Study of Pharmacokinetics and Pharmacodynamics of Artesunate in Pregnant Women in the Democratic Republic of Congo

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.