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.
Department of Physics, Humboldt University Berlin, Newtonstraße 15, 12489 Berlin, Germany.
J Control Release. 2019 Aug 28;308:57-70. doi: 10.1016/j.jconrel.2019.06.029. Epub 2019 Jun 24.
Foscan®, a formulation comprising temoporfin dissolved in a mixture of ethanol and propylene glycol, has been approved in Europe for palliative photodynamic therapy of squamous cell carcinoma of the head and neck. During clinical and preclinical studies it was observed that considering the administration route, the drug presents a rather atypical plasma profile as plasma concentration peaks delayed. Possible explanations, as for example the formation of a drug depot or aggregation after intravenous administration, are discussed in current literature. In the present study an advanced in silico model was developed and evaluated for the detailed description of Foscan® pharmacokinetics. Therefore, in vitro release data obtained from experiments with the dispersion releaser technology investigating dissolution pressures of various release media on the drug as well as in vivo data obtained from a clinical study were included into the in silico models. Furthermore, precipitation experiments were performed in presence of biorelevant media and precipitates were analyzed by nanoparticle tracking analysis. Size analysis and particle fraction were also incorporated in this model and a sensitivity analysis was performed. An optimal description of the in vivo situation based on in vitro release and particle characterization data was achieved, as demonstrated by an absolute average fold error of 1.21. This in vitro-in vivo correlation provides an explanation for the pharmacokinetics of Foscan® in humans.
Foscan®，一种由替莫泊芬溶解在乙醇和丙二醇混合物中的制剂，已在欧洲获得批准，用于头颈部鳞状细胞癌的姑息性光动力疗法。在临床和临床前研究中观察到，考虑到给药途径，该药物的血浆浓度峰值延迟，表现出相当非典型的血浆特征。目前的文献中讨论了可能的解释，例如静脉给药后形成药物库或聚集。在本研究中，开发并评估了一种先进的计算模型，以详细描述 Foscan®的药代动力学。因此，将通过使用分散释放技术获得的体外释放数据，该技术研究了各种释放介质对药物的溶解压力，以及从临床研究中获得的体内数据，纳入到计算模型中。此外，还在生物相关介质中进行了沉淀实验，并通过纳米颗粒跟踪分析对沉淀物进行了分析。该模型还纳入了大小分析和颗粒分数，并进行了敏感性分析。通过体外释放和颗粒特征数据实现了对体内情况的最佳描述，证明了绝对平均折叠误差为 1.21。这种体外-体内相关性解释了 Foscan®在人体中的药代动力学。
