Abstract：
Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia\'s formula (ΔQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice-monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.
摘要：
Cofrogliptin（HSK7653）是一种长效二肽基肽酶-4抑制剂，用于每月两次给药方案治疗2型糖尿病。这项研究包括62名参与者(48名无食物效应，14具有食物效应）接受单剂量的HSK7653（5、10、25、50、100和150mg）或安慰剂。在给药后24小时内收集药代动力学样品,并且将采样时间与源自连续ECG记录的12导联心电图(ECG)对齐。对于校正心率的浓度-QT间期（C-QTc）分析，我们使用线性混合效应模型来表征HSK7653血浆浓度与QT间期自基线的变化之间的相关性，该变化由Fridericia公式（ΔQTcF）校正。结果表明，在平均最大观察浓度（Cmax）（411ng/mL）与推荐治疗剂量（每月两次25mg）相关的情况下，安慰剂校正的Fridericia校正的QT间期（ΔQTcF）延长不可能超过10毫秒，即使在最高的治疗浓度（2425ng/mL）。因此，HSK7653在推荐剂量或最高超治疗浓度下都不会显着影响QT延长。
