Pharmacokinetic profile of artemisinin derivatives and companion drugs used in artemisinin-based combination therapies for the treatment of Plasmodium falciparum malaria in children.

Malaria is one of the most common parasitic infections worldwide. Plasmodium falciparum is the most prevalent strain in Africa and also the most fatal. The disease especially affects children, with those under age 5 years accounting for approximately 86 % of malaria deaths in 2010. The objectives of this review are to summarize and evaluate published literature reporting the pharmacokinetic parameters of artemisinin-based combinations used to treat P. falciparum in paediatric populations and to identify and discuss controversies regarding pharmacokinetics of these agents in children. A search of MEDLINE (1948-September 2012), EMBASE (1980-September 2012), International Pharmaceutical Abstracts (1970-September 2012), Google and Google Scholar was conducted for articles describing pharmacokinetics of antimalarials in children. Our search produced 30 articles, of which 23 were included in the review: artemisinin compounds, 12 articles; lumefantrine, four articles; amodiaquine, five articles; sulfadoxine, six articles; pyrimethamine, one article; mefloquine, three articles; and piperaquine, two articles. Studies were summarized based on comparison groups and major findings. Many controversies were identified, including pharmacokinetic equivalence of novel dosage forms, altered pharmacokinetic parameters in children versus adults, effect of drug interactions, and association of pharmacokinetic changes with clinical outcomes. A large variation in pharmacokinetic parameters of many antimalarial agents was shown, which may be a consequence of the wide range of ages and/or bodyweights of each paediatric cohort. These studies may mask important associations with age and bodyweight and produce mean data that do not adequately represent the paediatric population as a whole. In order to properly assess the clinical implications of such pharmacokinetic changes and recommend safe and effective dosage regimens, there is an urgent need for dose-optimization studies for all recommended first- and second-line agents, along with the different drug formulations, used in paediatric populations with P. falciparum.