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基于生理学的药物动力学建模,以预测德西米拉贡 (MT-7117) 的潜在药物相互作用
Akihito Ogasawara1, Koki Kojima1, Yukiko Murata1
1Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
British journal of clinical pharmacology
|October 5, 2024
概括
德西米拉贡 (Dersimelagon) 是一种新型抗原皮症药物,在较低剂量使用阿托瓦斯塔丁和罗斯瓦斯塔丁时,药物相互作用风险很小. 基于生理学的药理动力学建模表明需要谨慎,但没有显著的临床影响.
科学领域:
- 药理学和药物新陈代谢
- 临床药理学 临床药理学
- 药用化学 医学化学
背景情况:
- 德西米拉贡是一种临床的口服选择性黑色皮质素-1受体激动剂,用于原形皮质症.
- 之前的研究表明,在更高剂量的情况下,与阿托瓦斯塔丁和罗斯瓦斯塔丁等乳腺癌抗性蛋白 (BCRP) 基质存在潜在的药物相互作用 (DDI).
- 基于生理学的药理动力学 (PBPK) 建模对于预测较低,治疗相关剂量的DDI至关重要.
研究的目的:
- 调查低剂量德西米拉贡 (100毫克和200毫克) 与BCRP基质,阿托瓦斯塔丁和罗斯瓦斯塔丁的DDI潜力.
- 利用PBPK建模来模拟和预测同时使用药物的药理学变化.
- 评估这些潜在的DDI的临床意义.
主要方法:
- 使用in silico,in vitro和in vivo数据构建了dersimelagon的PBPK模型.
- 模拟与阿托瓦斯塔丁和罗斯瓦斯塔丁同时服用德西米拉贡 (100 mg 和 200 mg) 的实验.
- 评估DDI潜力与各种输送系统,包括BCRP,CYP3A4,P-gp,OATP1B1/1B3和OAT3.3的评估.
主要成果:
- PBPK建模预测,在100-200毫克德西米拉贡时,阿托瓦斯塔丁暴露率增加了1.21至1.45倍.
- 预计罗苏瓦斯塔丁暴露的增加在100-200毫克德西米拉贡的1.34至2.40倍之间.
- 对两种他类药物系统性暴露的模拟增加不被认为具有临床意义.
结论:
- PBPK建模表明,与阿托瓦斯塔丁或罗斯瓦斯塔丁同时服用100毫克或200毫克德西米拉贡并不会导致临床上显著的DDI.
- 虽然模拟暴露变化并不显著,但建议进行临床监测.
- 这项研究为低剂量的德西米拉贡的DDI概况提供了有价值的见解.
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