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）感染是发病率和儿童死亡率。儿童非常容易受到艾滋病毒和结核病感染的双重流行病的影响在非洲。感染HIV的儿童患有主动结核病和结核病死亡的风险更高。高风险结核病/HIV共感染儿童的死亡部分是由于治疗延迟或次优药物治疗或两种感染。特别是，由于不适当的药物制剂或剂量可能导致儿童死亡率高。缺乏新的儿科配方的PK数据在非洲儿童中治疗结核病和艾滋病毒是优化结果的主要障碍。我们的长期目标是生成抗抗剂量组合（FDC）的新型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与新的儿童FDC配方的PK中的个体变异性相关的PK和协变量用于儿童的异烟肼/利福平/吡嗪酰胺以及青少年使用的通用FDC抗逆转录病毒。这总体假设是先前的研究低估了发育和遗传的影响药物代谢，药物相互作用的因素以及次优浓度的风险孩子们。我们的目标将通过三个特定目标来追求。 AIM 1将评估新的儿科的PK 异烟肼/利福平/吡嗪酰胺FDC配方，并使用PK数据开发人口PK模型和预测儿童最佳体重剂量的刺激。 AIM 2将检查利福平 - 与患有结核病/HIV共同感染儿童的病毒学反应的抗TB疗法相比单独使用基于Efavirenz的治疗的HIV。 AIM 3将确定替诺福韦的细胞内PK 10至19岁的青少年中的双磷酸和三磷酸酯，并检查年龄和结核病共同感染对这些合成代谢的PK的影响。作为抗TB和在撒哈拉以南非洲，非洲儿童的PK和PK-PD数据中，ARV需要缩放验证配方和给药指南或提供相关数据以进行指南修订。这创新提案有可能提供关键数据，以优化治疗方案儿童结核病，艾滋病毒和结核病/艾滋病毒共同感染。

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）

Could pharmacogenetics aid the prediction of nevirapine pharmacokinetics and allow individualized treatment?

药物遗传学能否帮助预测奈韦拉平药代动力学并允许个体化治疗？

DOI：
10.2217/pgs-2021-0106
发表时间：
2021
期刊：
Pharmacogenomics
影响因子：
2.1
作者：
Kwara,Awewura
通讯作者：
Kwara,Awewura

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

DOI：
10.1111/jphp.12812
发表时间：
2017-12
期刊：
The Journal of pharmacy and pharmacology
影响因子：
0
作者：
Cao L;Kwara A;Greenblatt DJ
通讯作者：
Greenblatt DJ

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

DOI：
10.1002/phar.1388
发表时间：
2014-03
期刊：
PHARMACOTHERAPY
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.