Adult Intensive Care Unit, Department of Anaesthesiology-SAMU de Paris, University hospital Necker, Assistance publique-Hôpitaux de Paris, 149-161, rue de Sèvres, 75015 Paris, France; EA7323 Evaluation of therapeutics and pharmacology in perinatality and paediatrics, université Paris Descartes, hôpitaux universitaires Cochin-Broca-Hôtel Dieu, Site Tarnier, 75006 Paris, France.
University Paris 13, groupe hospitalier Paris Seine-Saint-Denis, Assistance publique-Hôpitaux de Paris, 93000 Bobigny, France; Molecular Mycology Unit-CNRS UMR 2000, Pasteur Institute, 75015 Paris, France.
Anaesth Crit Care Pain Med. 2021 Feb;40(1):100640. doi: 10.1016/j.accpm.2020.01.007. Epub 2020 Apr 3.
There is major concern regarding the pharmacokinetics of drugs under continuous renal replacement therapy (CRRT), including anti-infectious agents and more especially antifungal agents. From a regulatory viewpoint, only dialysis and filtration are considered meanwhile there is growing evidence that adsorption may also significantly alter the pharmacokinetics of anti-infectious agents. Adsorption results from a complex drug-filter interaction and might be considered an unexpected adverse effect induced by CRRT. Measurement of total plasma concentrations instead of the unbound, free, active concentrations in in vitro as well as in clinical studies hides this major adverse effect, which may jeopardise the therapeutic effect and even result in treatment failure. Noteworthy, minimal inhibitory concentrations (MIC) of anti-infectious agents are performed using solid and liquid medium without proteins testing only the antimicrobial activity of the free fraction of drugs. In a new in vitro model using crystalloid solution instead of blood, we report data supporting the assumption that the assessment of the disposition of the free fraction of caspofungin and micafungin unveils adverse effects of ST150® filter, which might eventually result in non-detectable drug concentrations and treatment failure. From a technical viewpoint, we conclude the measurement of the free fraction of drugs that largely bound to plasma proteins, including caspofungin and micafungin, should be considered instead of total plasma concentrations to assess all effects induced by filters used in CRRT.
人们非常关注连续肾脏替代疗法（CRRT）下药物的药代动力学，包括抗感染药物，尤其是抗真菌药物。从监管的角度来看，仅考虑了透析和过滤，而越来越多的证据表明，吸附也可能显著改变抗感染药物的药代动力学。吸附是由药物-过滤器的复杂相互作用引起的，可能被认为是 CRRT 引起的意外不良影响。在体外和临床研究中，测量总血浆浓度而不是未结合的、游离的、活性浓度，掩盖了这种主要的不良影响，这可能危及治疗效果，甚至导致治疗失败。值得注意的是，最小抑菌浓度（MIC）是使用不含蛋白质的固体和液体培养基进行测试的，仅测试药物游离部分的抗菌活性。在一个使用晶体溶液代替血液的新体外模型中，我们报告的数据支持了这样一种假设，即评估卡泊芬净和米卡芬净游离部分的处置情况揭示了 ST150®过滤器的不良影响，这可能最终导致不可检测的药物浓度和治疗失败。从技术的角度来看，我们得出结论，应该考虑测量与血浆蛋白（包括卡泊芬净和米卡芬净）结合的药物游离部分，而不是总血浆浓度，以评估 CRRT 中使用的过滤器引起的所有影响。
