title: Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria.
abstract: BACKGROUND
  The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC.
  
  
  METHODS
  Data were obtained from 26 pregnant women in the second (22-26 weeks) or the third (32-36 weeks) trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling.
  
  
  RESULTS
  A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788-1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7-72.3%).
  
  
  CONCLUSIONS
  In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls.
authors.affiliation: University of Iowa, College of Pharmacy, 115 South Grand Avenue, Iowa City, IA 52242, USA.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Morris
authors.forename: Marie A
authors.initials: MA
authors.lastname: Onyamboko
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Koch
authors.forename: Joseph
authors.initials: J
authors.lastname: Atibu
authors.forename: Vicky
authors.initials: V
authors.lastname: Lokomba
authors.forename: Macaya
authors.initials: M
authors.lastname: Douoguih
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hemingway-Foday
authors.forename: David
authors.initials: D
authors.lastname: Wesche
authors.forename: Robert W
authors.initials: RW
authors.lastname: Ryder
authors.forename: Carl
authors.initials: C
authors.lastname: Bose
authors.forename: Linda
authors.initials: L
authors.lastname: Wright
authors.forename: Antoinette K
authors.initials: AK
authors.lastname: Tshefu
authors.forename: Steven
authors.initials: S
authors.lastname: Meshnick
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fleckenstein
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077332:Artesunate; D016022:Case-Control Studies; D015023:Democratic Republic of the Congo / Q000453:epidemiology; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D008954:Models, Biological; D015233:Models, Statistical; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; C039060:artenimol