Population pharmacokinetics, tolerability and safety of dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine-piperaquine in pregnant and non-pregnant Papua New Guinean women
- Author(s)
- Benjamin, JM; Moore, BR; Salman, S; Page-Sharp, M; Tawat, S; Yadi, G; Lorry, L; Siba, PM; Batty, KT; Robinson, LJ; Mueller, I; Davis, TM;
- Journal Title
- Antimicrobial Agents and Chemotherapy
- Publication Type
- Journal Article in press
- Abstract
- The tolerability, safety and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 non-pregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine-PQ (three daily PQ doses, single-dose SP). All doses were observed and subjects fasted for 2 h post-dose. Plasma PQ was assayed by high performance liquid chromatography and DHA by liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two non-pregnant women had Plasmodium falciparum parasitaemia. Parasite clearance was <48 h and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths, obstetric outcomes consistent with those in the general population. The area under the plasma PQ concentration-time curve (AUC0-infinity) was lower in the pregnant patients (median [inter-quartile range] 23,721 [21,481-27,951] vs 35,644 [29,546-39,541] mug.h/liter, P<0.001) in association with a greater clearance relative to bioavailability (73.5 [69.4-78.4] vs 53.8 [49.7-58.2] liters/h, P<0.001), but pregnancy did not influence the pharmacokinetics of DHA. The apparent pharmacokinetic differences between the present and other studies of women with uncomplicated malaria that showed no effect of pregnancy on AUC0-infinity and greater bioavailability may reflect differences in post-dose fat intake, proportions of women with malaria, and/or racial differences in drug disposition.
- Publisher
- ASM
- Research Division(s)
- Population Health And Immunity
- PubMed ID
- 25963981
- Publisher's Version
- https://doi.org/10.1128/AAC.00326-15
- NHMRC Grants
- NHMRC/634343, NHMRC/1052760, NHMRC/1036951, NHMRC/1043345, NHMRC/572561,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-05-22 11:19:35
Last Modified: 2019-04-01 09:01:05