• To estimate the pharmacokinetic of MQ-AS for treatment of P. falciparum or mixed infection in pregnant compared to non-pregnant women. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  

• The proportion of women in each treatment group with parasitological cure at 63 days, corrected by PCR for re-infection. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  

Malaria during pregnancy constitutes a major public health problem in Sub-Saharan Africa, where it increases the risk of low birth weight (<2500g), infant mortality, infant morbidity during the first year of life, prematurity and infant anemia. Over the past decades, P. falciparum has shown increasing resistance to standard antimalarial therapy (chloroquine CQ and Sulphadoxine-Pyrimethamine). The inexorable development and spread of P.

falciparum resistance to antimalarials has prompted a change in treatment approach; artemisinin containing combination therapies (ACTs) are now the standard treatment of P. falciparum malaria in areas with established resistance to the traditional therapies. The use of combinations reduces the theoretical likelihood of selecting resistant mutants; it is hoped that this strategy will delay the development of new resistances.

A standard approach for using ACT in pregnancy does not exist in Africa. Even if the World Health Organization endorses the use of ACTs for treatment of uncomplicated malaria in 2nd and 3rd trimesters of pregnancy, some countries keep on using quinine, while others allow the use of ACTs. These different approaches point out to the necessity of establishing the safety and efficacy of ACTs in malaria-infected pregnant women. Nevertheless, considering that the pharmacokinetic of antimalarials may be altered during pregnancy (potentially leading to under-dosing) and that the available safety and pharmacokinetic data are still somewhat limited, it is important to carry out a preliminary pharmacokinetic study confirming or disproving available data (collected in South-East Asia), before starting any larger African efficacy and safety trials.

The ACT regimen mefloquine-artesunate (MQ-AS) has recently been developed as a fixed-dose combination by the Drugs for Neglected Diseases Initiative (DNDi) and has been registered in Brazil (the country of manufacture) in 2008. Artesunate is an artemisinin derivative with a rapidly increasing positive experience in pregnancy, while Mefloquine (Lariam®) has been used for many years for both prevention and treatment of malaria, and has been shown to be safe in pregnant women. The convenient dosing afforded by a fixed drug combination makes MQ-AS a very promising candidate for use in treating pregnant women in Africa, as rescue treatment alternative to quinine. Since preliminary data suggest that the peak concentration of mefloquine is lowered in pregnant women, further studies on safety, efficacy, and dose optimization are imperative, prior to wide-spread adoption of this medicine.

Therefore, we propose to compare the pharmacokinetics of the fixed combination of MQ-AS for treatment of P.falciparum in 24 pregnant women in the second and third trimesters to the pharmacokinetics of this regimen in 24 matched non-pregnant P.falciparum infected women, in an African setting. This will allow for dose optimization in pregnant women.