，在治疗剂量的6倍时排除了超过10毫秒的ΔΔQTcF效应。该研究提供了证据表明，早期临床研究中可靠的QT评估可以取代全面的QT研究。
