Abstract
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.
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The author thanked the sponsor of the study, MicuRx Pharmaceuticals, Inc.
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This study was financially supported by the Major Research and Development Project of Innovative Drugs, Ministry of Science and Technology of China (2017ZX09304005).
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Wu, J., Wang, K., Chen, Y. et al. Concentration–response modeling of ECG data from early-phase clinical studies to assess QT prolongation risk of contezolid (MRX-I), an oxazolidinone antibacterial agent. J Pharmacokinet Pharmacodyn 46, 531–541 (2019). https://doi.org/10.1007/s10928-019-09650-7
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DOI: https://doi.org/10.1007/s10928-019-09650-7