慢性血液透析患者中单剂达托霉素的药代动力学。
Single-dose daptomycin pharmacokinetics in chronic haemodialysis patients.
机构信息
University of Michigan College of Pharmacy, Department of Clinical, Social & Administrative Sciences, Ann Arbor, MI, USA.
出版信息
Nephrol Dial Transplant. 2010 Apr;25(4):1279-84. doi: 10.1093/ndt/gfp655. Epub 2009 Dec 10.
BACKGROUND
Daptomycin has concentration-dependent antibacterial activity against Gram-positive bacteria. Its use is increasing in haemodialysis units. The manufacturer recommends a 4-6-mg/kg dose administered every 48 hrs for patients receiving haemodialysis. However, there are no published data about daptomycin pharmacokinetics and clearance during haemodialysis. The recommended dosing regimen would conflict with asymmetric thrice-weekly haemodialysis, which yields two ~44-hr and one ~68-hr interdialytic periods. This is the first study to evaluate daptomycin pharmacokinetics in haemodialysis patients, assess the extent of daptomycin dialytic removal and model serum concentrations at 44 and 68 hrs.
METHODS
Six otherwise healthy subjects on chronic haemodialysis (55.3 +/- 16.1 years old, three females, 66.2 +/- 14.2 kg) received a single 6-mg/kg dose of daptomycin post-haemodialysis infused over 30 minutes. Serial blood samples were collected for ~44 hrs (pre-next haemodialysis) and throughout the subsequent haemodialysis session with a high permeability haemodialyser. Individual pharmacokinetic parameters determined by compartmental analysis were used to model trough serum concentrations at 44 and 68 hrs with 6-, 8- and 10-mg/kg post-haemodialysis doses.
RESULTS
The haemodialysis session in this trial yielded mean urea and daptomycin reduction ratios of 79.6 +/- 5.8% and 57.6 +/- 9.2%, respectively. Daptomycin half-life was 19.4 +/- 6.5 and 3.8 +/- 1.1 hrs 'off' and 'on haemodialysis', respectively, with minimal rebound 1 hr post-haemodialysis. All modelled trough concentrations at 44 and 68 hrs at all doses exceed typical minimum inhibitory concentration (MIC(90)) values for Staphylococcus aureus and Enterococcus faecalis.
CONCLUSIONS
Daptomycin serum concentrations declined by ~50% after a 4-hr haemodialysis session with a high permeability haemodialyser. A 6-mg/kg i.v. post-haemodialysis thrice-weekly dose should result in sufficient pre-haemodialysis daptomycin serum concentrations even after a 68-hr interdialytic period.
背景
达托霉素对革兰氏阳性菌具有浓度依赖性的抗菌活性。它在血液透析单位中的使用正在增加。制造商建议对于接受血液透析的患者，给予 4-6mg/kg 的剂量，每 48 小时给药一次。然而，目前尚无关于达托霉素在血液透析过程中的药代动力学和清除率的发表数据。推荐的给药方案与不对称性每周三次血液透析相冲突，后者产生两个约 44 小时和一个约 68 小时的透析间隔期。这是第一项评估血液透析患者达托霉素药代动力学的研究，评估达托霉素透析清除的程度，并对 44 小时和 68 小时的血清浓度进行建模。
方法
六名慢性血液透析患者（55.3 ± 16.1 岁，女性三人，66.2 ± 14.2kg）在血液透析后 30 分钟内接受单次 6mg/kg 的达托霉素剂量。在约 44 小时（下次血液透析前）和随后的整个血液透析过程中，使用高通量血液透析器采集连续血样。通过房室分析确定的个体药代动力学参数用于建模 6-、8-和 10-mg/kg 血液透析后剂量的 44 小时和 68 小时的谷浓度。
结果
本试验中的血液透析治疗产生了平均尿素和达托霉素减少率分别为 79.6 ± 5.8%和 57.6 ± 9.2%。达托霉素半衰期为 19.4 ± 6.5 和 3.8 ± 1.1 小时，分别为“脱机”和“联机”时，血液透析后 1 小时有轻微反弹。所有剂量在 44 小时和 68 小时的模拟谷浓度均超过金黄色葡萄球菌和粪肠球菌的典型最小抑菌浓度（MIC90）值。
结论
使用高通量血液透析器进行 4 小时血液透析后，达托霉素血清浓度下降约 50%。每周三次血液透析后给予 6mg/kg 的静脉内剂量，即使在 68 小时的透析间隔后，也应能确保足够的血液透析前达托霉素血清浓度。
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