Impact of Plasma Alpha-1-acid Glycoprotein Variability on Free Lopinavir Levels

描述(由申请人提供)：这是一个综合的职业发展计划，包括临床和抗逆转录病毒(ARV)药代动力学(PK)研究方法的培训。目标是使候选人能够建立一个专注于抗逆转录病毒临床药理学的独立研究生涯。教学培训部分将在候选人最近完成的临床研究硕士项目和艾滋病临床试验小组培训奖学金的基础上进行扩展。在过去的两年里，候选人的导师参与了对候选人的指导，并致力于促进他的职业发展。ARV治疗的主要临床难题是毒性通常是由于循环药物浓度较高，而病毒耐药性和治疗失败与ARV暴露不足有关。ARV的血浆游离分数与蛋白结合量呈负相关。蛋白水解酶抑制物(PI)主要与cc-1-酸性糖蛋白(AAG)结合，AAG是一种急性期蛋白，其血浆水平随着HIV疾病的严重程度和炎症的背景而变化。由于这种变异性，以及由于AAG的高结合亲和力和低饱和能力，该蛋白已被证明调节肿瘤学中使用的化疗药物的处置和治疗结果。因此，可以想象，AAG水平的变化可能会对PIs的PK和药效学(PD)产生类似的影响。我们假设，由于病毒学抑制和免疫重建，经ARV治疗的HIV感染者的血浆AAG水平随着时间的推移而下降；血浆AAG水平的变化与洛匹那韦(LPV)的游离浓度呈负相关。在实施基于LPV/r的治疗后，将测量血浆AAG水平随时间的变化，并与从基线到第16周的游离LPV PK曲线的变化相关联。血浆AAG和LPV游离水平将分别用固定时间比浊法和高效液相色谱-MS/MS法测定。AAG水平从基线到第16周的平均变化将使用重复测量分析来估计和比较。ARV治疗后第16周AAG水平变化和第16周游离LPV PK曲线变化之间的相关性将使用皮尔逊乘积矩相关系数和Spearman等级相关系数进行评估。由于血浆中药物的游离分数更准确地反映了靶细胞可获得的药物，因此其PD活性，发现血浆AAG水平与游离LPV浓度之间的负相关关系在HIV药物治疗中具有重要意义。

DESCRIPTION (provided by applicant): This proposal is an integrated career development plan that includes training in clinical and antiretroviral (ARV) pharmacokinetic (PK) research methods. The goal is to enable the candidate to establish an independent research career focused on ARV clinical pharmacology. The didactic training component will expand on the MSc in Clinical Research program and the AIDS Clinical Trials Group training fellowship which the candidate recently completed. The candidate's mentors have been involved in mentoring the candidate over the past two years and are committed to fostering his career development. The chief clinical conundrum of ARV therapy is that toxicity is often due to higher circulating drug concentrations, while viral resistance and treatment failure are related to inadequate ARV exposure. The plasma free fraction of ARV is inversely related to protein binding. Protease inhibitors (PI) are bound primarily to cc-1-acid glycoprotein (AAG), an acute phase protein whose plasma levels vary with HIV disease severity and in the setting of inflammation. As a result of this variability, and because of the high binding affinity and low saturation capacity of AAG, this protein has been shown to modulate the disposition and the therapeutic outcomes of chemotherapeutics agents used in oncology. It is therefore conceivable that changes in AAG levels could have similar effects on the PK and pharmacodynamic (PD) of the PIs. We hypothesize that plasma AAG levels in ARV-treated HIV-infected subjects decrease over time due to virologic suppression and immune reconstitution; and that changes in plasma AAG levels are inversely correlated with free concentrations of lopinavir (LPV). Changes in plasma AAG levels over time following institution of LPV/r based therapy will be measured, and correlated with changes in free LPV PK profile from baseline to week-16. Plasma AAG and LPV free levels will be measured by a fixed-time nephelometric method and HPLC-MS/MS respectively. The mean changes in AAG level from baseline to week-16 will be estimated and compared overtime using repeated-measures analyses. The correlation between week-16 changes in AAG levels and week-16 changes in free LPV PK profile following ARV therapy will be evaluated using a Pearson product moment correlation coefficient and the Spearman rank correlation coefficient. Since the free fraction of drug in plasma more accurately reflects the drug available to the target cell, and as a result its PD activities, the finding of an inverse relationship between plasma AAG levels and free LPV concentrations could have important implication in HIV pharmacotherapy.