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.

项目总结 好了！ 结核病是感染艾滋病毒的儿童的主要死亡原因，但最佳的共同治疗方案是 缺乏，特别是对于最年幼和最脆弱的儿童。因此，世界卫生组织 世界卫生组织(WHO)已指定对艾滋病毒/结核病合并感染儿童的新治疗方案进行评估 研究优先。为了解决这个问题，我们将进行前瞻性药代动力学(PK)和安全性研究 评估一种新的儿科联合治疗策略的研究。3岁以下儿童服用洛匹那韦/利托那韦 基于LPV/r的抗逆转录病毒疗法(ART)是目前世卫组织首选的治疗艾滋病毒的一线方案 感染。然而，强烈的药物相互作用禁止在标准的结核病治疗中使用LPV/r 合并感染的儿童，因为利福平可使LPV浓度降低75%以上。适用于需要蛋白酶的成年人 如LPV/r等抑制剂，世卫组织建议替代利福布汀，后者对LPV的影响最小 浓度。这一策略还没有在儿童中得到充分的研究，因此通常无法获得。 作为一种儿科治疗方案。 哈佛/APIN儿科ART项目支持尼日利亚成人和儿童使用利福布汀 自2008年以来。我们小组之前报道了利福布汀在儿童中的良好方案经验，以及 目前正在研究利福布汀PK和需要基于LPV/R的ART的老年儿科队列的安全性。在… 中期分析，我们发现大多数患者的利福平浓度远远高于目标值， 而严重的中性粒细胞减少，最受关注的潜在严重不良事件，是不常见的(5%)。 然而，因为代谢利福布汀的肝酶至少要到12点才能达到成人的活性。 几个月大时，预计婴儿需要较高剂量的利福布汀mg/kg。因此，我们将 评估2周至12个月大的HIV/TB混合感染婴儿中利福布汀的浓度。我们 假设在这个队列中每天服用5毫克/公斤的利福布汀将达到足够的利福布汀浓度， 相当于在老年队列中观察到的每天2.5毫克/公斤的剂量。此外，由于药物的可变性 儿童的浓度仍然是实现安全有效的剂量建议的障碍， 我们将利用人口PK模型来量化变异性，评估患者因素，如营养不良 和先进的免疫妥协，以预测最佳利福布汀重量剂量。最后，考虑到挑战 对于最年幼儿童的结核病诊断，我们还将评估新的尿液结核病诊断方法 这群人。本研究的目标是通过提供必要的信息来影响世卫组织的治疗指南 了解这种治疗策略的有效性和安全性，以便我们可以遏制结核病的破坏性死亡 在这些高度脆弱的人群中。