Caballero Unai, Eraso Elena, Pemán Javier, Quindós Guillermo, Vozmediano Valvanera, Schmidt Stephan, Jauregizar Nerea
Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.
Department of Immunology, Microbiology and Parasitology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.
Pharmaceutics. 2021 Oct 22;13(11):1767. doi: 10.3390/pharmaceutics13111767.
The aims of this study were to characterize the antifungal activity of amphotericin B against in a static in vitro system and to evaluate different dosing schedules and MIC scenarios by means of semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation. A two-compartment model consisting of a drug-susceptible and a drug-resistant subpopulation successfully characterized the time-kill data and a modified E sigmoidal model best described the effect of the drug. The model incorporated growth rate constants for both subpopulations, a death rate constant and a transfer constant between both compartments. Additionally, the model included a parameter to account for the delay in growth in the absence or presence of the drug. Amphotericin B displayed a concentration-dependent fungicidal activity. The developed PK/PD model was able to characterize properly the antifungal activity of amphotericin B against . Finally, simulation analysis revealed that none of the simulated standard dosing scenarios of 0.6, 1 and 1.5 mg/kg/day over a week treatment showed successful activity against infection. Simulations also pointed out that an MIC of 1 mg/L would be linked to treatment failure for invasive infections and therefore, the resistance rate to amphotericin B may be higher than previously reported.
本研究的目的是在静态体外系统中表征两性霉素B对[具体对象未明确]的抗真菌活性，并通过半机制药代动力学/药效学（PK/PD）建模和模拟评估不同的给药方案和最低抑菌浓度（MIC）情况。一个由药物敏感亚群和耐药亚群组成的二室模型成功地表征了时间-杀菌数据，并且一个修正的E型 sigmoid 模型能最好地描述药物的作用。该模型纳入了两个亚群的生长速率常数、一个死亡率常数以及两个隔室之间的转移常数。此外，该模型包含一个参数以说明在有或无药物情况下生长的延迟。两性霉素B表现出浓度依赖性杀菌活性。所建立的PK/PD模型能够恰当地表征两性霉素B对[具体对象未明确]的抗真菌活性。最后，模拟分析表明，在为期一周的治疗中，模拟的0.6、1和1.5mg/kg/天的标准给药方案均未显示出对[具体感染未明确]感染的成功活性。模拟还指出，对于[具体侵袭性感染未明确]，MIC为1mg/L将与治疗失败相关，因此，对两性霉素B的耐药率可能高于先前报道。
