Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California, USA.
Clin Infect Dis. 2022 Aug 31;75(3):406-415. doi: 10.1093/cid/ciab965.
Intermittent preventive treatment with monthly dihydroartemisinin-piperaquine (DHA-PQ) is highly effective at preventing both malaria during pregnancy and placental malaria. Piperaquine prolongs the corrected QT interval (QTc), and it is possible that repeated monthly dosing could lead to progressive QTc prolongation. Intensive characterization of the relationship between piperaquine concentration and QTc interval throughout pregnancy can inform effective, safe prevention guidelines.
Data were collected from a randomized controlled trial, where pregnant Ugandan women received malaria chemoprevention with monthly DHA-PQ (120/960 mg DHA/PQ; n = 373) or sulfadoxine-pyrimethamine (SP; 1500/75 mg; n = 375) during the second and third trimesters of pregnancy. Monthly trough piperaquine samples were collected throughout pregnancy, and pre- and postdose electrocardiograms were recorded at 20, 28, and 36 weeks' gestation in each woman. The pharmacokinetics-QTc relationship for piperaquine and QTc for SP were assessed using nonlinear mixed-effects modeling.
A positive linear relationship between piperaquine concentration and Fridericia corrected QTc interval was identified. This relationship progressively decreased from a 4.42 to 3.28 to 2.13 millisecond increase per 100 ng/mL increase in piperaquine concentration at 20, 28, and 36 weeks' gestation, respectively. Furthermore, 61% (n = 183) of women had a smaller change in QTc at week 36 than week 20. Nine women given DHA-PQ had grade 3-4 cardiac adverse events. SP was not associated with any change in QTc.
Repeated DHA-PQ dosing did not result in increased risk of QTc prolongation and the postdose QTc intervals progressively decreased. Monthly dosing of DHA-PQ in pregnant women carries minimal risk of QTc prolongation.
NCT02793622.
每月给予二氢青蒿素-哌喹（DHA-PQ）间歇性预防治疗，可有效预防妊娠疟疾和胎盘疟疾。哌喹会延长校正 QT 间期（QTc），而且重复每月给药可能会导致 QTc 延长逐渐加重。在整个妊娠期间，深入研究哌喹浓度与 QTc 间隔之间的关系，可以为制定有效的、安全的预防指南提供信息。
数据来自一项随机对照试验，乌干达孕妇在妊娠第二和第三个三个月期间接受每月 DHA-PQ（120/960mgDHA/PQ；n=373）或磺胺多辛-乙胺嘧啶（SP；1500/75mg；n=375）的疟疾化学预防。整个妊娠期间采集每月哌喹谷浓度样本，并在每位女性妊娠 20、28 和 36 周时记录给药前和给药后的心电图。使用非线性混合效应模型评估哌喹的药代动力学-QTc 关系和 SP 的 QTc。
确定了哌喹浓度与 Fridericia 校正 QTc 间隔之间的正线性关系。这种关系分别从妊娠 20、28 和 36 周时，哌喹浓度每增加 100ng/mL，QTc 分别增加 4.42、3.28 和 2.13 毫秒逐渐降低。此外，61%（n=183）的女性在 36 周时的 QTc 变化小于 20 周。9 名接受 DHA-PQ 治疗的女性发生 3-4 级心脏不良事件。SP 与 QTc 变化无关。
重复给予 DHA-PQ 不会增加 QTc 延长的风险，而且给药后 QTc 间隔逐渐缩短。在孕妇中每月给予 DHA-PQ 剂量不会导致 QTc 延长的风险增加。
NCT02793622。
