Study of Pharmacokinetics and Pharmacodynamics of Artesunate in Pregnant Women in the Democratic Republic of Congo
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      The objective of this study is to assess the pharmacokinetics (PK) and pharmacodynamics (PD)
      of a standard dose of orally administered artesunate, in order to determine if the current
      adult dose (200 mg) is appropriate in parasitemic pregnant women when compared to the same
      women at three months postpartum and to parasitemic non-pregnant women. Preliminary evidence
      on safety, tolerability and efficacy will be gathered.
    

Detailed description: 
      Annually, approximately 25 million African women become pregnant and are at risk of
      Plasmodium falciparum malaria infection during pregnancy [WHO]. The adverse effects of
      malaria during pregnancy include increased risk of maternal anemia, low birth weight (LBW)
      and infant death. The World Health Organization (WHO) recommends that intermittent preventive
      treatment (IPT) of malaria be used routinely in pregnant women living in areas of Africa
      where malaria infection is endemic. IPT involves the periodic presumptive administration of
      antimalarial treatment to all pregnant women as part of routine antenatal care.

      This strategy has proven to be effective in much of sub-Saharan Africa where diagnostic
      facilities are often unavailable and pregnant woman are at high risk for malaria infection
      [WHO 2005]. This is representative of our study site in Kinshasa, Democratic Republic of
      Congo (DRC), where a 2004 pilot study conducted by the Global Network for Women's and
      Children's Health Research (GN) revealed that the prevalence of malaria in pregnant women was
      34.3% [personal communication, Tshefu]. Currently sulfadoxine-pyrimethamine (SP) is the
      WHO-recommended drug for prevention of malaria during pregnancy where transmission of
      Plasmodium falciparum malaria is stable and where resistance to SP is low.

      The DRC is an area of stable malaria transmission. In stable areas of transmission,
      non-pregnant adults have high levels of immunity to malaria and usually do not become
      severely ill with infection. However, pregnant women, especially primigravidas, have
      increased susceptibility to malaria. Pregnant women are not protected by immunity acquired in
      the non-pregnant state because parasites are exposed to different antigens in pregnancy than
      in the non-pregnant state. In addition, Plasmodium falciparum infection in pregnancy can lead
      to anemia and can affect placental nutrient transport, resulting in the birth of low birth
      weight infants with an increased risk for infant mortality [Steketee, 2001]. In a 2004 pilot
      study conducted by the Global Network in two large maternity clinics in Kinshasa, DRC, 34.3%
      (182/530) of pregnant women were thick smear positive for malaria [personal communication,
      Tshefu].

      Currently, in Kinshasa, DRC the standard of care for IPT treatment of malaria during
      pregnancy is to administer 1500 mg sulfadoxine with 75 mg pyrimethamine during the second
      trimester (after the fourth month and usually in association with the mother's report of
      fetal quickening) and again during the third trimester, between 28-32 weeks gestation. SP has
      proven to be safe when used as IPT in pregnant women; clinical studies have shown no serious
      adverse events or cases of kernicterus nor has there been a significant difference in the
      rate of spontaneous abortions, premature deliveries, or neonatal deaths between IPT/SP and
      other interventions [Newman, 2004].

      Since the 1980's, SP resistance in Africa and Asia has been steadily increasing. The
      1999-2000 data from the East African Network for Monitoring Anti-malarial Treatment indicated
      that in vivo SP failure at some sites in Kenya was greater than 25% and had reached 45% at
      one site in Tanzania. Focal areas of low- to moderate-level SP resistance exist throughout
      Africa [Bilj, 2000; Deloron 1989; Landgraf, 1994; Nizla, 2000]. Resistance is likely to
      progress geographically and rapidly if nothing is done to interrupt this course. One of the
      reasons for the increasingly high SP failure rates may be the recently observed
      cross-resistance between SP and cotrimoxazole (sulfamethoxazole-trimethoprim) in Plasmodium
      falciparum [Lyer, 2001]. A second possible reason is that the long half-life of the drug may
      result in prolonged maintenance of subtherapeutic concentrations of the drug in the plasma
      [Nzila, 2000].

      Resistance of Plasmodium falciparum to SP in Kinshasa appears to be low, but on the verge of
      increasing with selective pressure. In 2000, an in vivo drug efficacy trial in children found
      that 94.5% of the subjects responded adequately to SP [Kazadi, 2003]. These results have been
      corroborated by the genotyping of clinical samples from pregnant women in the 2004 pilot
      study conducted by the Global Network in Kinshasa for molecular markers for drug resistance
      [personal communication, Tshefu]. Molecular markers are used to survey the development and
      evolution of drug resistance. SP resistance is associated with mutations in the genes DHFR
      and DHPS. Presence of a quintuplet mutation (51, 59, 108, 437, and 540) is most strongly
      associated with SP resistance. Only 4.1% of the clinical samples in the pilot study contained
      the quintuplet mutation, which suggests that drug resistance was minimal at the time the
      study was conducted. However, 33.2% of the samples were found to be one mutation away from
      having the quintuplet mutation, indicating that full SP resistance (5 mutations) is likely to
      occur soon. Therefore, if adequate selective pressure were applied, e.g. by widespread use of
      SP, as is currently being practiced in the DRC, the prevalence of the quintuplet mutation and
      treatment failure due to drug resistance would increase dramatically.

      Drug resistance to SP has spread more rapidly in the eastern part of the DRC, some 2000
      kilometers (km) from Kinshasa. A report from a 2001 in vivo drug efficacy study in Bukavu,
      located on the Rwandan border in Eastern DRC, reported that 85.0% of the children responded
      adequately to SP [Kazadi, 2003]; however, a subsequent drug efficacy study in Rutshuru, also
      located on the Rwanda/Uganda border of Eastern DRC approximately 200 km south of Bukavu,
      demonstrated that only 39.4% of children responded adequately to treatment [Kazadi, personal
      communication]. In addition, 43.4% of these clinical samples contained the quintuplet
      mutation [Alker, personal communication]. Given this rise in resistance to SP in eastern DRC
      and the likelihood of increased resistance in Kinshasa, it is necessary to begin to explore
      other alternatives for SP.

      While the pharmacokinetics of artemisinin is well known in non-pregnant adults, little is
      known about the specific pharmacokinetics of artemisinin in pregnant women, particularly
      pregnant women in developing countries. Dosages of drugs often need to be adjusted because of
      physiological and metabolic changes associated with pregnancy. The aim of this study is to
      determine the most appropriate dosage of artesunate to use in pregnant women in order to
      begin to investigate artesunate and artesunate combinations as options for IPT.
    

Intervention name(s): Artesunate
Intervention type(s): Drug
Intervention description(s): A 200 mg dose of orally administered artesunate at the beginning of a 48-hour clinical sampling period.
Other intervention name(s): Arsumax®
Intervention MeSH terms: Artesunate
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Keywords: Malaria; Pregnancy; Artesunate; Pharmacokinetics; Pharmacodynamics; Democratic Republic of Congo