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

Abstract

c Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series. Children under the age of 5 years and pregnant women are especially vulnerable to malaria. An estimated 85 million pregnancies occurred in areas with falciparum malaria transmission during 2007 (13). Malaria during pregnancy is responsible for maternal and fetal mortality (42,43). Both falciparum malaria and vivax malaria during pregnancy are associated with low birth weight resulting from intrauterine growth restriction (8, 9, 48). Effective treatment and prophylaxis of malaria in pregnancy rely on the use of efficacious antimalarial drugs.Pregnancy has substantial effects on the pharmacokinetic characteristics of many antimalarial drugs. Previous studies report artesunate, artemether, dihydroartemisinin, sulfadoxine, atovaquone, proguanil, cycloguanil, pyrimethamine, and lumefantrine concentrations to be reduced in pregnant women (25,33,34,36,44,58). This may contribute to lower antimalarial cure rates in pregnant than nonpregnant adults (58). Other studies report no pharmacokinetic differences in pregnant women compared to nonpregnant women (e.g., pyrimethamine and amodiaquine/desethylamodiaquine) or even a higher drug exposure during pregnancy (pyrimethamine) (15,25,46).Artemisinin-based combi...

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

“…Enzyme auto-induction cannot be excluded as an underlying cause to the time-dependent difference in exposure. However, previous detailed PK studies of oral and parenteral administration of ARS have demonstrated a clear malaria effect on the relative bioavailability thought to result from reduced first pass metabolism (40,41). The decreased absorption rate with increasing parasite density was unexpected and opposite to previous observations (39,(42)(43)(44)(45)(46)(47)(48).…”

“…However, in some reports, peripheral compartment structures have been proposed for DHA. Differences are likely to reflect sampling methodologies and data censoring due to quantification issues (39,40). Malaria infection (measured by the parasite density) had a significant impact on both absorption rate and relative bioavailability of ARS, resulting in increased absorption during the acute malaria infection compared to the convalescent phase.…”

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.…”

“…The World Health Organization (WHO) recommends sulfadoxinepyrimethamine (SP) as IPTp in combination with the use of insecticide-treated bed nets (ITNs) (6,7). However, as SP-resistant Plasmodium falciparum continues to spread, new IPTp regimens, including azithromycin-SP (AZI-SP), dihydroartemisinin-piperaquine (DHA-PQ), and AZI-PQ are being assessed (8)(9)(10)(11)(12)(13)(14)(15).…”