Evaluation of the Effect of Contezolid (MRX-I) on the Corrected QT Interval in a Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study in Healthy Chinese Volunteers
- 21 May 2020
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 64 (6)
- https://doi.org/10.1128/aac.02158-19
Abstract
Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections (cSSTI) caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1600 mg) dose, placebo, and oral moxifloxacin 400 mg in 4 separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated. Time-point analysis indicated that the upper bounds of the two-sided 90% confidence interval (CI) for placebo-corrected change-from-baseline QTc (ΔΔQTc) were <10 ms for the contezolid therapeutic dose at each time point. The upper bound of the 90% CI for ΔΔQTc were slightly more than 10 ms with the contezolid supratherapeutic dose at 3 and 4 hours postdose, and the prolongation effect on the QT/QTc interval was less than that of the positive control, moxifloxacin 400 mg. At 3 and 4 h after the moxifloxacin dose, the moxifloxacin group met the assay sensitivity criteria outlined in ICH Guidance E14 with having a lower confidence bound ≥5 ms. The results of a linear exposure-response model which were similar to that of a time point analysis demonstrated a slightly positive relationship between contezolid plasma levels and ΔQTcF interval with a slope of 0.227 ms per mg/L (90% CI: 0.188 to 0.266). In summary, contezolid did not prolong the QT interval at a therapeutic dose and may have a slight effect on QT interval prolongation at a supratherapeutic dose.Funding Information
- The Major Research and Development Project of Innovative Drugs, Ministry of Science and Technology of China (2017ZX09304005)
This publication has 21 references indexed in Scilit:
- Concentration–response modeling of ECG data from early-phase clinical studies to assess QT prolongation risk of contezolid (MRX-I), an oxazolidinone antibacterial agentJournal of Pharmacokinetics and Pharmacodynamics, 2019
- Vancomycin-Resistant Enterococci: A Review of Antimicrobial Resistance Mechanisms and Perspectives of Human and Animal HealthMicrobial Drug Resistance, 2018
- Single- and Multiple-Dose Study To Determine the Safety, Tolerability, Pharmacokinetics, and Food Effect of Oral MRX-I versus Linezolid in Healthy Adult SubjectsAntimicrobial Agents and Chemotherapy, 2017
- The role of methicillin-resistant Staphylococcus aureus in skin and soft tissue infectionsCurrent Opinion in Infectious Diseases, 2017
- New Potent Antibacterial Oxazolidinone (MRX-I) with an Improved Class Safety ProfileJournal of Medicinal Chemistry, 2014
- Early Investigation of QTc LiabilityDrug Safety, 2012
- Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug developmentBritish Journal of Pharmacology, 2010
- Concentration‐QT Relationships Play a Key Role in the Evaluation of Proarrhythmic Risk During Regulatory ReviewThe Journal of Clinical Pharmacology, 2008
- New oxazolidinonesCurrent Opinion in Microbiology, 2007
- Linezolid: The First Oxazolidinone AntimicrobialAnnals of Internal Medicine, 2003