Rifabutin pharmacokinetics and safety among HIV/TB coinfected infants receiving lopinavir

接受洛匹那韦治疗的 HIV/TB 合并感染婴儿中利福布汀的药代动力学和安全性

• 批准号: 9926695
• 负责人: Holly Elizabeth Rawizza
• 金额: $ 16.06万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-09 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926695
• 关键词: 15 year old; 3 year old; Address; Adolescent; Adult; Age; Age-Months; Applications Grants; Biological Assay; Caring; Cause of Death; Characteristics; Child; Childhood; Data; Diagnosis; Dose; Drug Interactions; Drug Kinetics; Drug resistance; Enzymes; Evaluation; FDA approved; Goals; Guidelines; HIV; HIV Infections; HIV/TB; Immunocompromised Host; Individual; Infant; Inferior; International; K-Series Research Career Programs; Knowledge; Liver; Lopinavir; Lopinavir/Ritonavir; Malnutrition; Modeling; National Institute of Allergy and Infectious Disease; Neutropenia; Nigeria; Nucleosides; Nutritional status; Outcome; Participant; Patients; Pediatric cohort; Performance; Pharmaceutical Preparations; Pilot Projects; Population; Protease Inhibitor; Recommendation; Regimen; Reporting; Research; Research Priority; Rifabutin; Rifampin; Safety; Serious Adverse Event; Specimen; Treatment Protocols; Treatment outcome; Tuberculosis; United States National Institutes of Health; Urine; Viral Load result; Vulnerable Populations; Weight; World Health Organization; antiretroviral therapy; base; co-infection; cohort; design; effective therapy; experience; immunological status; improved; mortality; novel; pediatric human immunodeficiency virus; pharmacokinetic model; programs; prospective; safety study; treatment guidelines; treatment strategy; tuberculosis diagnostics; tuberculosis treatment; urinary

PROJECT SUMMARY ! Tuberculosis is the leading cause of death among children with HIV, yet optimal cotreatment regimens are lacking, particularly for the youngest and most vulnerable children. As a result, the World Health Organization (WHO) has designated evaluation of newer treatment options for HIV/TB coinfected children a research priority. To address this issue, we will carry out a prospective pharmacokinetic (PK) and safety study to evaluate a novel pediatric cotreatment strategy. For children <3 years of age, lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) is the current WHO-preferred first-line regimen to treat HIV infection. However, potent drug interactions prohibit use of LPV/r along with standard TB treatment in coinfected children, as rifampin lowers LPV concentrations by over 75%. For adults who require protease inhibitors such as LPV/r, the WHO recommends substituting rifabutin, which has minimal effect on LPV concentrations. This strategy has not been adequately studied in children, and so is generally unavailable as a pediatric treatment regimen. The Harvard/APIN pediatric ART program has supported rifabutin access for adults and children in Nigeria since 2008. Our group previously reported favorable programmatic experience with rifabutin in children, and are currently studying rifabutin PK and safety in older pediatric cohorts requiring LPV/r-based ART. At interim analysis, we found that most patients achieved rifabutin concentrations well above the target value, and severe neutropenia, the most concerning potential serious adverse event, was uncommon (5%). However, because the liver enzymes that metabolize rifabutin do not reach adult activity until at least 12 months of age, it is expected that higher rifabutin mg/kg dosing is necessary in infants. Thus, we will evaluate rifabutin concentrations among HIV/TB coinfected infants 2 weeks to <12 months of age. We hypothesize that rifabutin dosed 5 mg/kg daily in this cohort will achieve adequate rifabutin concentrations, equivalent to that observed with 2.5 mg/kg daily in the older cohort. Further, since variability in drug concentrations among children remains a barrier to achieving safe and effective dosing recommendations, we will utilize population PK modeling to quantify variability, evaluating patient factors such as malnutrition and advanced immunocompromise to predict optimal rifabutin dosing by weight. Finally, given the challenge of TB diagnosis among the youngest children, we will also evaluate newer urine-based TB diagnostics in this cohort. The goal of this study is to influence WHO treatment guidelines by providing essential knowledge of the efficacy and safety of this treatment strategy so that we may curb TB’s devastating toll among this highly vulnerable population.

项目摘要 呢 结核病是艾滋病毒儿童死亡的主要原因，但最佳的共同治疗方案是 缺乏，特别是对于最年轻，最脆弱的孩子。结果，世界健康 组织（WHO）已指定对HIV/TB共感染儿童的新治疗方案的评估 研究优先。为了解决这个问题，我们将执行前瞻性药代动力学（PK）和安全性 评估新的小儿共同治疗策略的研究。对于<3岁的儿童，Lopinavir/Ritonavir （基于LPV/R）基于抗逆转录病毒疗法（ART）是当前偏爱的一线疗法，用于治疗HIV 感染。但是，潜在的药物相互作用禁止使用LPV/R以及标准结核病治疗 共同感染的儿童，因为利福平将LPV浓度降低了75％以上。对于需要蛋白酶的成年人 抑制剂，例如LPV/R，谁建议取代利法布丁，对LPV的影响很小 浓度。这种策略在儿童中尚未充分研究，因此通常不可用 作为小儿治疗方案。 哈佛/阿普丁儿科艺术计划已支持尼日利亚成人和儿童的利法布丁访问 自2008年以来。我们的小组以前报告了利法布丁在儿童中的有利的程序经验， 目前正在研究需要LPV/R基于ART的较旧的小儿同类群体中的Rifabutin PK和安全性。在 临时分析，我们发现大多数患者达到利福布丁浓度远高于目标值， 严重的中性粒细胞减少症是最关心的潜在严重不良事件，并不常见（5％）。 但是，由于代谢利福丁的肝酶直到至少12个才能达到成人活性 几个月大，预计在婴儿中需要更高的利福布丁MG/kg剂量。那我们会的 评估2周至<12个月大的HIV/TB共感染婴儿中的利福布丁浓度。我们 假设利法布丁在该队列中每天服用5 mg/kg的利法布丁将获得足够的利福布丁浓度， 相当于较老的队列中每天2.5 mg/kg观察到的。此外，由于药物的变异性 儿童的集中仍然是实现安全有效的给药建议的障碍， 我们将利用总体PK建模来量化可变性，评估患者因素（例如营养不良） 和先进的免疫功能低下，以预测重量最佳的利法布林剂量。最后，考虑到挑战 在最小的孩子中，结核病诊断，我们还将评估新的基于尿液的结核病诊断。 这个队列。这项研究的目的是通过提供必不可少的人来影响谁的治疗指南 了解该治疗策略的效率和安全性，以便我们可以遏制结核病的毁灭性损失 在这个高度脆弱的人群中。