Quantifying Sex-and-Age-Related Differences in Antiretroviral Exposure and Adverse Effects in the MACS/WIHS Combined Cohort Study

摘要 拟议工作的长期目标是提供基于证据的建议，以尽量减少 代谢不良事件，特别是体重增加，在不同的艾滋病毒携带者(PLWH)人群中 识别和量化药物暴露中可能增加患者亚组风险的可变性。我们会 考虑一系列影响药物暴露的因素，包括人口统计特征，之前 实验室价值、人体测量学、脆弱表型和药物基因组学。我们的重点是 整合酶链转移抑制剂(INSTI)多洛替格韦(DTG)和比替格列韦(BIC)以及替诺福韦 丙氨酰胺(TAF)。MWCCS包括在第三阶段临床试验中代表性不足的各种PLWH，因此， 在赞助商开发的人群中，药物的药代动力学模型。在目标1中，我们将招收不同的PLWH 从四个MWCCS站点收集药代动力学数据，并进一步提炼影响因素的知识 DTG、BIC和TAF的药代动力学。药物浓度将在血浆和外周血中进行测量 北卡罗来纳大学艾滋病研究临床药理学和分析中心的血液单个核细胞(仅限TAF) 化学实验室(CFAR CPAC)。将使用非线性混合效应模型来开发一个全面的 每种感兴趣药物的PK模型。然后，使用这些模型，在AIM 2中，我们将回溯测量药物 储存库样本中的浓度(使用与AIM 1相同的方法和实验室，并预测药物 男性和女性从DTG、BIC和/或TAF开始的清除。这些毒品清除，预计将 每个参与者多次访问，然后将被分析为体重增加的预测因素，腰围到臀部增加 比率，并增加胰岛素抵抗(由HOMA-IR测量)在治疗过程中的药物 利息，以及药物暴露的多种衡量标准。假设是那些有较高药物暴露的PLWH (通过较慢的药物清除)将更有可能经历这些药物的代谢不良事件。vt.在.的基础上 完成后，我们希望为进一步开发基于模型的风险估计器奠定基础 前瞻性验证。

ABSTRACT The long-term objective of the proposed work is to provide evidenced-based recommendations for minimizing metabolic adverse events, particularly weight gain, in a diverse population of people living with HIV (PLWH) by identifying and quantifying variability in drug exposure that may increase risk in patient subgroups. We will consider a broad array of modifying factors of drug exposure, including demographic characteristics, prior laboratory values, body anthropometrics, frailty phenotype, and pharmacogenomics. Our focus is on the integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG) and bictegravir (BIC), as well as tenofovir alafenamide (TAF). The MWCCS includes diverse PLWH underrepresented in Phase III clinical trials and thus, in the sponsor-developed population pharmacokinetic models of the drug. In AIM 1, we will enroll diverse PLWH from four MWCCS sites to collect pharmacokinetic data and further refine the knowledge of factors that influence DTG, BIC, and TAF pharmacokinetics. Drug concentrations will be measured in blood plasma and peripheral blood mononuclear cells (TAF only) in the UNC Center for AIDS Research Clinical Pharmacology and Analytical Chemistry Laboratory (CFAR CPAC). Nonlinear mixed effects models will be used to develop a comprehensive PK model for each drug of interest. Using these models, then, in AIM 2, we will retrospectively measure drug concentrations in repository specimens (using the same methods and laboratory as AIM 1, and predict drug clearance in men and women from initiation of DTG, BIC, and/or TAF. These drug clearances, predicted for multiple visits per participant, will then be analyzed as the predictors of body weight gain, increased waist to hip ratio, and increased insulin resistance (as measured by HOMA-IR) over the course of treatment on the drug of interest, with multiple measures of drug exposure. The hypothesis is that those PLWH with higher drug exposure (via slower drug clearance) will be more likely to experience the metabolic adverse events of these drugs. Upon completion, we expect to have the underpinnings of a model-based risk estimator developed for further prospective validation.