Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria

Abstract

Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P ‫؍‬ 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P ‫؍‬ 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P ‫؍‬ 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days; P ‫؍‬ 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h ؋ ng/ml versus 1,220 h ؋ ng/ml, P ‫؍‬ 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.In the eastern and western border areas of Thailand, Plasmodium falciparum has developed resistance to almost every antimalarial drug (5). This poses particular problems for the treatment of pregnant women, a group especially vulnerable to P. falciparum infections. The World Health Organization (WHO) recommends the use of artemisinin combination therapy (ACT) (short-course, 3-day treatments) in the second and third trimester of pregnancy (37). However, pregnant women often have lower antimalarial blood concentrations than nonpregnant women and are therefore at risk of undertreatment (13-16, 34, 36). Dihydroartemisinin-piperaquine (DHA-PPQ) is one of the most promising ACTs. It is a coformulation of dihydroartemisinin and piperaquine. Randomized clinical trials in Asia, Africa, and South America indicate excellent tolerability and high cure rates in nonpregnant populations (2-4, 8, 25, 31, 35, 38). Recently, DHA-PPQ was found to be well tolerated and effective in the treatment of multiple recrudescent P. falciparum infections in 50 pregnant women in Thailand (27) and in 104 pregnan...

Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

“…As reported previously, the pregnant and nonpregnant women were well matched (Table 1), and the study drug was efficacious, well tolerated, and with no serious adverse events (47). Patients in the nonpregnant group were followed for 63 days, and those in the pregnant group were followed for 63 days or to the time of delivery (whichever was latest).…”

“…Renal blood flow and glomerular filtration rate rise during pregnancy, but these changes are a less likely explanation of the observed increase in elimination clearance since studies in the rat indicate negligible renal elimination of piperaquine (57). A noncompartmental analysis of these data suggested no difference in oral clearance and a significantly lower volume of distribution in pregnant women than nonpregnant women (47). This is in agreement with the results from the population modeling since a proportional increase in relative bioavailability and elimination clearance would explain the noncompartmental net result of a decreased apparent volume of distribution since changes in volume of distribution and relative bioavailability cannot reliably be separated in a noncompartmental analysis.…”

“…This pharmacokinetic study was conducted in the Wang Pha Clinic of the Shoklo Malaria Research Unit (SMRU), Mae Sot, Thailand. The clinical assessment with a preliminary noncompartmental analysis is reported in full elsewhere (47). Approval for the study was obtained from the ethics committee of the faculty of Tropical Medicine, Bangkok, Thailand (MUTM 2007-111) and the Oxford Tropical Research Ethic Committee (OxTREC 017-07).…”

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

“…In an African pediatric IPT efficacy study of monthly DHA-PQ or SP-PQ (30), incident malaria was lower in the SP-PQ-treated children. There is evidence that the elimination half-life of the pyrimethamine component of SP may be particularly long in pregnancy (19 days versus 10 days in nonpregnant women) (19) which, given that DHA is eliminated within hours of dosing (14,27), might suggest that SP-PQ is a better choice for IPTp than DHA-PQ.…”

“…A fixed-dose combination is in widespread use for treatment of uncomplicated falciparum and vivax malaria outside pregnancy (25,26). Available pharmacokinetic and efficacy data from Southeast Asia (14,27,28) and Africa (12,13) suggest that DHA-PQ is safe, well tolerated, and efficacious in pregnant women with uncomplicated malaria and that PQ exposure is similar in pregnant and nonpregnant women, even if DHA exposure may be lower in pregnancy.…”