Drug-Drug Interaction Between Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine During Malaria Chemoprevention in Pregnant Women.

Abstract

Co-administration of dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) may be superior in preventing adverse birth outcomes compared with either therapy alone, but potential drug-drug interactions require investigation. We conducted intensive and sparse pharmacokinetic (PK) studies in a subset of Ugandan women participating in a randomized controlled trial of monthly IPTp with SP vs. DP vs. DP + SP. Intensive PK sampling was performed from day 0 to 23 after dosing at 28 weeks gestation in 87 participants across treatment arms. Sparse sampling was performed on day 28 (trough) after dosing at 20 and 28 gestational weeks in additional 196 participants receiving SP vs. DP + SP. Intensive PK analysis demonstrated that compared with SP alone, co-administration of DP + SP was associated with lower maximal concentrations, the area under the concentration-time curves (AUC), and day 23 concentrations of sulfadoxine (25%, 25%, and 27%) and pyrimethamine (26%, 34%, and 32%) (P < 0.05 for all comparisons). Sparse PK results demonstrated participants co-administered DP + SP had lower trough concentrations after dosing at 20 and 28 gestational weeks for sulfadoxine (6%, P = 0.68 and 31%, P = 0.023, respectively) and pyrimethamine (18%, P = 0.032 and 33%, P < 0.001, respectively) compared with SP alone. Co-administration of DP + SP was associated with a 19% reduction in piperaquine AUC (P = 0.046), but no significant difference in other PK parameters compared with DP alone. In summary, co-administration of DP + SP was associated with significantly reduced SP exposure, with a greater magnitude during the third vs. second trimester. The clinical consequences of this interaction are yet unknown.