EFFECT OF PUBERTY ON THE PHARMACOKINETICS 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

• 批准号: 8167317
• 负责人: NATELLA Y RAKHMANINA
• 金额: $ 0.63万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167317
• 关键词: Adolescent; Adverse event; Affect; Anti-Retroviral Agents; Appearance; Body Composition; CD4 Lymphocyte Count; CYP2B6 gene; Child; Clinical; Computer Retrieval of Information on Scientific Projects Database; Cross-Sectional Studies; Cytochrome P450; Cytochromes; Data; Development; Dose; Drug Kinetics; Employee Strikes; Funding; Genetic; Grant; Growth; Hormonal Change; Hydroxylation; In Vitro; Institution; Measures; Metabolic Biotransformation; Metabolic Pathway; Metabolism; Outcome; Outcome Measure; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Puberty; Research; Research Personnel; Resources; Sexual Maturation; Source; Staging; Therapeutic; Toxic effect; Treatment Failure; United States National Institutes of Health; Viral Load result; base; cohort; efavirenz; prospective; viral resistance

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. Study Aim1: 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 I-IV. Study 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 I-II. Study 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 I-II.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 青春期的特征是生长速度，人体成分的变化以及引人注目的体细胞变化的出现显着增加。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。研究AIM1：通过对制革商I-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（CL/F）的关系。研究目标2：评估青春期（通过体细胞生长和性成熟）与CYP2B6活性（通过EFV的形成对其代谢物8-羟基韦氏素的形成确定的）在研究目标1和22岁儿童纵向研究中的44个儿童中的关系（通过其代谢产物8-羟基福利伦斯的形成确定）。研究目标3：探索CYP2B6活性的发育变化对临床结果的影响（通过HIV-RNA病毒载量和CD4+细胞计数测量）和基于EFV治疗的HIV感染儿童和青少年在Tanner阶段的22名儿童中基于HIV感染的儿童和青少年的毒性（通过CNS不良事件测量）。