title: Parasitological Clearance Rates and Drug Concentrations of a Fixed Dose Combination of Azithromycin-Chloroquine in Asymptomatic Pregnant Women with Plasmodium Falciparum Parasitemia: An Open-Label, Non-Comparative Study in Sub-Saharan Africa.
abstract: BACKGROUND
  Malaria remains one of the most important causes of morbidity and mortality in pregnant women and their newborn babies in sub-Saharan Africa. Intermittent preventive treatment in pregnancy (IPTp) is recommended by the World Health Organization (WHO) to reduce the burden of disease and improve maternal and neonatal survival and general health. Due to the growing resistance to sulfadoxine-pyrimethamine (SP), the current WHO-recommended drug for IPTp, identification of new and effective drugs is an urgent priority.
  
  
  RESULTS
  This was an open-label, non-comparative study (NCT01103713) in 5 countries in East and sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) to assess parasitological response and drug concentrations of a single, 3-day course of four tablets of a fixed-dose combination of azithromycin-chloroquine (AZCQ) 250/155 mg given during the second or third trimester to women with asymptomatic Plasmodium falciparum parasitemia in their first or second pregnancy. Parasitemia was determined by microscopy and molecular genotyping was performed to characterize parasites relative to the baseline infection. Weekly follow-up visits took place until day 42 after first dose and additional follow-up occurred after delivery. Systemic concentrations of azithromycin (AZ), chloroquine (CQ), and the CQ metabolite, desethyl CQ (DECQ) were evaluated at Day 0 (pre-dose), at Day 2 (pre-dose, 2 and 8 hours) and randomly at Days 7 and 14. Systemic concentrations of CQ and DECQ were also measured randomly at Day 21 and Day 28. In total, 404 women were screened for eligibility and 168 were treated, 155 of whom completed the study. PCR-adjusted parasitological response in the modified intent-to-treat population at day 28 (the primary efficacy endpoint) was estimated by the Kaplan-Meier method as 99.35% (95% confidence interval [CI]: 97.76, 100.00). PCR-adjusted parasitological response remained high at day 42 (95.19%; 95% CI: 91.35, 99.03). In general, the mean concentrations of serum AZ, plasma CQ, and plasma DECQ showed large CV% values (ranges of 33-156%, 42-228%, and 57-109%, respectively). There were 157 live births, three stillbirths, and eight pregnancies of unknown outcome: 7 due to withdrawal of participant consent and 1 lost to follow-up. The most frequent treatment-emergent adverse events were vomiting (20.8%) and dizziness (19.6%).
  
  
  CONCLUSIONS
  These results suggest that a 3-day course of AZCQ can lead to an adequate 28-day parasitological response.
authors.affiliation: College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: Kamija
authors.initials: K
authors.lastname: Phiri
authors.affiliation: College of Health Sciences, University of Nairobi, Nairobi, Kenya.
authors.forename: Joshua
authors.initials: J
authors.lastname: Kimani
authors.affiliation: National Institute for Medical Research, Amani Medical Research Centre, Tanga, Tanzania.
authors.forename: George A
authors.initials: GA
authors.lastname: Mtove
authors.affiliation: Pfizer Inc., Groton, Connecticut, United States of America.
authors.forename: Qinying
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Pfizer Inc., Groton, Connecticut, United States of America.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rojo
authors.affiliation: Pfizer Inc., Groton, Connecticut, United States of America.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Robbins
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.affiliation: Pfizer Inc., Sandwich, Kent, United Kingdom.
authors.forename: Ayman
authors.initials: A
authors.lastname: Ayoub
authors.affiliation: Pfizer Inc., New York, New York, United States of America.
authors.forename: Pol
authors.initials: P
authors.lastname: Vandenbroucke
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara; D058070:Asymptomatic Diseases; D017963:Azithromycin / Q000008:administration & dosage*; D002738:Chloroquine / Q000008:administration & dosage*; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000469:parasitology*; D059208:Parasite Load; D018512:Parasitemia; D010963:Plasmodium falciparum / Q000187:drug effects*; D011247:Pregnancy; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D017963:Azithromycin; D002738:Chloroquine