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

描述（由申请人提供）：在非洲，儿童承担了结核病（TB）负担的很大一部分。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）和儿童中的剂量往往不足。2010年，世界卫生组织（世卫组织）提出了经修订的儿童抗结核药物mg/kg剂量策略。修订后的准则所依据的数据非常有限。由于体重与药物清除率之间存在非线性关系，因此与较大儿童相比，标准化mg/kg剂量可能导致较小儿童的剂量不足。PI建议通过评估一线抗结核药物在儿科人群（<12岁，HIV感染和未感染，不同营养状况）和地区（南非开普敦和马拉维布兰太尔）的240名儿童中的药代动力学，评价2010年WHO剂量指南。提高对一线抗结核药物在儿童中的药代动力学的理解将有助于制定儿科结核治疗的循证指南。在撒哈拉以南非洲，儿童感染艾滋病毒的负担仍然很重。结核病和艾滋病毒儿童的重要管理挑战包括药物相互作用和重叠的药物毒性。利福平的共同管理显着降低蛋白酶抑制剂的浓度。使用市售4：1比例的双倍剂量洛匹那韦/利托那韦（LPV/r）已被证明是不够的。以LPV/r=1：1的比例给予LPV/r可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利托那韦口服溶液的有效期较短，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方案。PI建议在接受利福平为基础的TB治疗的儿童中，使用市售LPV/r，评价LPV/r的8小时体重带为基础的给药策略。在许多情况下，奈韦拉平（NVP）为基础的方案仍然是唯一有效的ART。在存在利福平的情况下，幼儿可能处于亚治疗NVP的高风险中。拟议的研究将确定儿童抗结核药物的最佳剂量，并为儿童结核病/艾滋病毒合并感染的优化提供证据。

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.