Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt (Main), Germany; Institute of Pharmaceutical Technology, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt (Main), Germany.
Institute of Pharmaceutical Technology, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt (Main), Germany.
Eur J Pharm Biopharm. 2020 Apr;149:121-134. doi: 10.1016/j.ejpb.2020.02.001. Epub 2020 Feb 6.
Over the years, the performance of the liposomal formulations of temoporfin, Foslip® and Fospeg®, was investigated in a broad array of cell-based assays and preclinical animal models. So far, little attention has been paid to the influence of drug release and liposomal stability on the plasma concentration-time profile. The drug release is a key attribute which impacts product quality and the in vivo efficacy of nanocarrier formulations. In the present approach, the in vitro drug release and the drug-protein transfer of Foslip® and Fospeg® was determined using the dispersion releaser technology. To analyze the stability of both formulations in physiological fluids, nanoparticle tracking analysis was applied. A comparable drug release behavior and a high physical stability with a vesicle size of approximately 92 ± 2 nm for Foslip® and at 111 ± 5 nm for Fospeg® were measured. The development of a novel hybrid in silico model resulted in an optimal representation of the in vivo data. Based on the information available for previous formulations, the model enabled a prediction of the performance of Foslip® in humans. To verify the simulations, plasma concentration-time profiles of a phase I clinical trial were used. An absolute average fold error of 1.4 was achieved. Moreover, a deconvolution of the pharmacokinetic profile into different fractions relevant for the in vivo efficacy and safety was achieved. While the total plasma concentration reached a c of 2298 ng/mL after 0.72 h, the monomolecular drug accounted for a small fraction of the photosensitizer with a c of 321 ng/mL only.
多年来，替莫泊芬的脂质体制剂 Foslip® 和 Fospeg® 的性能已在广泛的基于细胞的测定和临床前动物模型中进行了研究。到目前为止，人们对药物释放和脂质体稳定性对血浆浓度-时间曲线的影响关注甚少。药物释放是一个关键属性，它会影响产品质量和纳米载体制剂的体内疗效。在本研究中，采用分散释放剂技术测定了 Foslip® 和 Fospeg® 的体外药物释放和药物蛋白转移。为了分析两种制剂在生理流体中的稳定性，应用了纳米颗粒跟踪分析。结果表明，Foslip® 的药物释放行为相似，物理稳定性高，囊泡大小约为 92 ± 2nm；Fospeg® 的囊泡大小约为 111 ± 5nm。一种新的混合计算机模型的开发导致了对体内数据的最佳拟合。基于之前制剂的信息，该模型能够预测 Foslip®在人体内的性能。为了验证模拟结果，使用了 I 期临床试验的血浆浓度-时间曲线。获得了绝对平均折叠误差为 1.4。此外，还将药代动力学曲线分解为与体内疗效和安全性相关的不同分数。尽管总血浆浓度在 0.72 小时后达到 2298ng/mL，但单分子药物仅占药物的一小部分，浓度为 321ng/mL。
