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

Wellcome Open Research

article

Sofia Birgersson¹  Innocent Valea²  Halidou Tinto²  Maminata Traore-Coulibaly²  Laeticia C. Toe²  Richard M. Hoglund⁵  Jean-Pierre Van Geertruyden⁷  Stephen A. Ward⁸  Umberto D’Alessandro⁹  Angela Abelö¹  Joel Tarning⁵ 

[1] Department of Pharmacology, University of Gothenburg;Institut de Recherche en Sciences de la Santé;Institut de Recherche en Sciences de la Sante´;Department of Food Safety, Quality and Health, Faculty of Bioscience Engineering, Ghent University;Mahidol-Oxford Tropical Medicine Resarch Unit, Faculty of Tropical Medicine, Mahidol University;Nuffield Department of Medicine, University of Oxford;Global Health Institute, University of Antwerp;Department of Parasitology, Liverpool School of Tropical Medicine;MRC Unit, London School of Hygiene & Tropical Medicine

关键词: Artemisinin-based combination therapy;    Artesunate;    Dihydroartemisinin;    Mefloquine;    Pregnancy;    Malaria;    Population pharmacokinetics;    NONMEM;   

DOI  :  10.12688/wellcomeopenres.14849.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

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 uncomplicatedP. 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 completein 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 enzyme levels (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.

【 授权许可】

CC BY