ANTIRETROVIRAL THERAPY PHARMACOKINETICS DURING PUBERTY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这是一项探索性的观察性试验，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，幼儿与成人相比，许多抗逆转录病毒药物的口服血浆清除率相差高达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尚未得到很好的定义。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，正在接受抗逆转录病毒药物治疗。所有受试者在入院时都将进行密集的药代动力学研究，以准确确定其口服清除率（CL/F）。一部分受试者（大约15-20人）将继续研究，每年两次使用贝叶斯药代动力学方法进行稀疏抽样确定的CL/F纵向评估。将比较处于青春期不同临床阶段受试者CL/F的差异。评估的协变量包括体表面积、肝脏体积、血清药物结合蛋白浓度和性激素。此外，该研究将评估细胞内核苷逆转录酶抑制剂浓度与线粒体毒性、脂肪分布和脂质代谢之间的关系。本研究的目的是收集描述性和初步数据，以便将来在该人群中设计重点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.