title: Opposite malaria and pregnancy effect on oral bioavailability of artesunate - a population pharmacokinetic evaluation.
abstract: OBJECTIVE
  The aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7.
  
  
  METHODS
  Non-linear mixed-effects modelling was used to compare plasma concentration-time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously.
  
  
  RESULTS
  Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%.
  
  
  CONCLUSIONS
  The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy.
authors: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok.
authors: Frank
authors: F
authors: Kloprogge
authors: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok.|Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: Rose
authors: R
authors: McGready
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: Aung Pyae
authors: AP
authors: Phyo
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: Marcus J
authors: MJ
authors: Rijken
authors: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok.
authors: Warunee
authors: W
authors: Hanpithakpon
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: Hla Hla
authors: HH
authors: Than
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: Nathar
authors: N
authors: Hlaing
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: Naw Thida
authors: NT
authors: Zin
authors: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok.
authors: Nicholas P J
authors: NP
authors: Day
authors: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok.
authors: Nicholas J
authors: NJ
authors: White
authors: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok.|Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: François
authors: F
authors: Nosten
authors: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok.
authors: Joel
authors: J
authors: Tarning
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000962:Antimalarials / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000077332:Artesunate; D001682:Biological Availability; D005260:Female; D006801:Humans; D008288:Malaria / Q000097:blood / Q000378:metabolism*; D008954:Models, Biological; D049590:Postpartum Period; D011247:Pregnancy / Q000097:blood / Q000378:metabolism*; D015597:Pregnancy Complications, Parasitic
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; C039060:artenimol
keywords: artesunate; dihydroartemisinin; nonmem; population pharmacokinetics; post-partum women; pregnant women