Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Center for Drug Evaluation, National Medical Product Agency, Beijing, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission, Shanghai, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission, Shanghai, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
Clin Ther. 2020 May;42(5):818-829. doi: 10.1016/j.clinthera.2020.03.020. Epub 2020 May 7.
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 fAUC/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 fAUC/MIC and PTA values. Results suggest that dose adjustments are not necessary for patient sex in confirmatory studies. Chinese Clinical Trial Registration identifier: CTR20140056.
康替唑（MRX-I）是一种新型噁唑烷酮类抗生素，具有很强的抗革兰氏阳性病原体的体外活性。本研究的目的是建立剂量-药代动力学（PK）-暴露-药效动力学（PD）-反应关系，并定量评估在喂食条件下连续口服 600mg 每日 2 次和 800mg 每日 2 次 14 天后，MRX-I 的 PK 变异性，用于治疗皮肤和皮肤结构感染。另一个目标是根据 PK/PD 分析评估两种剂量方案对耐甲氧西林金黄色葡萄球菌感染的疗效。
将健康志愿者和患者的 PK 数据合并，采用非线性混合效应模型方法建立群体 PK 模型。使用蒙特卡罗模拟预测在喂食条件下单次口服 600 和 800mg MRX-I 后，目标浓度达标率（PTA）和累积反应分数。
口服 MRX-I 的 PK 特征采用 1 个具有 1 阶消除的 2 隔室模型来描述。MRX-I 的吸收可能受食物摄入的影响。志愿者的类型可能会影响外周隔室的吸收常数速率和分布容积，体重可能会影响中央隔室的分布容积。其他因素如年龄、性别、肌酐清除率、合并用药和基础疾病对 PK 参数无明显影响。基于蒙特卡罗模拟，普通进食状态下连续口服 600 或 800mg 每日 2 次，14 天可产生满意的抗耐甲氧西林金黄色葡萄球菌疗效，累积反应分数 >90%，fAUC/MIC 目标值为 2.3。对于 MRX-I 600mg 每日 2 次，MIC≤2.0μg/ml，或 MRX-I 800mg 每日 2 次，MIC≤4.0μg/ml，在喂食状态下连续 14 天给药，两种方案均能获得满意的临床和抗菌疗效，PTA>90%。因此，建议在皮肤和皮肤结构感染患者中进行确认性临床试验时采用 800mg 每日 2 次，7-14 天的 MRX-I 治疗方案。
使用 2 隔室 PK 模型可以很好地描述 MRX-I 的 PK 特征，疾病状态、食物摄入和体重被发现显著影响 PK 特征。基于模拟的 fAUC/MIC 和 PTA 值，建议采用普通进食状态下 800mg 每日 2 次，7-14 天的给药方案进行关键性研究。结果提示在确认性研究中，无需根据患者性别调整剂量。中国临床试验注册中心注册号： CTR20140056。
