Shakushiro Kohsuke, Kawano Hiroki, Nakata Mari, Kita Aya, Maeda Atsushi, Watanabe Shunsuke, Sako Kazuhiro, Oku Naoto
Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc.,, 180 Ozumi, Yaizu-shi,, Shizuoka, 425-0072, Japan,
Pharm Res. 2015 Jan;32(1):238-47. doi: 10.1007/s11095-014-1458-4. Epub 2014 Jul 18.
Sepantronium bromide (YM155) is administered by 168-hour continuous infusions in clinical studies due to its time-dependent pharmacological efficacy and rapid elimination from plasma. To enable more convenient administration, i.e., bolus injections with low frequency, we prepared liposomal formulations of YM155 and evaluated their antitumor activities.
A kinetic simulation model of liposomal YM155 to predict the free drug concentration in both tumor and plasma was developed. A liposomal formulation with the target drug release rate was prepared based on the simulation. Antitumor activities of the formulation were examined in various tumor xenograft mouse models. In addition, antitumor activities of liposomal formulations with different drug release rates were compared in order to confirm the validity of the simulation-based prediction.
Liposomal YM155 with the release half-life of 48 h was prepared as a promising formulation. This formulation showed significantly potent antitumor activities in tumor xenograft models by weekly bolus injections. Further studies demonstrated that this release rate was optimal for YM155 in terms of both efficacy and safety.
We successfully developed a liposomal formulation of YM155 that could substitute for long-term continuous infusion of the drug solution in clinical settings by being given as weekly bolus injections.
由于溴化塞帕替尼（YM155）具有时间依赖性药理作用且能迅速从血浆中清除，在临床研究中采用168小时持续输注给药。为了实现更便捷的给药方式，即低频推注，我们制备了YM155脂质体制剂并评估了其抗肿瘤活性。
建立了脂质体YM155的动力学模拟模型，以预测肿瘤和血浆中的游离药物浓度。基于该模拟制备了具有目标药物释放速率的脂质体制剂。在多种肿瘤异种移植小鼠模型中检测了该制剂的抗肿瘤活性。此外，比较了不同药物释放速率的脂质体制剂的抗肿瘤活性，以确认基于模拟预测的有效性。
制备了释放半衰期为48小时的脂质体YM155，作为一种有前景的制剂。通过每周推注给药，该制剂在肿瘤异种移植模型中显示出显著的抗肿瘤活性。进一步研究表明，就疗效和安全性而言，该释放速率对YM155是最佳的。
我们成功开发了一种YM155脂质体制剂，通过每周推注给药，可在临床环境中替代药物溶液的长期持续输注。
