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


Phase 1
18 Years
40 Years
Open (Enrolling)
Female
Malaria

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Trial Information

Phase I 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.

Inclusion Criteria


Inclusion Criteria for Cases:

- 2nd trimester (22-26 weeks) or 3rd trimester (32-36 weeks) of pregnancy, based on an
ultrasound conducted at <22 weeks gestation (composite of BPD, HC, AC, FL)

- Singleton pregnancy documented by ultrasound

- Parasitemic (> 500 parasites/μl)

- Afebrile and asymptomatic

- Hematocrit ≥ 30%

- Negative HIV test result

- At least 18 years of age and less than 40 years of age

- Able to spend three days in the clinic following their laboratory screening visit
and again at three months postpartum

- Willing to provide informed consent

Inclusion Criteria for Non-pregnant Controls:

- Negative urine pregnancy test

- Parasitemic (> 500 parasites/μl)

- Afebrile and asymptomatic

- Hematocrit ≥ 30%

- Negative Determine® HIV test result

- At least 18 years of age and less than 40 years of age

- Able to spend three days in the clinic following screening

- Willing to provide informed consent

Inclusion Criteria for Internal controls:

- Negative urine pregnancy test

Exclusion Criteria for Cases:

- Parasitemia > 300,000 parasites/μl or symptomatic malaria

- Medical contraindications to participation or medical disorders (known high blood
pressure, diabetes, sickle cell disease or tuberculosis)

- Have taken artesunate or any medicine containing artesunate during the current
pregnancy

- Have taken any antimalarial in the past two weeks

- Have taken any medication in the past two weeks other than antipyretics (e.g.,
acetyl- salicylic acid, acetaminophen), folic acid or iron

- Have a fetus with any ultrasonographically visible structural fetal abnormalities
identified on entry by ultrasound

- Past or present pregnancy complications that would preclude participation in the
study (gestational diabetes/diabetes, incompetent cervix, pre-eclampsia/ eclampsia,
and high blood pressure)

- Between 32-36 weeks gestation and have already participated in the study at 22-26
weeks gestation

Exclusion Criteria for Non-pregnant Controls:

- Parasitemia > 300,000 parasites/μl or have symptomatic malaria

- Medical contraindications to participation or medical disorders (known high blood
pressure, diabetes, sickle cell disease or tuberculosis)

- Have taken any antimalarial in the past two weeks

- Have taken any medication in the past two weeks other than antipyretics (e.g.,
acetyl- salicylic acid, acetaminophen), folic acid or iron

Exclusion Criteria for Internal Controls:

- Parasitemia > 300,000 parasites/μl or have symptomatic malaria

- Have taken antimalarial medication in the past two weeks.

- Have taken any medication in the past two weeks other than antipyretics (e.g.,
acetyl- salicylic acid, acetaminophen), folic acid or iron

- Pregnant

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

Levels of the unbound active major metabolite, dihydroartemisinin (DHA), will be similar for parasitemic pregnant women during their 2nd and 3rd trimesters vs. the same women 3 months postpartum (PK parameters = t1/2, Cmax, Tmax, CL/F, Vz/F, AUC).

Outcome Time Frame:

48 hours after drug administration

Principal Investigator

Carl Bose, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of North Carolina

Authority:

United States: Food and Drug Administration

Study ID:

GN02- PK/PD of artesunate

NCT ID:

NCT00538382

Start Date:

May 2007

Completion Date:

March 2009

Related Keywords:

  • Malaria
  • Malaria
  • Pregnancy
  • Artesunate
  • Pharmacokinetics
  • Pharmacodynamics
  • Democratic Republic of Congo
  • Malaria

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