Immune activation mediated change in alpha-1-acid glycoprotein: impact on total and free lopinavir plasma exposure.
Immune activation mediated change in alpha-1-acid glycoprotein: impact on total and free lopinavir plasma exposure.
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DOI：
10.1177/0091270010385118
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发表时间：
2011-11
影响因子：
2.9
通讯作者：
Acosta EP
中科院分区：
文献类型：
--
作者：
Ofotokun I;Lennox JL;Eaton ME;Ritchie JC;Easley KA;Masalovich SE;Long MC;Acosta EP
免疫介导的循环α-1-酸性糖蛋白（AAG）的改变可能改变蛋白质结合并导致PI的药代动力学（PK）变异性。AAG是一种与蛋白酶抑制剂（PI）结合的1型急性期蛋白。在一项前瞻性、2期强化PK研究中，接受洛匹那韦/利托那韦治疗的HIV感染者在治疗第2周和第16周进行稳态PK采样和AAG测定。入职年龄中位数为43岁（n = 16）。中位血浆log10 HIV-1 RNA、CD4 t细胞计数和AAG分别为5.16 copies/mL、28 cells/μL和143 mg/dL。洛匹那韦在浓度时间曲线下的总面积（AUC12_total）和最大浓度（Cmax_total）随AAG呈线性变化，平均速率为16±7 mg*hr/L（斜率±SE）；AAG水平每增加100 mg/dL， P = 0.04, P = 0.02，分别为1.6±0.6 mg/L （n = 15）。在第2周和第16周之间，AAG水平下降29%，AUC12_total和Cmax_total分别减少14%（几何平均比[GMR] = 0.86； 90%置信区间[CI] = 0.74-0.98）和13% （GMR = 0.87; 90% CI = 0.79-0.95）。血浆AAG的变化既不影响游离洛匹那韦PK参数，也不影响抗病毒活性（HIV-1 RNA平均AUC减去基线）。血浆AAG水平的变化会改变洛匹那韦的总浓度，但不会改变游离洛匹那韦暴露量或抗病毒活性。这一观察结果可能对治疗药物监测有影响。
Immune mediated changes in circulating α-1-acid glycoprotein (AAG), a type 1 acute phase protein, which binds protease inhibitors (PI), may alter protein binding and contribute to PI's pharmacokinetic (PK) variability. In a prospective, 2-phase intensive PK study on antiretroviral naive human immunodeficiency virus (HIV)-infected subjects treated with a lopinavir-/ritonavir-based regimen, steady state PK sampling and AAG assays were performed at weeks 2 and 16 of treatment. Median entry age was 43 years (n = 16). Median plasma log10 HIV-1 RNA, CD4 T-cell counts, and AAG were 5.16 copies/mL, 28 cells/μL, and 143 mg/dL, respectively.The total lopinavir area under the concentration time curve (AUC12_total) and maximum concentration (Cmax_total) changed linearly with AAG at mean rates of 16±7 mg*hr/L (slope ± SE); P = .04, and 1.6 ± 0.6 mg/L, P = .02, per 100 mg/dL increase in AAG levels, respectively (n = 15).A 29% drop in AAG levels between week 2 and week 16 was associated with 14% (geometric mean ratio [GMR] = 0.86; 90% confidence interval [CI] = 0.74-0.98) and 13% (GMR = 0.87; 90% CI = 0.79-0.95) reduction in AUC12_total and Cmax_total, respectively. Neither free lopinavir PK parameters nor antiviral activity (HIV-1 RNA average AUC minus baseline) was affected by change in plasma AAG. Changes in plasma AAG levels alter total lopinavir concentrations, but not the free lopinavir exposure or antiviral activity. This observation may have implications in therapeutic drug monitoring.
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影响因子：
4.9
作者：
Flaherty, JF;Gatti, G;Gambertoglio, JG
通讯作者：
Gambertoglio, JG
影响因子：
3.7
作者：
Pruessner, JC;Kirschbaum, C;Hellhammer, DH
通讯作者：
Hellhammer, DH
DOI：
10.1111/j.1749-6632.1982.tb22124.x
发表时间：
1982-01-01
影响因子：
5.2
作者：
KUSHNER, I
通讯作者：
KUSHNER, I
影响因子：
4.1
作者：
van der Lugt, Jasper;Colbers, Angela;Burger, David
通讯作者：
Burger, David
影响因子：
3.8
作者：
King, JR;John, JG;Acosta, EP
通讯作者：
Acosta, EP