Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children

结核病和人体免疫缺陷病毒感染是发病的主要原因， 儿童死亡率。儿童特别容易感染艾滋病毒和结核病这两种流行病， 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。的高风险 结核病/艾滋病病毒合并感染儿童的死亡部分是由于治疗延迟或药物治疗不佳， 或两种感染。特别是，由于不适当的药物制剂或 剂量可能导致儿童的高死亡率。缺乏新儿科制剂的PK数据 非洲儿童结核病和艾滋病毒的治疗是取得最佳成果的主要障碍。 我们的长期目标是生成新的抗-HCV固定剂量复方制剂（FDC）的新PK数据。 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 PK和与新型儿童友好型FDC制剂PK个体间变异性相关的协变量 用于儿童的异烟肼/利福平/吡嗪酰胺以及用于青少年的通用FDC抗逆转录病毒药物。的 总体假设是，以前的研究低估了发育和遗传的影响， 药物代谢、药物间相互作用以及药物浓度低于最佳水平的风险因素， 孩子我们将通过三个具体目标来实现我们的目标。目的1将评价新的儿科药代动力学 异烟肼/利福平/吡嗪酰胺FDC制剂，并使用PK数据开发群体PK模型， 刺激来预测儿童的最佳体重范围剂量。目标2将检查利福平的作用- 结核病/艾滋病病毒合并感染儿童的病毒学应答 仅接受基于依法韦仑的治疗的HIV。目的3测定替诺福韦的细胞内PK 在10至19岁的青少年中使用二磷酸和三磷酸恩曲西巴因，以及检查 年龄和TB合并感染对这些同化物PK的影响。作为新的儿科抗结核制剂， 在撒哈拉以南非洲，抗逆转录病毒药物的规模正在扩大，需要非洲儿童的PK和PK-PD数据， 验证制剂和给药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、艾滋病毒和结核病/艾滋病毒合并感染。

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.