Optimal dosing of 1st line antituberculosis and antiretroviral drugs in children

儿童一线抗结核药物和抗逆转录病毒药物的最佳剂量

• 批准号: 8515761
• 负责人: Helen McIlleron
• 金额: $ 34.74万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-22 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515761
• 关键词: 12 year old; 2 year old; Adult; Africa; Africa South of the Sahara; Age; Anti-Retroviral Agents; Antitubercular Agents; Child; Childhood; Data; Development; Dose; Drug Combinations; Drug Formulations; Drug Interactions; Drug Kinetics; Drug toxicity; Ethambutol; Guidelines; HIV; HIV Infections; Infection; Knowledge; Life; Lopinavir; Lopinavir/Ritonavir; Malawi; Modeling; Nevirapine; Nutritional status; Oral; Overdose; Petit mal status; Pharmaceutical Preparations; Population; Population Sizes; Process; Protease Inhibitor; Public Health; Pyrazinamide; Regimen; Research; Rifampin; Risk; Ritonavir; Solutions; South Africa; Therapeutic; Tuberculosis; Uncertainty; Weight; World Health Organization; absorption; base; cohort; drug clearance; evidence based guidelines; high risk; improved; isoniazid; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): In Africa, children carry a large proportion of the burden of tuberculosis (TB). Recent studies suggest that first line anti-TB drugs (isoniazid, rifampin, ethambutol and pyrazinamide) are often under-dosed in adults, especially with HIV, and children. In 2010, the World Health Organization (WHO) proposed a revised mg/kg dosing strategy for anti-TB drugs for children. The revised guidelines are based on a very limited body of data. As there is a non-linear relationship between weight and drug clearance, the standardized mg/kg dosing is likely to result in under-dosing in small children compared to larger children. The PIs propose to evaluate the 2010 WHO dosing guidelines by assessing the pharmacokinetics of first line anti-TB drugs in 240 children across pediatric populations (<12 years, HIV infected and uninfected, and varied nutritional status) and regions (Cape Town, South Africa and Blantyre, Malawi). Improving the understanding of the pharmacokinetics of first line anti-TB drugs in children will aid in the development of evidence-based guidelines for pediatric TB treatment. In sub-Saharan Africa, the burden of HIV infection in children remains high. Important management challenges in children with TB and HIV include drug-drug interactions and overlapping drug toxicities. Co-administration of rifampicin dramatically reduces the concentrations of protease inhibitors. Using double dose lopinavir/ritonavir (LPV/r) in the commercially available 4:1 ratio has been shown to be insufficient. LPV/r in a ratio of LPV/r=1:1 results in adequate pharmacokinetic parameters but is not feasible because of the complexity of dosing LPV/r and ritonavir separately, and the short shelf life of oral ritonavir solution. Alternative solutions for the management of HIV and TB concomitantly in children are thus urgently needed. The PIs propose to evaluate an 8-hourly weight band-based dosing strategy for LPV/r using commercially available LPV/r in children receiving rifampicin-based TB treatment. In many settings nevirapine (NVP)-based regimens remain the only effective ART available. Young children may be at high risk of subtherapeutic NVP in the presence of rifampin. The proposed research will define optimal dosing of anti-TB drugs in children and generate evidence for optimization TB/HIV co-infection in children.

描述(申请人提供)：在非洲，儿童承担了很大比例的结核病(TB)负担。最近的研究表明，一线抗结核药物(异烟肼、利福平、乙胺丁醇和吡嗪酰胺)在成人中通常剂量不足，特别是在艾滋病毒携带者和儿童中。2010年，世界卫生组织(WHO)提出了修订后的儿童抗结核病药物毫克/公斤剂量战略。修订后的指导方针所依据的数据非常有限。由于体重和药物清除量之间存在非线性关系，与较大的儿童相比，标准化的mg/kg剂量很可能导致较小儿童的剂量不足。PIS建议通过评估240名儿童的一线抗结核药物在240名儿童中的药代动力学来评估2010年世卫组织剂量指南，这些儿童分布在儿童人口(12岁，艾滋病毒感染和未感染，以及不同的营养状况)和地区(南非开普敦和马拉维布兰太尔)。提高对一线抗结核药物在儿童中的药代动力学的了解将有助于制定儿童结核病治疗的循证指南。在撒哈拉以南非洲，儿童感染艾滋病毒的负担仍然很重。患有结核病和艾滋病毒的儿童面临的重要管理挑战包括药物-药物相互作用和重叠的药物毒性。联合应用利福平可显著降低蛋白水解酶抑制剂的浓度。使用商业上可用的4：1比例的双剂量洛比那韦/利托那韦(LPV/r)已被证明是不够的。LPV/r=1：1的LPV/r可获得较好的药代动力学参数，但由于LPV/r和利托那韦分别给药的复杂性，以及利托那韦口服液的货架期较短，这是不可行的。因此，迫切需要在儿童中管理艾滋病毒和结核病的替代解决办法。PIs建议对接受利福平结核病治疗的儿童使用市面上可获得的LPV/r评估LPV/r的8小时重量条带剂量策略。在许多情况下，基于奈韦拉平(NVP)的方案仍然是唯一有效的可用ART。在利福平存在的情况下，年幼的儿童可能有较高的非治疗性NVP风险。这项拟议的研究将确定儿童抗结核病药物的最佳剂量，并为优化儿童结核病/艾滋病毒联合感染提供证据。