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

描述（由申请人提供）：青春期的特征是生长速度显著增加，身体组成发生变化，出现显著的躯体变化。这些变化有可能显著影响抗逆转录病毒（ARV）药物的药代动力学（PK）和药效学（PD），特别是那些治疗窗口较窄的药物。在抗逆转录病毒药物中，依法韦仑（EFV）对病毒耐药性和治疗失败的发展具有最小的窗口和非常低的遗传屏障。EFV是细胞色素（CYP）P450代谢途径（主要是CYP 2B 6）的底物，EFV代谢的体外数据表明EFV的8-羟基化是CYP 2B 6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的分布，并有可能通过影响剂量-血浆浓度关系来改变基于EFV的HIV感染儿童和青少年治疗的临床结局。Studv Aimi：通过对44名坦纳I-IV期儿童和青少年进行的横断面研究，评价青春期发育变化与EFV清除率（CL/F）的关系。研究目标2：在研究目的1的44名儿童的横断面队列和坦纳I-II期的22名儿童的纵向前瞻性队列中，评价青春期发育变化（通过躯体生长和性成熟测量）与CYP 2B 6活性（通过EFV对其代谢产物8-羟基非韦仑的形成清除率测定）的关系。研究目标3：在一个前瞻性队列中，在22名坦纳I-II期儿童中，探索CYP 2B 6活性的发育变化对基于EFV的治疗HIV感染儿童和青少年的临床结局（通过HIV-RNA病毒载量和CD 4+细胞计数测量）和毒性（通过CNS不良事件测量）的影响。公共卫生相关性：拟议研究的长期目标是改善艾滋病毒感染儿童和青少年的EFV剂量，从而改善结局并减少药物不良反应。

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.