@article{Birgersson2019-ri,

title = {Population pharmacokinetics of artesunate and dihydroartemisinin  in pregnant and non-pregnant women with uncomplicated Plasmodium  falciparum malaria in Burkina Faso: an open label trial},

author = {Sofia Birgersson and Innocent Valea and Halidou Tinto and Maminata Traore-Coulibaly and Laeticia C Toe and Richard M Hoglund and Jean-Pierre Van Geertruyden and Stephen A Ward and Umberto D'Alessandro and Angela Abel\"{o} and Joel Tarning},

doi = {10.12688/wellcomeopenres.14849.2},

issn = {2398-502X},

year  = {2019},

date = {2019-03-01},

urldate = {2019-03-01},

journal = {Wellcome Open Res.},

volume = {4},

pages = {45},

publisher = {F1000 Research Ltd},

abstract = {Background: Malaria during pregnancy is a major health risk for 

 both the mother and the foetus. Pregnancy has been shown to 

 influence the pharmacokinetics of a number of different 

 antimalarial drugs. This might lead to an under-exposure in 

 these patients which could increase the risk of treatment 

 failure and the development of drug resistance. The study aim 

 was to evaluate the pharmacokinetics of artesunate and 

 dihydroartemisinin in pregnant and non-pregnant patients using a 

 population modelling approach. Methods: Twenty-four women in 

 their second and third trimester of pregnancy and twenty-four 

 paired non-pregnant women, all with uncomplicated P. falciparum 

 malaria, were enrolled in this study. Treatment was a fixed-dose 

 combination of oral artesunate and mefloquine once daily for 

 three days. Frequent blood samples were collected and 

 concentration-time data for artesunate and dihydroartemisinin 

 were analysed simultaneously using nonlinear mixed-effects 

 modelling. Results: Artesunate pharmacokinetics was best 

 described by a transit-compartment absorption model followed by 

 a one-compartment disposition model under the assumption of 

 complete in vivo conversion of artesunate into 

 dihydroartemisinin. Dihydroartemisinin pharmacokinetics was best 

 described by a one-compartment disposition model with 

 first-order elimination. Pregnant women had a 21% higher 

 elimination clearance of dihydroartemisinin, compared to 

 non-pregnant women, resulting in proportionally lower drug 

 exposure. In addition, initial parasitaemia and liver status 

 (alanine aminotransferase) were found to affect the relative 

 bioavailability of artesunate. Conclusions: Results presented 

 here show a substantially lower drug exposure to the 

 antimalarial drug dihydroartemisinin during pregnancy after 

 standard oral treatment of artesunate and mefloquine. This might 

 result in an increased risk of treatment failure and drug 

 resistance development, especially in low transmission settings 

 where relative immunity is lower. Trial registration: 

 ClinicalTrials.gov NCT00701961 (19/06/2008).},

keywords = {Artemisinin-based combination therapy; Artesunate;   Dihydroartemisinin; Malaria; Mefloquine; NONMEM; Population   pharmacokinetics; Pregnancy},

pubstate = {published},

tppubtype = {article}

}