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2亿例病例 每年有50万人死亡孕妇和儿童是最脆弱的群体， 建议进行预防性治疗。我们的计划已经解决了一些基本问题， 妊娠和儿童发育影响药物的药代动力学（PK）和药效学（PD） 二氢青蒿素（DHA）-哌喹（PQ），优选的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%， 与未怀孕的成年人相比。然而，考虑到PQ是高度蛋白结合的， 妊娠和儿童发育期间的蛋白质结合可能会影响游离的未结合PQ分数， 穿过生物膜并在靶部位发挥药理作用，因此，剂量调整 应考虑未结合PQ暴露。尽管已对总PQ暴露进行了充分研究，但未结合游离PQ 暴露情况仍有待探索。在本提案中，我们将评价未结合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20 pg/mL的游离PQ，并将探索二维 液相色谱法（2D-LC），用于分离和定量较小的血浆样品的未结合PQ 音量.最后，我们还将探索使用未结合PQ的PK/PD建模，并确定未结合PQ 与疟疾保护有关的浓度。获得的关于未结合PQ暴露的知识是 预计将优化总PQ暴露的解释，为孕妇提供治疗指南 和儿童该方法如能成功，可作为一种通用的分析方法，用于其他化合物的分析。 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.