Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV
Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV
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DOI：
10.1097/qad.0000000000001755
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发表时间：
2018-03-27
期刊：
影响因子：
3.8
通讯作者：
Mirochnick, Mark
中科院分区：
文献类型：
--
作者：
Mulligan, Nikki;Best, Brookie M.;Mirochnick, Mark
目的：为了评价度鲁特韦药代动力学在怀孕期间与产后和婴儿洗脱样品比较后deliver.Design：正在进行的，非随机，开放标签，平行组，多中心IV期前瞻性研究抗逆转录病毒药代动力学在HIV感染的孕妇和婴儿。在妊娠中期（2 T），对dolutegravir 50 mg每日一次给药后的强化稳态24 h药代动力学特征进行了研究，妊娠晚期（3 T）和产后。在出生后收集产妇分娩和出生后婴儿样品。通过经验证的LC-MS/MS测量度鲁特韦;定量限为0.005 μ g/ml。一个双尾Wilcoxon符号秩检验（α = 0.10）进行配对内subjectcomparation.Results：29名参加者的中位年龄为32岁（范围21-42）。15例（2 T）、28例（3 T）和23例（产后）女性的药代动力学数据可用。与产后相比，2 T和3 T中的中位度鲁特韦AUC（0-24）、C-max和C-24降低了25-51%。中位脐带血/母体血浆浓度比为1.25（n = 18）。在21名婴儿中，宫内暴露后的中位消除半衰期为32.8小时。27/29名妇女（93%）分娩时病毒载量低于50拷贝/ml。29名婴儿的艾滋病毒检测呈阴性。肾脏异常超声两个婴儿被认为可能与dolutegravir.Conclusion：Dolutegravir暴露是较低的，在怀孕期间，产后在同一妇女每天一次给药。妊娠期间的中位AUC（0-24）与非妊娠成人相似，但谷浓度低于非妊娠成人。妊娠期谷浓度远高于度鲁特韦EC 90（0.064 μ g/ml）。多鲁特韦易于穿过胎盘。婴儿消除时间延长，半衰期是历史成人对照的两倍多。版权所有（C）2018威科医疗集团All rights reserved.
Objective: To evaluate dolutegravir pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery.Design: Ongoing, nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and infants.Methods: Intensive steady-state 24 h pharmacokinetic profiles after dolutegravir 50 mg once-daily were performed during the second trimester (2T), third trimester (3T) and postpartum. Maternal delivery and postnatal infant samples were collected after birth. Dolutegravir was measured by validated LC-MS/MS; quantitation limit was 0.005 mu g/ml. A two-tailed Wilcoxon signed-rank test (alpha = 0.10) was employed for paired within-subject comparisons.Results: Twenty-nine enrolled participants had a median age of 32 years (range 21-42). Pharmacokinetic data were available for 15 (2T), 28 (3T) and 23 (postpartum) women. Median dolutegravir AUC(0-24), C-max and C-24 were 25-51% lower in the 2T and 3T compared with postpartum. The median cord blood/maternal plasma concentration ratio was 1.25 (n = 18). In 21 infants, median elimination half-life was 32.8 h after in utero exposure. Viral load at delivery was less than 50 copies/ml for 27/29 women (93%). Twenty-nine infants were HIV-negative. Renal abnormalities noted on ultrasound in two infants were deemed possibly related to dolutegravir.Conclusion: Dolutegravir exposure is lower in pregnancy compared with postpartum in the same women on once-daily dosing. Median AUC(0-24) during pregnancy was similar to, whereas trough concentrations were lower than, those seen in nonpregnant adults. Trough concentrations in pregnancy were well above dolutegravir EC90 (0.064 mu g/ml). Dolutegravir readily crosses the placenta. Infant elimination is prolonged, with half-life over twice that of historical adult controls. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.