University of New Mexico College of Pharmacy, Albuquerque, NM, USA.
Crit Care Med. 2011 Jan;39(1):19-25. doi: 10.1097/CCM.0b013e3181fa36fb.
To investigate daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis to develop dosing recommendations.
Prospective, open-label pharmacokinetic study.
: Intensive care units located within a teaching medical center.
Eight adults with known/suspected Gram-positive infections receiving continuous venovenous hemodialysis and daptomycin.
Daptomycin at 8 mg/kg intravenously over 30 mins. Serial blood and effluent samples were collected over the next 48 hrs. Daptomycin protein binding was determined by equilibrium dialysis. Daptomycin continuous venovenous hemodialysis transmembrane clearance was determined by dividing daptomycin effluent by serum concentrations and multiplying by mean effluent production rate for each subject. Equations describing a two-compartment, open-pharmacokinetic model were fitted to each subject's daptomycin concentration-time data and pharmacokinetic parameters were determined by standard methods. Serum concentration-time profiles were simulated for two daptomycin regimens (8 mg/kg every 48 hrs and 4 mg/kg every 24 hrs).
A total of 7.7 ± 0.6 mg/kg (mean ± sd) of daptomycin was administered, resulting in an observed peak concentration of 81.2 ± 19.0 μg/mL. Daptomycin steady-state volume of distribution (0.23 ± 0.14 L/kg) and free fraction (17.5% ± 5.0%) were increased in critically ill subjects receiving continuous venovenous hemodialysis compared with previous values reported in healthy volunteers. Daptomycin transmembrane clearance (6.3 ± 2.9 mL/min) accounted for more than half of total clearance (11.3 ± 4.7 mL/min). Simulations demonstrated 8 mg/kg daptomycin every 48 hrs would result in higher peak (88.8 ± 20.0 μg/mL vs. 53.0 ± 12.3 μg/mL) and lower trough concentrations (7.2 ± 5.2 μg/mL vs. 12.3 ± 5.1 μg/mL) than 4 mg/kg every 24 hrs.
Daptomycin at 8 mg/kg every 48 hrs in critically ill patients receiving continuous venovenous hemodialysis resulted in good drug exposure, achieved high peak concentrations to maximize daptomycin's concentration-dependent activity, and resulted in trough concentration that would minimize the risk of myopathy. CLINICALTRIALS.GOV IDENTIFIER: NCT00663403.
研究接受连续静脉-静脉血液透析的危重症患者中达托霉素的药代动力学，为制定给药建议提供参考。
前瞻性、开放标签药代动力学研究。
教学医学中心内的重症监护病房。
8 名患有已知/疑似革兰阳性感染的成人，接受连续静脉-静脉血液透析和达托霉素治疗。
达托霉素 8mg/kg 静脉输注 30 分钟。在接下来的 48 小时内连续采集血液和流出液样本。通过平衡透析法测定达托霉素的蛋白结合率。通过将达托霉素流出液除以血清浓度，并乘以每个受试者的平均流出液产生率，来确定达托霉素连续静脉-静脉血液透析膜间清除率。通过标准方法确定每个受试者的达托霉素浓度-时间数据的描述两室、开放药代动力学模型的方程，并确定药代动力学参数。模拟两种达托霉素方案（48 小时 8mg/kg 一次和 24 小时 4mg/kg 一次）的血清浓度-时间曲线。
共给予 7.7±0.6mg/kg（平均值±标准差）的达托霉素，导致观察到的峰浓度为 81.2±19.0μg/mL。与先前在健康志愿者中报告的值相比，接受连续静脉-静脉血液透析的危重症患者的达托霉素稳态分布容积（0.23±0.14L/kg）和游离分数（17.5%±5.0%）增加。达托霉素膜间清除率（6.3±2.9mL/min）占总清除率（11.3±4.7mL/min）的一半以上。模拟结果表明，每 48 小时 8mg/kg 达托霉素的峰浓度（88.8±20.0μg/mL 比 53.0±12.3μg/mL）更高，谷浓度（7.2±5.2μg/mL 比 12.3±5.1μg/mL）更低，而每 24 小时 4mg/kg 一次的峰浓度（88.8±20.0μg/mL 比 53.0±12.3μg/mL）更低。
接受连续静脉-静脉血液透析的危重症患者中每 48 小时给予 8mg/kg 的达托霉素可获得良好的药物暴露，达到高峰浓度以最大程度发挥达托霉素的浓度依赖性活性，并使谷浓度降至最低，从而最大程度降低肌病风险。
NCT00663403。
