Mind the gaps: Pharmacokinetic research to advance pediatric HIV/TB cotreatment and TB prevention

注意差距：推进儿科艾滋病毒/结核病联合治疗和结核病预防的药代动力学研究

• 批准号: 10390005
• 负责人: Holly Elizabeth Rawizza
• 金额: $ 32.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-07 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390005
• 关键词: 6 year old; Address; Adolescent; Adult; Adverse event; Age; Antimycobacterial Agents; Biological Markers; CYP3A4 gene; Caring; Cause of Death; Child; Childhood; Cholesterol; Country; Data; Disease; Dose; Drug Kinetics; Exhibits; Exposure to; FDA approved; Funding; Goals; Guidelines; HIV; HIV/TB; Home; Hydroxycholesterols; Individual; Infrastructure; International Maternal Pediatric Adolescent AIDS Clinical Trials; Knowledge; Lopinavir/Ritonavir; Methods; Mind; Nigeria; Outcome; Persons; Pharmacodynamics; Phenotype; Population; Positioning Attribute; Prevention; Prevention strategy; Prospective cohort study; Public Health; Research; Rifabutin; Rifampin; Rifamycins; Safety; Services; Tablets; Testing; Time; Treatment Protocols; Treatment outcome; Tuberculosis; Ursidae Family; Vulnerable Populations; appropriate dose; base; cohort; design; dosage; drug action; efficacious treatment; improved; improved outcome; inter-individual variation; isoniazid; novel; novel drug combination; novel marker; pediatric human immunodeficiency virus; pharmacodynamic model; programs; prospective; rifapentine; safety study; treatment duration; treatment guidelines; tuberculosis treatment

PROJECT SUMMARY Tuberculosis (TB) is the leading cause of death among children with HIV, yet insufficient data are available on the pharmacokinetics (PK) of newer HIV/TB cotreatment and TB prevention strategies in children. Global expansion of dolutegravir use for young children has the potential to significantly improve HIV treatment outcomes, but there are no PK data to inform use of double-dose dolutegravir during rifampicin-containing HIV/TB cotreatment for children under 6 years of age. Further, multiple studies have shown that current WHO-recommended rifampicin dosages result in low concentrations in most children, and high-dose rifampicin may improve outcomes and shorten treatment duration in adults and children. Yet the impact of high-dose rifampicin on dolutegravir exposures has not been examined. Finally, it is well-established that treatment of latent TB infection (LTBI) significantly reduces incident TB among HIV-infected persons, yet this strategy is vastly underused in endemic settings. Short-course LTBI treatment regimens increase completion rates, but have not been studied among HIV-infected children receiving dolutegravir. To address these gaps in knowledge and provide needed PK and safety data to extend use of these promising strategies from adults to children, we will carry out two prospective PK studies to examine: (1) twice daily dolutegravir during both standard- and high-dose rifampicin, and (2) PK of dolutegravir during weekly rifapentine/isoniazid for TB prevention/LTBI treatment. To advance our understanding of underlying mechanisms of drug action we will also examine the impact of standard- and high-dose daily rifampicin and weekly rifapentine on the 4β-hydroxy-cholesterol to cholesterol ratio, an endogenous biomarker of CYP3A4 activity. This will provide critical pharmacodynamic (PD) data for use in population PK/PD models to quantify variability and inform optimal drug dosing in this vulnerable population of children. Nigeria is home to more children living with HIV than any other country in the world, and also bears one of the greatest burdens of incident TB. Since 2004, APIN Public Health Initiatives has provided HIV care and treatment to over 20,000 children in Nigeria and thus is uniquely positioned to support this vital PK research. This combination of studies addresses critical gaps in knowledge regarding PK and safety of newer drug combinations for HIV/TB cotreatment and TB prevention, findings that may inform WHO guidance on use in children, toward the goal of curbing TB’s devastating toll in this vulnerable population.

项目摘要 结核病（TB）是艾滋病毒儿童死亡的主要原因，但数据不足 关于儿童的较新的HIV/TB共同治疗和预防结核病预防策略的药代动力学（PK）。全球的 幼儿使用DoluteGravir的扩展有可能显着改善HIV治疗 结果，但是没有PK数据可以告知含双剂量的Dolutegravir在含利福平的情况下使用 6岁以下儿童的HIV/TB共同治疗。此外，多个研究表明当前 谁推荐的利福平剂量会导致大多数儿童浓度低，高剂量 利福平可能会改善成人和儿童的预后和缩短治疗持续时间。然而 尚未检查DoluteGravir暴露的高剂量利福平。最后，已经建立了 潜在结核病感染（LTBI）可显着降低HIV感染者的事件TB，但 在内在环境中，该策略充分利用了。短路LTBI治疗方案增加 完成率，但尚未在接受DoluteGravir的HIV感染儿童中进行研究。解决 这些知识的差距，并提供所需的PK和安全数据，以扩大这些诺言的使用 从成年人到儿童的策略，我们将进行两项前瞻性PK研究以进行检查：（1）每天两次 在标准和高剂量利福平期间的Dolutegravir，以及（2）每周的DoluteGravir 利福丁/异尼二嗪用于TB预防/LTBI治疗。 为了促进我们对毒品作用的潜在机制的理解，我们还将研究 4β-羟基 - 胆固醇上的标准和高剂量每日利福平和每周利福丁到胆固醇 比率，CYP3A4活性的内源性生物标志物。这将提供关键的药效学（PD）数据 用于人口PK/PD模型，以量化可变性并告知此脆弱的最佳药物剂量 儿童人口。 尼日利亚比世界上任何其他国家都有更多的艾滋病毒儿童的家园，也有一个 事件结核病最大的伯恩斯。自2004年以来，APIN公共卫生计划提供了艾滋病毒护理和 在尼日利亚为20,000多名儿童进行治疗，因此在支持这项重要的PK研究方面具有独特的位置。 这项研究的组合解决了有关PK知识和新药物安全性的关键差距 艾滋病毒/结核病共同治疗和预防结核病的组合，可能会告知谁使用的指南 儿童，目的是遏制结核病在这个脆弱人群中造成的毁灭性损失。