Töpper Christoph, Steinbach Cathérine L, Dorn Christoph, Kratzer Alexander, Wicha Sebastian G, Schleibinger Michael, Liebchen Uwe, Kees Frieder, Salzberger Bernd, Kees Martin G
*Department of Anaesthesiology and Intensive Care, Charité Universitätsmedizin Berlin-Campus Benjamin Franklin, Berlin, Germany; †Department of Clinical Pharmacy, Institute of Pharmacy, University of Regensburg, Regensburg, Germany; ‡Hospital pharmacy, University Hospital Regensburg, Regensburg, Germany; §Department of Pharmaceutical Biosciences, Uppsala Universitet, Uppsala, Sweden; ¶Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany; ‖Department of Pharmacology, University of Regensburg, Regensburg, Germany; and #Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
Ther Drug Monit. 2016 Oct;38(5):573-8. doi: 10.1097/FTD.0000000000000324.
Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population.
Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37°C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (Cmin) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, Cmin 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted.
Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mgh/L, calculated Cmin 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and Cmin were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or Cmin was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC ∼60 mgh/L, Cmin <0.4 mg/L). The median unbound fraction in all 20 patients was 90.9%.
Drug exposure after standard doses of linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.
利奈唑胺的标准剂量可能并不适用于所有患者群体。特别是重症监护病房（ICU）的患者，可能存在血药浓度不足的风险。本研究调查了该人群中药物暴露的变异性及其潜在来源。
采用高效液相色谱法测定了20例接受每日两次静脉注射600mg利奈唑胺治疗的ICU患者的便利样本中的血浆浓度。应用生理条件（pH 7.4/37°C）的超滤法测定游离分数。通过群体药代动力学（PK）建模估算个体PK参数。作为利奈唑胺暴露的指标，计算浓度-时间曲线下面积（AUC）和谷浓度（Cmin），并与已发表的治疗范围（AUC 200 - 400mg*h/L，Cmin 2 - 10mg/L）进行比较。记录同时使用的细胞色素P450和/或P-糖蛋白的抑制剂或诱导剂。
18例患者的数据纳入PK评估。药物暴露差异很大（中位数，范围：AUC 185，48 - 618mgh/L，计算的Cmin 2.92，0.0062 - 18.9mg/L），只有少数患者的值在目标范围内（分别为6例和7例）。AUC和Cmin呈线性相关（R = 0.98），根据AUC或Cmin对患者进行的分类（暴露不足/在治疗范围内/暴露过度）在15例中是一致的。同时使用抑制剂与药物暴露增加的趋势相关，而3例接受左甲状腺素治疗的患者药物暴露极低（AUC ∼60mgh/L，Cmin <0.4mg/L）。所有20例患者的游离分数中位数为90.9%。
标准剂量利奈唑胺后的药物暴露在ICU患者中差异很大且难以预测，治疗药物监测似乎是可取的。PK药物相互作用可能部分起作用，应进一步研究；蛋白结合似乎稳定且无关紧要。
