Effect of Puberty on the Phamacokinetics of Efavirenz in HIV-infected Children

青春期对 HIV 感染儿童依非韦伦药代动力学的影响

基本信息

批准号：
8099653
负责人：
Natella Yurievna Rakhmanina
金额：
$ 12.45万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-10 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8099653
关键词：
Address Adherence Adolescence Adolescent Adult Adverse event Affect Anti-Retroviral Agents Appearance Body Composition CD4 Lymphocyte Count CYP2B6 gene Child Childhood Clinical Cross-Sectional Studies Cytochrome P450 Cytochromes Data Development Dose Drug Exposure Drug Kinetics Drug resistance Employee Strikes Evaluation Failure Genetic Goals Growth Growth and Development function Guidelines HIV Health Hormonal Change Human Hydroxylation In Vitro Investigation Lead Maintenance Measures Metabolic Biotransformation Metabolic Pathway Metabolism Morbidity - disease rate Nucleosides Outcome Outcome Measure Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Phenotype Plasma Principal Investigator Puberty Reaction Regimen Research Proposals Reverse Transcriptase Inhibitors Risk Schedule Sexual Maturation Staging Surface Tablets Testing Therapeutic Toxic effect Treatment Failure Treatment Protocols Viral Load result Virus Diseases Virus Replication Weight antiretroviral therapy base cohort efavirenz improved intravenous drug use mortality neuropsychiatry non-nucleoside reverse transcriptase inhibitors prospective success viral RNA viral resistance

项目摘要

DESCRIPTION (provided by applicant): Puberty is characterized by a significant increase in growth velocity, changes in body composition and the appearance of striking somatic changes. Those changes have a potential to significantly affect the pharmacokinetics (PK) and pharmacodynamics (PD) of antiretroviral (ARV) drugs, particularly those with a narrow therapeutic window. Among the ARV drugs Efavirenz (EFV) has the smallest window as well as a very low genetic barrier for the development of viral resistance and treatment failure. EFV is a substrate of the cytochrome (CYP) P450 metabolic pathway (primarily CYP2B6), and in vitro data of EFV metabolism suggest that 8-hydroxylation of EFV is a specific marker of CYP2B6 activity. We propose to evaluate the effect of physical and hormonal changes during puberty on biotransformation and clearance of EFV. We hypothesize that the developmental changes during puberty affect the disposition of EFV and have the potential to alter the clinical outcome of EFV based therapy in HIV-infected children and adolescents by influencing the dose-plasma concentration relationship. Studv Aimi: Evaluate the relationship of developmental changes during puberty to clearance (CL/F) of EFV through a cross-sectional study of 44 children and adolescents in Tanner stages l-IV. Studv Aim 2: Evaluate the relationship of developmental changes during puberty (measured by somatic growth and sexual maturation) to CYP2B6 activity (determined by the formation clearance of EFV to its metabolite 8-hydroxyefavirenz) in the cross-sectional cohort of 44 children in study aim 1 and a longitudinal prospective cohort of 22 children in Tanner stages l-ll. Studv Aim 3: Explore the effect of developmental changes in CYP2B6 activity on the clinical outcome (measured by HIV-RNA viral load and CD4+ cell count) and toxicity (measured by CNS adverse events) of EFV based therapy in HIV-infected children and adolescents in a prospective cohort of 22 children in Tanner stages l-ll. PUBLIC HEALTH RELEVANCE: The long-term goal of the proposed investigations is to improve dosing of EFV in HIV-infected children and adolescents, leading to improved outcome and decreased adverse drug reactions.

描述（由申请人提供）：青春期的特征是生长速度的显着增加，身体成分的变化以及引人注目的体细胞变化的出现。这些变化有可能显着影响抗逆转录病毒（ARV）药物的药代动力学（PK）和药效学（PD），尤其是患有狭窄治疗窗口的药物。在ARV药物中，Efavirenz（EFV）具有最小的窗口，并且在病毒抗性和治疗衰竭的发展中具有非常低的遗传障碍。 EFV是细胞色素（CYP）P450代谢途径（主要是CYP2B6）的底物，EFV代谢的体外数据表明，EFV的8-羟基化是CYP2B6活性的特定标记。我们建议评估青春期期间物理和激素变化对EFV生物转化和清除率的影响。我们假设青春期期间的发育变化会影响EFV的处置，并有可能通过影响剂量 - 上皮浓度的关系来改变HIV感染的儿童和青少年在HIV感染的儿童和青少年中基于EFV的临床结果。 Studv Aimi：通过对Tanner L-IV阶段的44名儿童和青少年的横断面研究，评估青春期期间的发育变化与清除率（CL/F）的关系。 Studv Aim 2：评估青春期（通过躯体生长和性成熟度测量）与CYP2B6活性（通过EFV的形成与其代谢物8-羟基福利伦斯的形成确定的）在研究目标1和22岁儿童中的44个儿童的横截面组中的代谢物8-羟基福利伦的关系（确定）。 Studv AIM 3：探索CYP2B6活性的发育变化对临床结局的影响（通过HIV-RNA病毒载荷和CD4+细胞计数测量）和基于EFV的治疗在HIV感染的儿童和青少年的毒性（通过CNS不良事件测量）在Tanner阶段的22名儿童中的前瞻性群体中。公共卫生相关性：拟议的调查的长期目标是改善感染HIV感染的儿童和青少年的EFV剂量，从而改善结果并减少不良药物反应。