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

接受疟疾化学预防的乌干达孕妇和儿童中未结合的哌喹药代动力学暴露

• 批准号: 10439896
• 负责人: Liusheng Huang
• 金额: $ 20.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-28 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439896
• 关键词: 5 year old; Address; Adult; Antimalarials; Artemisinins; Binding Proteins; Biological; Biological Assay; Blood capillaries; Cardiovascular system; Cessation of life; Chemoprevention; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Communicable Diseases; Data; Development; Dimensions; Dose; Drug Kinetics; Evaluation; Exhibits; Exposure to; Falciparum Malaria; Future; Goals; Half-Life; Infant; Knowledge; Liquid Chromatography; Malaria; Malaria prevention; Measures; Membrane; Methods; Outcome; Parents; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Plasma; Population; Pregnancy; Pregnant Women; Prevention; Preventive treatment; Public Health; Recommendation; Regimen; Research; Resources; Risk; Sampling; Site; Special Population; Techniques; Testing; Time; Toxic effect; Uganda; Ultrafiltration; Vulnerable Populations; aged; base; cohort; dosage; improved; infancy; lead-binding proteins; novel; pharmacodynamic model; pharmacokinetics and pharmacodynamics; programs; tandem mass spectrometry; treatment guidelines; two-dimensional

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.

项目概要 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 每年有五十万人死亡。孕妇和儿童作为最脆弱的人群 建议进行预防性治疗。我们的计划已经解决了如何 妊娠和儿童发育影响药物的药代动力学（PK）和药效学（PD） 双氢青蒿素 (DHA)-哌喹 (PQ)，首选青蒿素联合疗法 化学预防。我们证明孕妇和孕妇的百草枯暴露量减少了近 40% 儿童与非怀孕成人相比。然而，考虑到 PQ 与蛋白质高度结合，改变 怀孕和儿童发育期间的蛋白质结合可能会影响自由结合的未结合 PQ 的比例。 穿过生物膜并在靶位点发挥药理作用，因此，剂量调整 应权衡未结合的 PQ 暴露。尽管总 PQ 暴露量已得到充分研究，但未结合的游离 PQ 暴露仍有待探索。在本提案中，我们将评估未结合的 PQ 药代动力学 利用现有临床研究的资源，对孕妇和儿童进行暴露。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 (2D-LC) 用于使用较小的血浆样品分离和定量未结合的 PQ 体积。最后，我们还将探索未结合 PQ 的 PK/PD 建模并识别未结合 PQ 与疟疾防护相关的浓度。从未结合的 PQ 暴露中获得的知识是 预计将优化对总百草枯暴露的解释，为孕妇提供治疗指南 和孩子们。这种新颖的二维液相色谱方法如果成功的话，可以作为分析其他物质的通用方法。 未结合的药物。

项目成果

Determination of sulfadoxine and pyrimethamine in microvolume human plasma using ultra high performance liquid chromatography-tandam mass spectrometry.

超高效液相色谱-串联质谱法测定微量人血浆中的磺胺多辛和乙胺嘧啶。

• DOI: 10.1016/j.jchromb.2024.124030
• 发表时间: 2024
• 期刊: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
• 作者: Sok,Vong;Marzan,Florence;Roh,Michelle;Guo,Kevin;Legac,Jenny;Mwebaza,Norah;Dorsey,Grant;Rosenthal,PhilipJ;Aweeka,FrancescaT;Huang,Liusheng
• 通讯作者: Huang,Liusheng