Abulfathi Ahmed A, de Jager Veronique, van Brakel Elana, Reuter Helmuth, Gupte Nikhil, Vanker Naadira, Barnes Grace L, Nuermberger Eric, Dorman Susan E, Diacon Andreas H, Dooley Kelly E, Svensson Elin M
Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
Department of Clinical Pharmacology and Therapeutics, College of Medical Sciences, University of Maiduguri, Maiduguri, Nigeria.
Front Pharmacol. 2021 Jun 29;12:637618. doi: 10.3389/fphar.2021.637618. eCollection 2021.
Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary and identify covariates explaining inter-individual variability. Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
美罗培南正被研究用于重新开发为一种抗结核药物。本研究旨在建立肺部疾病患者的美罗培南群体药代动力学模型，并确定解释个体间变异性的协变量。患者被随机分为四个治疗组之一：美罗培南2克每日三次加口服利福平20毫克/千克每日一次、美罗培南2克每日三次、美罗培南1克每日三次和美罗培南3克每日一次。美罗培南通过静脉输注0.5 - 1小时给药。所有患者在每次美罗培南给药时还同时接受口服阿莫西林/克拉维酸，治疗持续14天。在研究的第14天进行8小时的强化血浆药代动力学采样。采用非线性混合效应模型进行数据分析。根据似然度量、拟合优度图和简约性选择最佳模型。协变量进行逐步检验。分析纳入了49例患者的404次浓度测量值。一个用清除率（CL）、隔室间清除率（Q）以及中央室（V1）和外周室（V2）分布容积参数化的二室模型很好地拟合了数据。CL、Q、V1和V2的典型值分别为11.8升/小时、3.26升/小时、14.2升和3.12升。参数估计的相对标准误差范围为3.8%至35.4%。最终模型中纳入的协变量关系为肌酐清除率对CL的影响以及所有处置参数与体重的异速缩放关系。未发现年龄对CL有如先前报道的影响。一个二室模型很好地描述了肺部疾病患者的美罗培南群体药代动力学。发现可改善模型拟合的协变量是肌酐清除率和体重，而非利福平治疗。最终模型将用于将美罗培南暴露与早期杀菌活性联系起来的综合药代动力学/药效学分析。
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