Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children

儿童抗结核和抗逆转录病毒药物的药代动力学

基本信息

批准号：
10470380
负责人：
Awewura Jacob Kwara
金额：
$ 63.36万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470380
关键词：
19 year old Acquired Immunodeficiency Syndrome Adherence Adolescent Adult Affect Africa Africa South of the Sahara African Anti-Retroviral Agents Antitubercular Agents CYP2B6 gene Cessation of life Child Childhood Clinical Country Data Diphosphates Dose Drug Formulations Drug Interactions Drug Kinetics Drug usage Enrollment Epidemic Female of child bearing age Formulation Fumarates Funding Genetic Genotype Ghana Goals Guidelines HIV HIV Infections HIV-infected adolescents HIV/TB Incidence Infection Infrastructure Kidney Modeling Morbidity - disease rate Nevirapine Nucleosides Outcome Participant Persons Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacotherapy Population Prevention Pyrazinamide RNA-Directed DNA Polymerase Regimen Research Rifampin Risk Sample Size Tablets Tenofovir Treatment Protocols Treatment outcome Tuberculosis Tubular formation Vertebral column Virus Diseases Weight World Health Organization age effect aged base clinical effect co-infection design developmental genetics dosage drug metabolism efavirenz effective therapy emtricitabine follow-up high risk improved innovation inorganic phosphate inter-individual variation isoniazid mortality mortality risk novel pharmacokinetic model public health relevance response scale up treatment guidelines treatment optimization treatment response tripolyphosphate tuberculosis drugs tuberculosis treatment

项目摘要

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.

结核病 (TB) 和人类免疫缺陷病毒 (HIV) 感染是发病率和死亡率的主要原因儿童死亡率。儿童极易受到艾滋病毒和结核病双重流行的影响，尤其是在非洲。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较高。的高风险结核病/艾滋病毒双重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不理想或两者同时感染。特别是，由于不适当的药物配方或药物导致药代动力学 (PK) 不佳剂量可能会导致儿童的高死亡率。儿科新制剂缺乏 PK 数据非洲儿童结核病和艾滋病毒的治疗是优化结果的主要障碍。我们的长期目标是生成新型固定剂量组合 (FDC) 制剂的新 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新型儿童友好型 FDC 制剂的 PK 和与个体间差异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。这总体假设是，之前的研究低估了发育和遗传的影响药物代谢因素、药物间相互作用以及药物浓度不理想的风险孩子们。我们的目标将通过三个具体目标来实现。目标 1 将评估新儿科药物的 PK 异烟肼/利福平/吡嗪酰胺 FDC 制剂，并使用 PK 数据开发群体 PK 模型并预测儿童最佳体重带剂量的刺激。目标 2 将检查利福平的作用- 与患有结核病/艾滋病毒合并感染的儿童相比，含有抗结核治疗的儿童的病毒学反应单独使用基于依非韦伦的疗法治疗艾滋病毒。目标 3 将确定替诺福韦的细胞内 PK 10至19岁青少年的二磷酸盐和三磷酸恩曲西巴因，并检查年龄和结核病合并感染对这些合成代谢物的 PK 的影响。作为新型儿科抗结核制剂抗逆转录病毒药物在撒哈拉以南非洲地区得到推广，需要非洲儿童的 PK 和 PK-PD 数据验证配方和剂量指南或为指南修订提供相关数据。这创新提案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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Isoniazid mediates the CYP2B6*6 genotype-dependent interaction between efavirenz and antituberculosis drug therapy through mechanism-based inactivation of CYP2A6.

异烟肼通过基于机制的 CYP2A6 失活介导依非韦伦和抗结核药物治疗之间的 CYP2B6*6 基因型依赖性相互作用。

DOI：
发表时间：
2014-07
期刊：
影响因子：
4.9
作者：
Court, Michael H;Almutairi, Fawziah E;Greenblatt, David J;Hazarika, Suwagmani;Sheng, Hongyan;Klein, Kathrin;Zanger, Ulrich M;Bourgea, Joanne;Patten, Christopher J;Kwara, Awewura
通讯作者：
Kwara, Awewura

Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies.

通过体外抑制研究，对乙酰氨基酚（扑热息痛）与两种类黄酮（木犀草素和槲皮素）之间的代谢相互作用。

DOI：
发表时间：
2017-12
期刊：
影响因子：
0
作者：
Cao, Lei;Kwara, Awewura;Greenblatt, David J
通讯作者：
Greenblatt, David J

Inhibitory Effects of Selected Antituberculosis Drugs on Common Human Hepatic Cytochrome P450 and UDP-glucuronosyltransferase Enzymes.

选定抗结核药物对常见人肝细胞色素 P450 和 UDP-葡萄糖醛酸基转移酶的抑制作用。

DOI：
发表时间：
2017-09
期刊：
影响因子：
0
作者：
Cao, Lei;Greenblatt, David J;Kwara, Awewura
通讯作者：
Kwara, Awewura

Factors associated with variability in rifampin plasma pharmacokinetics and the relationship between rifampin concentrations and induction of efavirenz clearance.

与利福平血浆药代动力学变异相关的因素以及利福平浓度与依非韦伦清除诱导之间的关系。

DOI：
发表时间：
2014-03
期刊：
影响因子：
4.1
作者：
Kwara, Awewura;Cao, Lei;Yang, Hongmei;Poethke, Pamela;Kurpewski, Jaclynn;Tashima, Karen T;Mahjoub, Behrang D;Court, Michael H;Peloquin, Charles A
通讯作者：
Peloquin, Charles A

Maximum Likelihood Estimation of Titer via a Power Family of Four-Parameter Logistic Model.

通过四参数 Logistic 模型的幂族对滴度进行最大似然估计。