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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

  • Junzhen Wu
  • Kun Wang
  • Yuancheng Chen
  • Hong Yuan
  • Li Li
  • Jing ZhangEmail author
Original Paper
  • 21 Downloads

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.

Keywords

MRX-I QT interval Population pharmacodynamics C-QT model 

Notes

Acknowledgements

The author thanked the sponsor of the study, MicuRx Pharmaceuticals, Inc.

Funding

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.

Supplementary material

10928_2019_9650_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 13 kb)
10928_2019_9650_MOESM2_ESM.pptx (1.2 mb)
Supplementary material 2 (PPTX 1257 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of Antibiotics, Huashan HospitalFudan UniversityShanghaiChina
  2. 2.Key Laboratory of Clinical Pharmacology of AntibioticsNational Health and Family Planning CommissionShanghaiChina
  3. 3.National Clinical Research Center for Aging and Medicine, Huashan HospitalFudan UniversityShanghaiChina
  4. 4.Phase I Unit, Huashan HospitalFudan UniversityShanghaiChina
  5. 5.Certara Strategic Consulting ChinaShanghaiChina

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