Abstract

BACKGROUND: 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 and safe prevention guidelines.METHODS: Data were collected from a randomized controlled trial, where pregnant Ugandan women received malaria chemoprevention with monthly DHA-PQ (120/960mg DHA/PQ; n=373) or sulfadoxine-pyrimethamine (1500/75mg S/P; n=375) during the second and third trimesters of pregnancy. Monthly trough piperaquine samples were collected throughout pregnancy and pre- and post-dose electrocardiograms were recorded at 20, 28 and 36 weeks gestation in each women. The PK-QTc relationship for piperaquine and QTc for SP was assessed using nonlinear mixed effects modeling.RESULTS: A positive linear relationship between piperaquine concentration and Frederica corrected QTc interval was identified. This relationship progressively decreased from a 4.42 to 3.28 to 2.13 msec increase per 100ng/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 compared to week 20. Nine women given DHA-PQ had grade 3-4 cardiac adverse events. SP was not associated with any change in QTc.CONCLUSIONS: Repeated DHA-PQ dosing did not result in an increased risk of QTc prolongation and the post-dose QTc intervals progressively decreased. Monthly dosing of DHA-PQ in pregnant women carries minimal risk of QTc prolongation.

View details for DOI 10.1093/cid/ciab965

View details for PubMedID 34864925