Holzgrefe Henry H, Cavero Icilio, Buchanan Lewis V, Gill Michael W, Durham Stephen K
Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, NY 13221-4755, USA.
J Pharmacol Toxicol Methods. 2007 May-Jun;55(3):227-37. doi: 10.1016/j.vascn.2006.09.002. Epub 2006 Sep 15.
Moxifloxacin is the most widely used positive reference agent in clinical cardiac repolarization safety studies, but it has not been characterized in the cynomolgus monkey. This important experimental animal species exhibits pronounced heart rate variability, complicating the temporal evaluation of QT interval data.
Digitized epicardial ECGs and aortic blood pressures were collected for 20 h in telemetered cynomolgus monkeys (n=6) following the administration of either vehicle or moxifloxacin (10 or 50 mg/kg, p.o.). Moxifloxacin plasma concentrations were determined 4 h postdose. ECG intervals were analyzed by computerized algorithms. Individual probabilistic QT rate-corrections (QTc) were derived from the slopes of predose log-transformed QT-RR data where each QT value was the mean of >250 beats/RR increment. The resulting QTc was used to determine the repolarization effects of moxifloxacin, expressed as the placebo-adjusted change in QTc (DeltaQTc), and as the integrated response from 0 to 12 h (AUC(0-->12)) postdose.
No DeltaQTc effect was produced by 10 mg/kg moxifloxacin. However, moxifloxacin (50 mg/kg; 5.86+/-0.5 microg/mL C(max)) significantly prolonged the RR interval by 50 to 112 ms from 3.5 to 7.5 h postdose and DeltaQTc by >or=7.2 ms from 1.83 to 9.17 h, with a maximal DeltaQTc effect of +26.4 ms. No notable effects on either systemic blood pressure or body temperature occurred with either dose.
Probabilistic QT rate-corrections appear to have eliminated the confounding effects of heart rate, provided for a stable QTc baseline, and enabled the demonstration of an exposure-dependent QTc prolongation by moxifloxacin. The duration and magnitude of the QTc effect paralleled moxifloxacin pharmacokinetics, and C(max) values were similar to those achieved clinically in thorough QT/QTc studies. Thus, novel probabilistic QT rate-corrections may offer highly robust assessments of repolarization risk in both nonclinical and clinical investigations.
莫西沙星是临床心脏复极化安全性研究中使用最广泛的阳性对照药，但尚未在食蟹猴中进行特性研究。这种重要的实验动物物种表现出明显的心率变异性，使得QT间期数据的时间评估变得复杂。
给遥测食蟹猴（n = 6）口服赋形剂或莫西沙星（10或50 mg/kg）后，收集20小时的数字化心外膜心电图和主动脉血压。给药后4小时测定莫西沙星血浆浓度。通过计算机算法分析心电图间期。个体概率性QT心率校正值（QTc）由给药前对数转换后的QT-RR数据的斜率得出，其中每个QT值是>250次心跳/RR增量的平均值。所得QTc用于确定莫西沙星的复极化效应，以QTc的安慰剂校正变化（DeltaQTc）表示，并以给药后0至12小时的综合反应（AUC(0→12)）表示。
10 mg/kg莫西沙星未产生DeltaQTc效应。然而，莫西沙星（50 mg/kg；C(max)为5.86±0.5 μg/mL）给药后3.5至7.5小时使RR间期显著延长50至112 ms，给药后1.83至9.17小时使DeltaQTc延长≥7.2 ms，最大DeltaQTc效应为+26.4 ms。两种剂量对全身血压或体温均无明显影响。
概率性QT心率校正似乎消除了心率的混杂效应，提供了稳定的QTc基线，并能够证明莫西沙星引起的暴露依赖性QTc延长。QTc效应的持续时间和幅度与莫西沙星的药代动力学平行，C(max)值与全面的QT/QTc研究中临床达到的值相似。因此，新的概率性QT心率校正可能在非临床和临床研究中对复极化风险提供高度可靠的评估。
