Population Pharmacokinetics Study of Contezolid (MRX-I), a Novel Oxazolidinone Antibacterial Agent, in Chinese Patients

• Published in: Clinical therapeutics Vol. 42; no. 5; pp. 818 - 829
• Main Authors: Li, Li, Wu, Hailan, Chen, Yuancheng, Yuan, Hong, Wu, Junzhen, Wu, Xiaojie, Zhang, Yingyuan, Cao, Guoying, Guo, Beining, Wu, Jufang, Zhao, Ming, Zhang, Jing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2020; Elsevier Limited
• Subjects: Absorption; Administration, Oral; Adolescent; Adult; Aged; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Antiinfectives and antibacterials; Bacteria; Body Weight; Clinical trials; Computer simulation; Creatinine; Dosage; Drug dosages; Drug resistance; FDA approval; Female; Food; Food intake; Food-Drug Interactions; healthy subjects; Healthy Volunteers; Humans; Infections; Male; Methicillin; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Minimum inhibitory concentration; Models, Biological; Monte Carlo Method; Monte Carlo simulation; MRX-I; Multidrug resistant organisms; Nosocomial infections; Oral administration; Oxazolidinones - administration & dosage; Oxazolidinones - pharmacokinetics; Pathogens; patients; pharmacodynamic pharmacokinetics; Pharmacodynamics; Pharmacokinetics; Pharmacology; Plasma; Population; Population studies; Pyridones - administration & dosage; Pyridones - pharmacokinetics; Sex; Skin; Skin Diseases - drug therapy; Skin Diseases - metabolism; Staphylococcal Infections - drug therapy; Staphylococcal Infections - metabolism; Staphylococcus aureus; Staphylococcus infections; Streptococcus infections; Weight; Young Adult; United States > US; Massachusetts; pharmacodynamic pharmacokinetics; PK; PD; MRX-I; healthy subjects; patients
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2020.03.020

Contezolid (MRX-I) is a novel oxazolidinone with potent in vitro activity against gram-positive pathogens. The aim of this study was to establish the dose-pharmacokinetic (PK) exposure-pharmacodynamic (PD)–response relationship and to quantitatively evaluate the variability of MRX-I after continuous oral administration of 600 mg BID and 800 mg BID for 14 days under fed conditions in patients with skin and skin structure infections. Another goal was to evaluate the 2 dosing regimens against methicillin-resistant Staphylococcus aureus infections based on PK/PD analysis. PK data from healthy volunteers and patients were pooled to develop a population PK model using a nonlinear mixed effect modeling method. Monte Carlo simulations were used to predict probability of target attainment (PTA) and cumulative fraction of response after single oral administration of 600 and 800 mg of MRX-I under fed conditions. The PK profile of oral administration of MRX-I was described by using a 2-compartment model with first-order elimination. Absorption of MRX-I may be affected by food intake. Type of volunteers could affect absorption constant rate and volume of distribution in the peripheral compartment, and weight could affect volume of distribution in the central department. No obvious effect on PK parameters was identified for other factors such as age, sex, creatinine clearance, concomitant medicine, and baseline diseases. Based on Monte Carlo simulation, MRX-I 600 or 800 mg BID up to 14 days on ordinary fed status could produce satisfactory efficacy against methicillin-resistant S aureus, with cumulative fraction of response >90% for fAUC0–24/MIC targeted at 2.3. At MIC ≤2.0 μg/mL for MRX-I 600 mg BID, or at MIC ≤4.0 μg/mL for MRX-I 800 mg BID, with continuous administration for 14 days at fed status, both regimens could obtain satisfactory clinical and antibacterial efficacy, with PTA >90%. Hence, the MRX-I regimen of 800 mg BID for 7–14 days can be recommended for confirmative clinical trials in patients with skin and skin structure infections. PK profiles of MRX-I were well captured by using a 2-compartment PK model, and disease status, food intake, and weight were found to significantly affect PK profiles. A dosing regimen of 800 mg BID for 7–14 days with ordinary food intake was recommended for pivotal study based on simulated fAUC0–24/MIC and PTA values. Results suggest that dose adjustments are not necessary for patient sex in confirmatory studies. Chinese Clinical Trial Registration identifier: CTR20140056.