Wu Junzhen, Yang Xinyi, Wu Jufang, Wang Jingjing, Wu Hailan, Wang Yu, Yuan Hong, Yang Huahui, Wang Hailin, Zhang Jing
Phase I Unit, Huashan Hospital, Fudan University, Shanghai, China.
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
Front Pharmacol. 2023 Mar 13;14:1135007. doi: 10.3389/fphar.2023.1135007. eCollection 2023.
Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC, 106.79 vs. 97.07 h μg/mL) of contezolid even though lower maximum concentration (C, 19.03 vs. 34.49 μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae) and renal clearance (CL) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower C, slightly lower AUC and Ae of M2 compared to the healthy controls. AUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed AUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant , MIC ≤4 mg/L) in patients with moderate hepatic impairment. Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. https://chinadrugtrials.org.cn, identifier: CTR20171377.
康替唑胺是一种新获批用于治疗革兰氏阳性菌感染的恶唑烷酮类抗菌药物。它主要通过肝脏代谢。本研究旨在评估对于中度肝功能损害患者是否需要调整康替唑胺剂量，以便临床医生更合理地使用该药物。开展了一项单中心、开放标签、平行组研究，比较口服800 mg康替唑胺片后中度肝功能损害患者与肝功能正常的健康对照者之间康替唑胺及其代谢物M2的药代动力学（PK）参数。基于PK和药效学数据进行蒙特卡洛模拟，以计算康替唑胺达到目标的概率（PTA）和累积反应分数（CFR）。口服800 mg康替唑胺片治疗在中度肝功能损害患者和健康对照者中均安全且耐受性良好。尽管与健康对照者相比，中度肝功能损害患者的康替唑胺最大浓度较低（C，19.03 vs. 34.49 μg/mL），但0至24小时浓度-时间曲线下面积（AUC，106.79 vs. 97.07 h·μg/mL）无显著差异。两组之间康替唑胺0至48小时尿液中排泄的平均累积量（Ae）和肾清除率（CL）无显著差异。与健康对照者相比，中度肝功能损害患者的C较低，M2的AUC和Ae略低。AUC/MIC是预测康替唑胺临床疗效的最佳PK/PD指标。蒙特卡洛模拟结果表明，在建议的AUC/MIC目标值为2.3时，口服康替唑胺800 mg q12h的给药方案可使中度肝功能损害患者中目标病原体（耐甲氧西林，MIC≤4 mg/L）达到满意的PTA和CFR（均>90%）。我们的初步数据表明，中度肝功能损害患者使用康替唑胺无需调整剂量。https://chinadrugtrials.org.cn，标识符：CTR20171377 。
