针对优化吸入喷雾干燥的酸配方的药理学考虑
Shekhar B Yeshwante1, Patrick Hanafin1, Brittany K Miller2
1Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
开发新的吸入型酸 (POA) 配方可以对抗耐药结核病 (TB). 最好的配方,POA马尔托德素,显示高肺部暴露,提供了对抗PZA耐药结核病有前途的战略.
科学领域:
- 药理学 药理学是指药理学的学科.
- 药物运输 药物运输 药物运输
- 传染性疾病 传染性疾病
背景情况:
- 结核病 (TB) 仍然是全球主要的健康威胁,耐药性使治疗复杂化.
- 皮拉津胺 (PZA) 对于结核病治疗至关重要,但耐药性,通常是由于*pncA*基因的突变,是一个越来越令人担忧的问题.
- 传统的PZA输送可能会导致肺部度不足,需要使用其他输送途径.
研究的目的:
- 开发和描述用于肺部输送的酸 (POA) 新型干粉配方.
- 在临床前的试验猪模型中评估POA配方的药理动力学概况.
- 利用基于机制的药代动力学模型 (MBM) 来预测肺部暴露的最佳配方.
主要方法:
- 开发了三种不同的干粉POA配方.
- 用于肺部输送可行性的配方的物理化学表征.
- 在口服,静脉注射和内内注射后,在几内亚猪中进行的药理动力学 (PK) 研究.
- 开发和应用基于机制的药物动力学模型 (MBM) 来分析PK数据.
主要成果:
- 与其他测试的配方相比,POA马尔托德素配方表现优越.
- 这种配方实现了最高的表皮内膜液 (ELF) - 血 (203) 和肺组织 - 血 (30.4) 暴露比率.
- 在肺部注射 (15.5分钟) 后迅速观察到高峰ELF度 (171nM).
结论:
- 吸入的POA,特别是马尔托德克斯特林配方,提供了一种有前途的策略,以克服结核病中PZA耐药性.
- 开发的MBM有效地描述了POA的药理动力学,通过不同的施用途径.
- 临床前数据支持吸入POA马尔托德林产品治疗耐药结核病的潜在可行性.
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