Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria.
OBJECTIVE
To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug resistant falciparum malaria, in the second and third trimesters of pregnancy.


METHODS
Serial plasma concentrations of artesunate and DHA were measured in 24 women after the final dose of a 3 day treatment with artesunate (4 mg kg(-1) day(-1)) and atovaquone (20 mg kg(-1) day(-1)) plus proguanil (8 mg kg(-1) day(-1)), daily. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data.


RESULTS
Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8-20.7] l hour(-1) kg(-1), total apparent volume of distribution (Vd/f) was 3.4 [0.9-60.7] l/kg, and terminal elimination half-life was 1.0 [0.6-2.4] h.


CONCLUSIONS
The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower than reported previously in non-pregnant adults. Dose-optimisation studies in pregnant women are needed.
Shoklo Malaria Research Unit, P.O. Box 46, Mae Sot, Thailand.
R
R
McGready
K
K
Stepniewska
S A
SA
Ward
T
T
Cho
G
G
Gilveray
S
S
Looareesuwan
N J
NJ
White
F
F
Nosten
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077332:Artesunate; D053626:Atovaquone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004338:Drug Combinations; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011256:Pregnancy Outcome; D011262:Pregnancy Trimester, Second; D011263:Pregnancy Trimester, Third; D002727:Proguanil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013785:Thailand
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D012717:Sesquiterpenes; D000077332:Artesunate; C039060:artenimol; D002727:Proguanil; D053626:Atovaquone