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Concentration-response modeling of ECG data from early-phase clinical studies to assess QT prolongation risk of contezolid (MRX-I), an oxazolidinone antibacterial agent.
Journal of Pharmacokinetics and Pharmacodynamics ( IF 2.2 ) Pub Date : 2019-08-13 , DOI: 10.1007/s10928-019-09650-7
Junzhen Wu 1, 2, 3 , Kun Wang 4 , Yuancheng Chen 1, 2, 3, 5 , Hong Yuan 1, 2, 3 , Li Li 1, 2, 3 , Jing Zhang 1, 2, 3, 5
Affiliation  

The effects of contezolid (MRX-I, an oxazolidinone antibacterial agent) on cardiac repolarization were evaluated retrospectively using a population modeling approach in a Phase I study incorporating single ascending dose, multiple ascending dose, and food effect assessments. Linear mixed effect models were used to assess the relationships between MRX-I plasma concentrations and QT/QTc/∆QTc (baseline-adjusted), in which different correction methods for heart rate have been included. The upper bound of the one-sided 95% confidence interval (CI) for predicted ∆∆QTc was < 10 ms (ms) at therapeutic doses of MRX-I. Model performance/suitability was determined using diagnostic evaluations, which indicated rationality of one-stage concentration-QT model, as well as C-QT model suggested by Garnett et al. The finding demonstrated that MRX-I may have no clinical effects on the QT interval. Concentration-QT model may be an alternative to conventional thorough QT studies.

中文翻译:

来自早期临床研究的ECG数据的浓度-响应模型,用于评估恶唑烷酮抗菌药康替利德(MRX-1)的QT延长风险。

在第一阶段研究中,采用人群建模方法回顾性评估了contezolid(MRX-1,恶唑烷酮类抗菌剂)对心脏复极的影响,该研究纳入了单次上升剂量,多次上升剂量和食物效果评估。线性混合效应模型用于评估MRX-1血浆浓度与QT / QTc / ∆QTc(经基线调整)之间的关系,其中包括了不同的心率校正方法。在MRX-1的治疗剂量下,预测的∆QTc的单侧95%置信区间(CI)的上限为<10 ms(ms)。使用诊断评估确定模型的性能/适用性,这表明一阶段浓度-QT模型以及Garnett等人建议的C-QT模型的合理性。该发现表明MRX-1可能对QT间隔没有临床影响。浓度-QT模型可以替代常规的全面QT研究。
更新日期:2019-08-13
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