Department of Clinical Pharmacology, Johns Hopkins University, Baltimore, MD 21287, USA.
J Acquir Immune Defic Syndr. 2010 Apr;53(5):598-605. doi: 10.1097/QAI.0b013e3181c9caac.
This substudy of AIDS Clinical Trials Group (ACTG) Protocol 5211 explored the relationship between antiretroviral effect and plasma concentrations of vicriviroc, an investigational CCR5 antagonist for HIV infection.
Eighty-six treatment-experienced subjects failing their current antiretroviral regimens were randomized to add vicriviroc 5, 10, or 15 mg once daily or placebo for 2 weeks. Beyond week 2, subjects were changed to optimized background antiretroviral treatment while continuing vicriviroc or placebo. Plasma samples collected at weeks 2 and 8 were assayed for vicriviroc concentrations and combined with vicriviroc concentration data from 110 seronegatives enrolled in 5 phase 1 studies. An inhibitory Emax model was used to assess pharmacokinetic (PK)/pharmacodynamic relationships and recursive partitioning was applied to determine the breakpoint in vicriviroc PK parameters associated with virologic suppression.
A 2-compartment model was fitted to the drug concentration data. At week 2, a higher vicriviroc Cmin was associated with a greater mean drop in HIV RNA (viral load) and a higher percentage of subjects experiencing a >1 log10 copies/mL drop in viral load. In subjects with Cmin > 54 ng/mL, the mean viral load decrease was 1.35 log10 copies/mL vs. 0.76 log10 with Cmin < 54 ng/mL (P = 0.003, Student t test). At this Cmin breakpoint, 70% of subjects with the higher Cmin had a >1 log drop in HIV RNA, compared with 44% with a lower Cmin (P = 0.048, Fisher exact test). Similar results were seen with an area under the curve breakpoint of 1460 ng h/mL. At weeks 16 and 24, all vicriviroc-treated subjects experienced better viral load responses than placebo recipients, but there was no apparent relationship between PK and change in viral load among these vicriviroc-treated subjects.
There was a positive correlation between vicriviroc Cmin, area under the curve, and viral load changes at week 2 in treatment-experienced HIV-infected subjects receiving no other new active antiretroviral drugs. This correlation did not persist beyond week 16, probably because treatment response at that point also depended on having other active drugs in the regimen.
这项艾滋病临床试验组（ACTG）方案 5211 的子研究旨在探索抗逆转录病毒效果与vicriviroc 血浆浓度之间的关系，vicriviroc 是一种用于 HIV 感染的新型 CCR5 拮抗剂。
86 名接受过治疗的患者因当前的抗逆转录病毒方案失败而被随机分为添加每日一次 5、10 或 15mg 的 vicriviroc 或安慰剂，为期 2 周。超过第 2 周后，根据优化背景抗逆转录病毒治疗方案，继续给予 vicriviroc 或安慰剂。在第 2 周和第 8 周收集的血浆样本用于检测 vicriviroc 浓度，并与 110 名参加 5 项 1 期研究的血清阴性者的 vicriviroc 浓度数据相结合。采用抑制 Emax 模型评估药代动力学（PK）/药效学关系，并采用递归分区法确定与病毒学抑制相关的 vicriviroc PK 参数的断点。
该药物浓度数据拟合了一个 2 室模型。在第 2 周时，更高的 vicriviroc Cmin 与 HIV RNA（病毒载量）平均下降幅度更大以及更多的患者出现病毒载量下降超过 1 个对数 10 拷贝/ml 相关。在 Cmin > 54ng/ml 的患者中，平均病毒载量下降为 1.35 个对数 10 拷贝/ml，而 Cmin < 54ng/ml 的患者为 0.76 个对数 10 拷贝/ml（P = 0.003，Student t 检验）。在这个 Cmin 分界点，70%的高 Cmin 患者的 HIV RNA 下降超过 1 个对数，而低 Cmin 患者的这一比例为 44%（P = 0.048，Fisher 精确检验）。在 AUC 分界点为 1460ng h/ml 时也出现了类似的结果。在第 16 周和第 24 周，所有接受 vicriviroc 治疗的患者与安慰剂组相比，病毒载量反应更好，但在这些接受 vicriviroc 治疗的患者中，PK 与病毒载量变化之间似乎没有明显的关系。
在未接受其他新型活性抗逆转录病毒药物治疗的经验丰富的 HIV 感染患者中，vicriviroc 的 Cmin、AUC 和病毒载量变化在第 2 周时呈正相关。这种相关性在第 16 周后不再持续，可能是因为那时的治疗反应也取决于治疗方案中是否有其他活性药物。
