title: Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects.
abstract: OBJECTIVE
  To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance.
  
  
  METHODS
  In a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4mgkg(-1) ) on the first day and oral ARS (4mgkg(-1) ) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4mgkg(-1) day(-1) ) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum).
  
  
  RESULTS
  I.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n= 20) and in controls (n= 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ngml(-1) h)/(mgkg(-1) )] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P= 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P= 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P= 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P= 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P= 0.084).
  
  
  CONCLUSIONS
  This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.
authors.affiliation: Shoklo Malaria Research Unit, PO Box 46, Mae Sot Tak 63110 Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Rose
authors.initials: R
authors.lastname: McGready
authors.forename: Aung Pyae
authors.initials: AP
authors.lastname: Phyo
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Rijken
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegardh
authors.forename: Warunee
authors.initials: W
authors.lastname: Hanpithakpon
authors.forename: Hla Hla
authors.initials: HH
authors.lastname: Than
authors.forename: Nathar
authors.initials: N
authors.lastname: Hlaing
authors.forename: Naw Thida
authors.initials: NT
authors.lastname: Zin
authors.forename: Pratap
authors.initials: P
authors.lastname: Singhasivanon
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: François
authors.initials: F
authors.lastname: Nosten
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000494:pharmacology; D037621:Artemisinins / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077332:Artesunate; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D049590:Postpartum Period; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000188:drug therapy / Q000378:metabolism*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; C039060:artenimol