Unbound piperaquine pharmacokinetic exposure in Ugandan pregnant women and children receiving malaria chemoprevention

项目摘要 疟疾仍然是世界上最具挑战性的传染病之一，造成约2亿病例 每年有50万人死亡。作为最脆弱的人群，孕妇和儿童 推荐用于预防性治疗。我们的节目已经解决了一些基本问题，比如如何 孕期和儿童期发育对阿司匹林药代动力学(PK)和药效学(PD)的影响 双氢青蒿素(DHA)-哌喹(PQ)，以青蒿素为基础的联合治疗 化学预防。我们证明，孕妇的PQ暴露减少了近40%， 将儿童与未怀孕的成年人进行比较。然而，考虑到PQ是高度结合蛋白质的，改变 妊娠和儿童发育期间的蛋白质结合可能会影响游离的PQ部分 横向生物膜在靶部位发挥药理作用，因此，剂量调整 应该权衡未绑定的PQ暴露。虽然总的PQ暴露已经得到了很好的研究，但非结合的自由PQ 曝光率仍有待探索。在这项建议中，我们将评估游离PQ的药代动力学 孕妇和儿童的暴露，利用现有临床研究的资源。我们 开发了一种灵敏的方法来测量低至20pg/ml的游离PQ，并将探索二维 以较小的血浆样品分离和定量游离PQ的高效液相色谱(2D-LC) 音量。最后，我们还将探索使用未绑定PQ的PK/PD建模，并确定未绑定PQ 与疟疾保护相关的浓度。从非绑定PQ暴露中获得的知识是 预计将优化对总PQ暴露的解释，为孕妇提供治疗指南 还有孩子。这种新的2D-LC方法如果成功，可以作为分析其他化合物的通用方法 未绑定的毒品。

Project Summary Malaria remains one of the most challenging infectious diseases in the world causing roughly 200 million cases and half a million deaths annually. As the most vulnerable populations, pregnant women and children are recommended for preventive treatment. Our program has addressed fundamental questions as to how pregnancy and childhood development impact the pharmacokinetics (PK) and pharmacodynamics (PD) of dihydroartemisinin (DHA)-piperaquine (PQ), the preferred artemisinin-based combination therapy for chemoprevention. We demonstrated nearly a 40 percent reduction in PQ exposure in pregnant women and children compared to nonpregnant adults. However, considering PQ is highly protein bound, alteration of protein binding during pregnancy and childhood development may impact fraction of unbound PQ that is free to transverse biological membranes and exert pharmacological effect at target sites, therefore, dose adjustment should weigh in unbound PQ exposure. Although total PQ exposure has been well studied, unbound free PQ exposure remains to be unexplored. In this proposal, we will evaluate the unbound PQ pharmacokinetic exposure in pregnant women and children, leveraging resource from the existing clinical studies. We developed a sensitive method to measure free PQ at as low as 20 pg/mL and will explore two dimensional liquid chromatography (2D-LC) for unbound PQ separation and quantitation with a smaller plasma sample volume. Finally, we will also explore PK/PD modelling with unbound PQ and identify the unbound PQ concentrations associated with malaria protection. The knowledge gained on unbound PQ exposure is expected to optimize interpretation of total PQ exposure to inform treatment guidelines for pregnant women and children. The novel 2D-LC method, if succeeded, can be used as a general method for analysis of other unbound drugs.