Acosta Edward P, Bardeguez Arlene, Zorrilla Carmen D, Van Dyke Russell, Hughes Michael D, Huang Sharon, Pompeo Lisa, Stek Alice M, Pitt Jane, Watts D Heather, Smith Elizabeth, Jiménez Eleanor, Mofenson Lynne
University of Alabama at Birmingham, Birmingham, Alabama, USA.
Antimicrob Agents Chemother. 2004 Feb;48(2):430-6. doi: 10.1128/AAC.48.2.430-436.2004.
The physiologic changes that occur during pregnancy make it difficult to predict antiretroviral pharmacokinetics (PKs), but few data exist on the PKs of protease inhibitors in human immunodeficiency virus (HIV)-infected pregnant women. The objective of the present study was to determine the PKs of ritonavir (RTV)-enhanced saquinavir (SQV) in HIV-infected pregnant women by an area under the curve (AUC)-targeted approach. A phase I, formal PK evaluation was conducted with HIV-infected pregnant woman during gestation, during labor and delivery, and at 6 weeks postpartum. The SQV-RTV regimen was 800/100 mg twice a day (b.i.d.), and nucleoside analogs were administered concomitantly. The SQV exposure targeted was an AUC at 24 h of 10,000 ng. h/ml. Participants were evaluated for 12-h steady-state PKs at each time period. Thirteen subjects completed the PK evaluations during gestation, 7 completed the PK evaluations at labor and delivery, and 12 completed the PK evaluations postpartum. The mean baseline weight was 67.4 kg, and the median length of gestation was 23.3 weeks. All subjects achieved SQV exposures in excess of the target AUC. The SQV AUCs at 12 h (AUC(12)s) during gestation (29,373 +/- 17,524 ng. h/ml [mean +/- standard deviation]), during labor and delivery (26,189 +/- 22,138 ng. h/ml), and during the postpartum period (35,376 +/- 26,379 ng. h/ml) were not significantly different. The mean values of the PK parameters for RTV were lower during gestation than during the postpartum period: for AUC(12), 7,811 and 13,127 ng. h/ml, respectively; for trough concentrations, 376 and 632 ng/ml, respectively; and for maximum concentrations, 1,256 and 2,252 ng/ml, respectively (P </= 0.05 for all comparisons). This is the first formal PK evaluation of a dual protease inhibitor regimen with HIV-infected pregnant women. The level of SQV exposure was sufficient at each time of evaluation. These data demonstrate large variability in SQV and RTV concentrations and suggest that RTV concentrations are altered by pregnancy. These PK results suggest that SQV-RTV at 800/100 mg b.i.d. appears to be a reasonable treatment option for this population.
孕期发生的生理变化使得预测抗逆转录病毒药物的药代动力学（PK）变得困难，但关于感染人类免疫缺陷病毒（HIV）的孕妇中蛋白酶抑制剂的PK数据很少。本研究的目的是通过曲线下面积（AUC）靶向方法确定HIV感染孕妇中利托那韦（RTV）增强的沙奎那韦（SQV）的PK。在HIV感染孕妇的妊娠期、分娩期和产后6周进行了I期正式PK评估。SQV-RTV方案为每日两次，每次800/100mg（bid），并同时给予核苷类似物。目标SQV暴露量为24小时AUC达到10,000ng·h/ml。在每个时间段对参与者进行12小时稳态PK评估。13名受试者在妊娠期完成了PK评估，7名在分娩期完成了PK评估，12名在产后完成了PK评估。平均基线体重为67.4kg，妊娠中位数为23.3周。所有受试者的SQV暴露量均超过目标AUC。妊娠期12小时的SQV AUC（AUC(12)）（29,373±17,524ng·h/ml[平均值±标准差]）、分娩期（26,189±22,138ng·h/ml）和产后（35,376±26,379ng·h/ml）无显著差异。RTV的PK参数平均值在妊娠期低于产后：AUC(12)分别为7,811和13,127ng·h/ml；谷浓度分别为376和632ng/ml；最大浓度分别为1,256和2,252ng/ml（所有比较P≤0.05）。这是首次对HIV感染孕妇进行的双重蛋白酶抑制剂方案的正式PK评估。在每个评估时间点，SQV暴露水平都足够。这些数据表明SQV和RTV浓度存在很大变异性，并提示RTV浓度受妊娠影响而改变。这些PK结果表明，每日两次800/100mg的SQV-RTV似乎是该人群的合理治疗选择。
