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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 青春期的特点是生长速度显着加快、身体成分发生变化以及出现显着的躯体变化。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），特别是那些治疗窗较窄的药物。在抗逆转录病毒药物中，依非韦伦 (EFV) 的窗口最小，并且病毒耐药性和治疗失败的遗传障碍非常低。 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 活性的特异性标志物。我们建议评估青春期身体和激素变化对 EFV 生物转化和清除的影响。我们假设青春期的发育变化会影响 EFV 的处置，并有可能通过影响剂量-血浆浓度关系来改变 HIV 感染儿童和青少年基于 EFV 治疗的临床结果。研究目的1：通过对 44 名 Tanner I-IV 期儿童和青少年的横断面研究，评估青春期发育变化与 EFV 清除率 (CL/F) 的关系。研究目标 2：在研究中的 44 名儿童的横断面队列中，评估青春期发育变化（通过体细胞生长和性成熟来衡量）与 CYP2B6 活性（通过 EFV 与其代谢物 8-羟基依非韦伦的形成清除率来确定）的关系目标 1 和由 22 名 Tanner I-II 期儿童组成的纵向前瞻性队列。研究目标 3：探索 CYP2B6 活性的发育变化对 HIV 感染儿童和青少年基于 EFV 治疗的临床结果（通过 HIV-RNA 病毒载量和 CD4+ 细胞计数衡量）和毒性（通过 CNS 不良事件衡量）的影响在由 22 名 Tanner I-II 期儿童组成的前瞻性队列中。