Concentration–response modeling of ECG data from early-phase clinical studies to assess QT prolongation risk of contezolid (MRX-I), an oxazolidinone antibacterial agent
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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.
KeywordsMRX-I QT interval Population pharmacodynamics C-QT model
The author thanked the sponsor of the study, MicuRx Pharmaceuticals, Inc.
This study was financially supported by the Major Research and Development Project of Innovative Drugs, Ministry of Science and Technology of China (2017ZX09304005).
Compliance with ethical standards
Conflicting of interest
The authors declare no conflicts of interest.
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