Komatsu Ryuichi, Mizuno Hiroshi, Ishizaka Tomomichi, Ito Akihito, Jikuzono Tatsuya, Kakoi Tadashi, Bando Masahiro, Koga Tadashi, Handa Jun, Takahashi Yukio, Kanno Akihiro, Ozaki Harushige, Chiba Katsuyoshi
Fuji Gotemba Research Laboratory, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, Japan.
J Pharmacol Toxicol Methods. 2019 Sep-Oct;99:106606. doi: 10.1016/j.vascn.2019.106606. Epub 2019 Jun 27.
The preclinical in vivo assay for QT prolongation is critical for predicting torsadogenic risk, but still difficult to extrapolate to humans. This study ran preclinical tests in cynomolgus monkeys on seven QT reference drugs containing the drugs used in the IQ-CSRC clinical trial and applied exposure-response (ER) analysis to the data to investigate the potential for translational information on the QT effect.
In each of six participating facilities in the J-ICET project, telemetered monkeys were monitored for 24 h following administration of vehicle or 3 doses of test drugs, and pharmacokinetic profiles at the same doses were evaluated separately. An individual rate-corrected QT interval (QTca) was derived and the vehicle-adjusted change in QTca from baseline (∆∆QTca) was calculated. Then the relationship of concentration to QT effect was evaluated by ER analysis.
For QT-positive drugs in the IQ-CSRC study (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and levofloxacin, the slope of the total concentration-QTca effect was significantly positive, and the QT-prolonging effect, taken as the upper bound of the confidence interval for predicted ∆∆QTca, was confirmed to exceed 10 ms. The ER slope of the negative drug levocetirizine was not significantly positive and the QTca effect was below 10 ms at observed peak exposure.
Preclinical QT assessment in cynomolgus monkeys combined with ER analysis could identify the small QT effect induced by several QT drugs consistently with the outcomes in humans. Thus, the ER method should be regarded as useful for translational prediction of QT effects in humans.
QT间期延长的临床前体内试验对于预测致心律失常风险至关重要，但仍难以外推至人类。本研究在食蟹猴身上对七种QT参考药物进行了临床前测试，这些药物包括IQ-CSRC临床试验中使用的药物，并对数据应用暴露-反应（ER）分析，以研究QT效应的转化信息潜力。
在J-ICET项目的六个参与机构中，对植入遥测设备的猴子在给予赋形剂或3剂受试药物后进行24小时监测，并分别评估相同剂量下的药代动力学特征。得出个体心率校正QT间期（QTca），并计算相对于基线的赋形剂校正QTca变化（∆∆QTca）。然后通过ER分析评估浓度与QT效应的关系。
对于IQ-CSRC研究中的QT阳性药物（多非利特、多拉司琼、莫西沙星、昂丹司琼和奎宁）以及左氧氟沙星，总浓度-QTca效应的斜率显著为正，并且QT延长效应（作为预测∆∆QTca置信区间的上限）经确认超过10毫秒。阴性药物左西替利嗪的ER斜率无显著正值，且在观察到的峰值暴露时QTca效应低于10毫秒。
食蟹猴的临床前QT评估结合ER分析能够一致地识别几种QT药物诱导的小QT效应，与人类结果相符。因此，ER方法应被视为对人类QT效应进行转化预测的有用方法。
