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

描述（由申请人提供）：本提案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独立的研究事业，专注于ARV临床药理学。教学培训部分将扩大在临床研究硕士课程和艾滋病临床试验组培训奖学金，候选人最近完成。候选人的导师在过去两年中一直参与指导候选人，并致力于促进其职业发展。抗逆转录病毒治疗的主要临床难题是，毒性通常是由于较高的循环药物浓度，而病毒耐药性和治疗失败与抗逆转录病毒暴露不足有关。ARV的血浆游离分数与蛋白结合呈负相关。蛋白酶抑制剂（PI）主要与α-1-酸性糖蛋白（AAG）结合，AAG是一种急性期蛋白，其血浆水平随HIV疾病严重程度和炎症情况而变化。由于这种可变性，并且由于AAG的高结合亲和力和低饱和能力，这种蛋白质已显示出调节肿瘤学中使用的化疗剂的处置和治疗结果。因此，可以想象AAG水平的变化可能对PI的PK和药效学（PD）具有相似的影响。我们假设，血浆AAG水平在抗逆转录病毒治疗的HIV感染者随着时间的推移，由于病毒抑制和免疫重建下降，血浆AAG水平的变化与洛匹那韦（LPV）的游离浓度呈负相关。将测量基于LPV/r的治疗开始后血浆AAG水平随时间的变化，并与游离LPV PK特征从基线至第16周的变化相关。将分别通过固定时间浊度法和HPLC-MS/MS测量血浆AAG和LPV游离水平。将估计AAG水平自基线至第16周的平均变化，并使用重复测量分析进行随时间推移的比较。将使用Pearson积矩相关系数和斯皮尔曼秩相关系数评价ARV治疗后第16周AAG水平变化与第16周游离LPV PK特征变化之间的相关性。由于血浆中药物的游离分数更准确地反映了靶细胞可利用的药物，因此其PD活性，血浆AAG水平和游离LPV浓度之间的反比关系的发现可能对HIV药物治疗具有重要意义。

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.