Pharmacokinetic of Mefloquine-Artesunate in Plasmodium Falciparum Malaria Infection in Pregnancy
Condition: Plasmodium Falciparum Malaria
MeSH terms: Infections; Malaria; Malaria, Falciparum
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Malaria in pregnancy is a major public health problem in Sub-Saharan Africa. Over the past
      decades, P. falciparum has shown increasing resistance to chloroquine and
      Sulphadoxine-Pyrimethamine, which 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 traditional therapies. However, a standard
      approach for using ACT in pregnancy does not exist in Africa, where some countries keep on
      using quinine, while others allow the use of ACTs. Thus, there is need of establishing the
      safety and efficacy of ACTs in malaria-infected pregnant women. Since the pharmacokinetic of
      antimalarials may be altered during pregnancy and since available pharmacokinetic data are
      still somewhat limited, we propose to carry out a study confirming or disproving existing
      pharmacokinetic data (collected in South-East Asia), before starting any larger African
      efficacy and safety trials. The fixed-dose combination mefloquine-artesunate (MQ-AS),
      developed by the Drugs for Neglected Diseases Initiative, will be used in the study, which
      will compare the pharmacokinetics 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. The study will be carried out in Burkina Faso.
    

Detailed description: 
      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.
    

Intervention name(s): Mefloquine-artesunate
Intervention type(s): Drug
Intervention description(s): Mefloquine-artesunate fixed dose combination comprised of 100 mg of artesunate and 220mg of mefloquine per tablet, developed by DNDi and manufactured by farmanguinhos (Brazil).
Other intervention name(s): MQ-AS
Intervention MeSH terms: Artesunate; Mefloquine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Mefloquine-artesunate; Malaria; Pregnancy; Pharmacokinetics; Sub-Saharan Africa; P falciparum malaria infection in pregnancy