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

描述(申请人提供)：青春期的特征是生长速度显著加快，身体成分发生变化，并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ARV药物中，Efavirenz(EFV)对于病毒耐药性的发展和治疗失败具有最小的窗口以及非常低的遗传障碍。EFV是细胞色素P450代谢途径(主要是细胞色素P450)的底物，体外代谢数据表明，EFV的8-羟基化是细胞色素P450活性的特异性标志。我们建议评估青春期生理和激素变化对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基于EFV治疗的HIV感染儿童和青少年的临床结果。STUDV AIMI：通过对44名处于制革阶段L-IV期的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(CL/F)的关系。研究目标2：在研究目标1的横断面队列中的44名儿童和处于制革阶段的纵向前瞻性队列中的22名儿童中，评估青春期发育变化(以躯体生长和性成熟来衡量)与细胞色素P450受体B6活性(由EFV对其代谢物8-羟基法维酮的形成清除来确定)之间的关系。研究目标3：在22名Tanner分期为L-11的儿童中，探讨发育变化对以EFV为基础的HIV感染儿童和青少年治疗的临床结局(以HIV-RNA病毒载量和CD_4细胞计数衡量)和毒性(以中枢神经系统不良事件衡量)的影响。公共卫生相关性：拟议调查的长期目标是改善感染艾滋病毒的儿童和青少年的EFV剂量，从而改善结果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.