Al-Shaer Mohammad H, Märtson Anne-Grete, Alghamdi Wael A, Alsultan Abdullah, An Guohua, Ahmed Shahriar, Alkabab Yosra, Banu Sayera, Houpt Eric R, Ashkin David, Griffith David E, Cegielski J Peter, Heysell Scott K, Peloquin Charles A
Infectious Disease Pharmacokinetics Laboratory, College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA.
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Antimicrob Agents Chemother. 2020 Aug 20;64(9). doi: 10.1128/AAC.00713-20.
Ethionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy volunteers and patients with MDR-TB. The TB centers included were two in the United States and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, regimens with a total of 1,000 to 2,250 mg daily were simulated, and target attainment using published MICs and targets of 1.0-log kill and resistance suppression was assessed with the Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag time. The mean (standard deviation [SD]) final population parameter estimates were as follows: absorption rate constant, 1.02 (1.11) h; elimination rate constant, 0.69 (0.46) h; volume of distribution, 104.16 (59.87) liters; lag time, 0.43 (0.32) h. A total daily dose of 1,500 mg or more was needed for ≥90% attainment of the 1.0-log kill target at a MIC of 1 mg/liter, and 2,250 mg/day led to 80% attainment of the resistance suppression target at a MIC of 0.5 mg/liter. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the predefined targets supporting the current recommendations for ETA deprioritization.
乙硫异烟胺（ETA）是一种异烟酸衍生物，是耐多药结核病（MDR-TB）治疗方案的一部分。目前的指南已将ETA的优先级降低，因为它可能比其他药物效果更差。我们的目的是建立一个群体药代动力学（PK）模型并模拟ETA给药方案，以评估目标达成情况。本研究纳入了来自四个不同地点的受试者，包括健康志愿者和耐多药结核病患者。纳入的结核病中心有两个在美国，一个在孟加拉国。纳入了接受ETA且至少报告了一次药物浓度的患者。建立了群体PK模型，模拟了每日总剂量为1000至2250毫克的给药方案，并使用Pmetrics R软件包根据已发表的最低抑菌浓度（MIC）以及1.0对数杀灭和耐药性抑制目标评估目标达成情况。我们纳入了94名受试者的1167份乙硫异烟胺浓度数据。最终的群体模型是一个具有一级消除和吸收且有滞后时间的单室模型。最终群体参数估计的均值（标准差[SD]）如下：吸收速率常数，1.02（1.11）小时；消除速率常数，0.69（0.46）小时；分布容积，104.16（59.87）升；滞后时间，0.43（0.32）小时。在MIC为1毫克/升时，要达到≥90%的1.0对数杀灭目标，每日总剂量需要1500毫克或更多；在MIC为0.5毫克/升时，每日2250毫克可使80%的患者达到耐药性抑制目标。总之，我们建立了一个群体PK模型并评估了不同ETA给药方案的目标达成情况。患者可能无法耐受达到预定义目标所需的剂量，这支持了目前将ETA优先级降低的建议。
