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

描述（由申请人提供）：在非洲，儿童承担着很大比例的结核病负担。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（特别是艾滋病毒感染者）和儿童中往往剂量不足。2010年，世界卫生组织（世卫组织）提出了一项修订的儿童抗结核药物mg/kg剂量战略。修订后的指导方针是基于非常有限的数据。由于体重和药物清除率之间存在非线性关系，标准化的mg/kg给药可能导致幼儿的给药量低于较大的儿童。这些项目建议通过评估240名儿童(儿童人群（12岁以下、艾滋病毒感染和未感染以及不同营养状况）和地区（南非开普敦和马拉维布兰太尔）一线抗结核药物的药代动力学来评估2010年世卫组织给药指南。提高对儿童一线抗结核药物药代动力学的了解将有助于制定儿童结核病治疗循证指南。在撒哈拉以南非洲，儿童感染艾滋病毒的负担仍然很高。结核病和艾滋病毒儿童的重要管理挑战包括药物-药物相互作用和重叠药物毒性。同时使用利福平可显著降低蛋白酶抑制剂的浓度。以市售的4:1比例使用双倍剂量洛匹那韦/利托那韦（LPV/r）已证明是不够的。LPV/r=1:1的LPV/r可以获得足够的药代动力学参数，但由于LPV/r和利托那韦单独给药的复杂性，以及口服利托那韦溶液的保质期短，因此不可行。因此，迫切需要在儿童中同时管理艾滋病毒和结核病的替代解决办法。pi建议在接受基于利福平的结核病治疗的儿童中使用市售的LPV/r，评估基于8小时体重带的LPV/r给药策略。在许多情况下，以奈韦拉平（NVP）为基础的治疗方案仍然是唯一有效的抗逆转录病毒疗法。在利福平存在的情况下，幼儿发生亚治疗性NVP的风险可能很高。拟议的研究将确定儿童抗结核药物的最佳剂量，并为优化儿童结核/艾滋病毒合并感染提供证据。

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.