Efavirenz-Based Antiretroviral Therapy but Not Pregnancy Increased Unbound Piperaquine Exposure in Women during Malaria Chemoprevention.
Efavirenz-Based Antiretroviral Therapy but Not Pregnancy Increased Unbound Piperaquine Exposure in Women during Malaria Chemoprevention.
复制标题
基于依非韦伦的抗逆转录病毒治疗会增加女性在疟疾化学预防期间未结合哌喹的暴露，但怀孕不会增加。
DOI：
10.1128/aac.01427-22
复制
发表时间：
2023
影响因子：
4.9
通讯作者：
Huang,Liusheng
中科院分区：
文献类型：
--
作者：
Hong,Howard;Aslam-Mir,Usman;Kajubi,Richard;Wallender,Erika;Mwebaza,Norah;Dorsey,Grant;Rosenthal,PhilipJ;Aweeka,FrancescaT;Huang,Liusheng
双氢青蒿素哌喹 (DP) 对于妊娠期间的疟疾化学预防非常有效，但用于非妊娠成人的 DP 标准剂量可能并不适合孕妇。我们之前报道过，在怀孕或基于依非韦伦 (EFV) 的抗逆转录病毒治疗 (ART) 的情况下，总哌喹（PQ；与血浆蛋白结合和未结合）的药代动力学暴露显着降低。然而，由于 PQ 的蛋白质结合率 >99%，因此妊娠期间蛋白质结合减少可能会导致药理活性未结合药物分数 (fu) 相对于总 PQ 增加。我们研究了妊娠和 EFV 使用对 PQ 的影响，为药代动力学的解释提供信息。从接受或未接受基于 EFV 的 ART 的妊娠 28 周孕妇以及未接受基于 EFV 的 ART 的产后 34 至 54 周的妇女（作为对照）中收集第三次（最后一次）DP 剂量后 0 至 24 小时的血浆样本。通过超滤和液相色谱-串联质谱法对未结合的 PQ 进行定量，并计算为 PQunbound/PQtotal。孕妇和产后妇女之间的几何平均fudid没有差异（P=0.66），但与未接受基于EFV的ART的产后妇女相比，接受基于EFV的ART的孕妇的几何平均fudid高出23%（P<0.01）。药物-蛋白质结合的改变可能是由于 EFV 将血浆蛋白中的 PQ 置换所致，在总 PQ 暴露量降低 31% (P< 0.01) 的情况下，未结合的 PQ 暴露量仅降低 14% (P= 0.13)，根据接受基于 EFV 的 ART 的孕妇从最后一次给药后 0 到 24 小时的浓度时间曲线下面积估计。结果表明，妊娠和基于 EFV 的 ART 对暴露量的影响以及 PQ 预防疟疾的功效可能并不像总 PQ 暴露量变化所表明的那样显着。在最终消除阶段（例如，给药后第 28 天）进行的进一步研究将有助于更好地表征整个给药间隔期间未结合的 PQ 暴露，从而了解 PQ 在这一特殊人群中预防疟疾化学预防的总体功效。
Dihydroartemisinin-piperaquine (DP) is highly effective for malaria chemoprevention during pregnancy, but the standard dosing of DP that is used for nonpregnant adults may not be optimal for pregnant women. We previously reported that the pharmacokinetic exposure of total piperaquine (PQ; both bound and unbound to plasma proteins) is reduced significantly in the context of pregnancy or efavirenz (EFV)-based antiretroviral therapy (ART). However, as PQ is >99% protein-bound, reduced protein binding during pregnancy may lead to an increase in the pharmacologically active unbound drug fraction (fu), relative to the total PQ. We investigated the impact of pregnancy and EFV use on the fuof PQ to inform the interpretation of pharmacokinetics. Plasma samples from 0 to 24 h after the third (final) DP dose were collected from pregnant women at 28 weeks gestation who were receiving or not receiving EFV-based ART as well as from women 34 to 54 weeks postpartum who were not receiving EFV-based ART, who served as controls. Unbound PQ was quantified via ultrafiltration and liquid chromatography-tandem mass spectrometry, with fubeing calculated as PQunbound/PQtotal. The geometric mean fudid not differ between pregnant and postpartum women (P= 0.66), but it was 23% (P< 0.01) greater in pregnant women receiving EFV-based ART, compared to that in postpartum women who were not receiving EFV-based ART. The altered drug-protein binding, potentially due to the displacement of PQ from plasma proteins by EFV, resulted in only a 14% lower unbound PQ exposure (P= 0.13) in the presence of a 31% lower total PQ exposure (P< 0.01), as estimated by the area under the concentration time curve from 0 to 24 h post-last dose in pregnant women who were receiving EFV-based ART. The results suggest that the impact of pregnancy and EFV-based ART on the exposure and, in turn, the efficacy of PQ for malaria prevention may not be as significant as was suggested by the changes in the total PQ exposure. Further study during the terminal elimination phase (e.g., on day 28 post-dose) would help better characterize the unbound PQ exposure during the full dosing interval and, thus, the overall efficacy of PQ for malaria chemoprevention in this special population.