ANTIRETROVIRAL THERAPY PHARMACOKINETICS DURING PUBERTY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这是一项探索性、观察性试验，旨在研究青春期抗逆转录病毒药物药代动力学的变化。众所周知，对于许多抗逆转录病毒药物，幼儿的口服血浆清除量与成人相比差异高达200%。然而，随着儿童的成熟，与药物代谢变化相关的时间和因素还没有很好地确定。这项研究将招募大约60名感染艾滋病毒的儿童、青少年和年轻人，年龄在7-24岁之间，他们正在接受抗逆转录病毒药物治疗。所有受试者在进入时都将接受密集的药代动力学研究，以准确确定他们的口腔清除量(CL/F)。一部分受试者(大约15-20人)将继续进行研究，使用贝叶斯药代动力学方法，每年对稀疏抽样确定的CL/F进行两次纵向评估。将比较青春期不同临床阶段受试者CL/F的差异。将评估的协变量将是身体表面积、肝脏体积、血清药物结合蛋白浓度和性激素。此外，该研究还将评估细胞内核苷逆转录酶抑制物浓度与线粒体毒性、脂肪分布和脂质代谢的关系。这项研究的目标是收集描述性和初步的数据，以便在未来能够在这一人群中设计有针对性的和明确的药代动力学研究。

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. This is an exploratory, observational trial to investigate changes in antiretroviral medication pharmacokinetics during puberty. It is well know that for many antiretroviral drugs' oral plasma clearance differs by as much as 200% for young children compared to adults. However, the timing and factors associated with the change in drug metabolism as the child matures have not been well defined. This study will enroll approximately 60 HIV infected children, adolescents, and young adults, age 7-24 years, who are receiving antiretroviral medications. All subjects will undergo an intensive pharmacokinetic study at entry to accurately define their oral clearance (CL/F). A subset of the subjects (approximately 15-20) will continue in the study for twice yearly longitudinal evaluations of CL/F determined with sparse sampling, using a Bayesian pharmacokinetic approach. Differences in CL/F will be compared between subjects at different clinical stages of puberty. Co-variates that will be assessed will be body surface area, liver volume, serum drug binding protein concentrations, and sex hormones. In addition, the study will evaluate relationships between intracellular nucleoside reverse transcriptase inhibitor concentrations and mitochondrial toxicity, fat distribution, and lipid metabolism. The goal of this study is to collect descriptive and preliminary data that will enable the design of focused and definitive pharmacokinetic studies in this population in the future.