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In vitro - in vivo relations for the parenteral liposomal formulation of Amphotericin B: A clinically relevant approach with PBPK modeling
European Journal of Pharmaceutics and Biopharmaceutics ( IF 4.9 ) Pub Date : 2020-03-05 , DOI: 10.1016/j.ejpb.2020.03.001
R. Díaz de León–Ortega , D.M. D'Arcy , D.A. Lamprou , N. Fotaki

In vitro release testing is a useful tool for the quality control of controlled release parenteral formulations, but in vitro release test conditions that reflect or are able to predict the in vivo performance are advantageous. Therefore, it is important to investigate the factors that could affect drug release from formulations and relate them to in vivo performance. In this study the effect of media composition including albumin presence, type of buffer and hydrodynamics on drug release were evaluated on a liposomal Amphotericin B formulation (Ambisome®). A physiologically based pharmacokinetic (PBPK) model was developed using plasma concentration profiles from healthy subjects, in order to investigate the impact of each variable from the in vitro release tests on the prediction of the in vivo performance. It was found that albumin presence was the most important factor for the release of Amphotericin B from Ambisome®; both hydrodynamics setups, coupled with the PBPK model, had comparable predictive ability for simulating in vivo plasma concentration profiles. The PBPK model was extrapolated to a hypothetical hypoalbuminaemic population and the Amphotericin B plasma concentration and its activity against fungal cells were simulated. Selected in vitro release tests for these controlled release parenteral formulations were able to predict the in vivo AmB exposure, and this PBPK driven approach to release test development could benefit development of such formulations.



中文翻译:

两性霉素B肠胃外脂质体制剂的体外-体内关系:PB​​PK建模的临床相关方法

体外释放测试是用于控制释放肠胃外制剂的质量控制的有用工具,但是反映或能够预测体内性能的体外释放测试条件是有利的。因此,重要的是研究可能影响制剂中药物释放的因素,并将其与体内性能联系起来。在这项研究中,使用脂质体两性霉素B制剂(Ambisome®)评估了培养基组成(包括白蛋白的存在,缓冲液的类型和流体动力学)对药物释放的影响。为了研究来自健康受试者的血浆浓度分布,开发了基于生理的药代动力学(PBPK)模型。体外释放试验对体内性能的预测。已发现白蛋白的存在是从Ambisome®释放两性霉素B的最重要因素。两种流体力学设置以及PBPK模型都具有可比的模拟体内血浆浓度分布的预测能力。将PBPK模型外推至假设的低白蛋白血症人群,并模拟两性霉素B血浆浓度及其对真菌细胞的活性。这些控释肠胃外制剂的选定体外释放测试能够预测体内 AmB暴露以及这种由PBPK驱动的释放测试开发方法可以有益于此类制剂的开发。

更新日期:2020-03-05
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