Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children

结核病(TB)和人类免疫缺陷病毒(HIV)感染是发病率和 儿童死亡率。儿童特别容易感染艾滋病毒和结核病的双重流行 在非洲。感染艾滋病毒的儿童患活动性结核病和死于结核病的风险更高。风险很高， 结核病/艾滋病毒混合感染儿童死亡的部分原因是延迟治疗或其中一种药物治疗效果不佳。 或者两种感染都有。特别是，由于药物配方不当或药物配方不当导致的次优药物动力学(PK) 剂量可能是导致儿童高死亡率的原因之一。缺乏新的儿科配方的PK数据 在非洲儿童中用于治疗结核病和艾滋病毒的资金是取得最佳结果的主要障碍。 我们的长期目标是产生新的PK数据的新的固定剂量组合(FDC)配方的抗 非洲儿童和青少年使用的结核病和抗逆转录病毒药物。我们的主要目标是确定 对儿童友好的新FDC配方的PK和与个体间变异性相关的协变量 儿童使用的异烟肼/利福平/吡津酰胺以及青少年使用的非专利FDC抗逆转录病毒药物。这个 最重要的假设是，以前的研究低估了发育和遗传的影响 药物代谢的因素、药物之间的相互作用以及药物浓度低于最佳水平的风险 孩子们。我们的目标将通过三个具体目标来实现。目标1将评估新儿科的PK 异烟肼/利福平/吡津酰胺FDC配方，并使用PK数据建立种群PK模型和 用于预测儿童最佳体重带剂量的刺激。目标2将检查利福平的效果- 抗结核治疗对结核/HIV混合感染儿童病毒学应答的影响 单独使用以法韦伦兹为基础的疗法治疗艾滋病毒。目标3将测定替诺福韦的细胞内PK 对10至19岁的青少年进行二磷酸盐和三磷酸恩曲西巴因的研究，并检查 年龄和结核合并感染对这些合成代谢PK的影响。作为新的儿科抗结核制剂和 抗逆转录病毒药物在撒哈拉以南非洲地区扩大，非洲儿童的PK和PK-PD数据需要 验证配方和剂量指南，或为指南修订提供相关数据。这 创新的建议有可能为优化治疗方案提供关键数据 儿童结核病、艾滋病毒和结核/艾滋病毒混合感染。

Tuberculosis (TB) and human immunodeficiency virus (HIV) infections are major causes of morbidity and mortality in children. Children are highly susceptible to the dual epidemics of HIV and TB infections especially in Africa. HIV-infected children are at a higher risk of developing active TB and dying of TB. The high risk of death in children with TB/HIV coinfection is in part due to delayed therapy or suboptimal drug treatment of one or both infections. In particular, suboptimal pharmacokinetics (PK) due to inappropriate drug formulations or dosing may contribute to the high mortality in children. The lack of PK data of new pediatric formulations rolled out for the treatment of TB and HIV in children in Africa represents a major obstacle to optimized outcomes. Our long-term goal is to generate novel PK data of the new fixed-dose combination (FDC) formulations of anti- TB and antiretroviral drugs used in children and adolescents in Africa. Our primary objective is to determine the PK and covariates associated with interindividual variability in the PK of the new child-friendly FDC formulation of isoniazid/rifampin/pyrazinamide for children as well as generic FDC antiretrovirals used in adolescents. The overarching hypothesis is that previous studies have underestimated the effect of developmental and genetic factors in drug metabolism, drug-drug interactions, as well as the risk for suboptimal drug concentrations in children. Our goal will be pursued through three specific aims. Aim 1 will evaluate the PK of the new pediatric isoniazid/rifampin/pyrazinamide FDC formulation, and use the PK data to develop a population PK model and stimulations to predict optimal weight-band dosages for children. Aim 2 will examine the effect of rifampin- containing anti-TB therapy on virological response in children with TB/HIV coinfection compared to those with HIV alone treated with efavirenz-based therapy. Aim 3 will determine the intracellular PK of tenofovir diphosphate and emtricibaine triphosphate in adolescents aged 10 to 19 years old, as well as examine the effect of age and TB coinfection on the PK of these anabolities. As new pediatric formulations of anti-TB and ARVs are scaled up in sub-Saharan Africa, PK and PK-PD data in African children are needed to either validate the formulations and dosing guidelines or provide relevant data for guidelines revisions. This innovative proposal has the potential to provide critical data for optimization of treatment regimens for childhood TB, HIV and TB/HIV coinfection.