Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration

Derivatives of the naturally occurring endoperoxide anti-malarial artemisinin form the foundation of the current global treatment approach for Plasmodium falciparum malaria. These derivatives, including artesunate (AS), artemether and dihydroartemisinin, produce more profound reductions in parasitaemia and more rapid symptom relief than agents from any other anti-malarial class. Of these derivatives, AS is the most therapeutically versatile agent. As with the other derivatives, AS can be administered orally for the treatment of uncomplicated malaria. Specifically, artemisinin-based combination therapies containing AS partnered with longer acting anti-malarial agents, such as mefloquine or sulphadoxine-pyrimethamine, are extensively utilized for oral treatment of uncomplicated falciparum malaria [1]. Among the artemisinin derivatives, however, only AS displays sufficient water solubility to be administered intravenously; per the World Health Organization treatment guidelines, intravenous AS is the preferred therapy for severe malaria infection in both adult and paediatric patients [1]. AS can also be administered intramuscularly or rectally, with AS suppositories for rectal administration representing a means of initiating treatment of severe malaria before patients are referred to distant facilities for intravenous therapy.Given the therapeutic significance and versatility of AS, and the necessity of appropriate dosing to avoid suboptimal efficacy or encouragement of resistance, research defining the pharmacokinetics (PK) of AS, and its active metabolite dihydroartemisinin (DHA), is of substantial clinical relevance. The intent of this review is to examine clinical pharmacokinetic findings of AS and DHA following AS administration by the intravenous (IV), intramuscular (IM), oral and rectal routes. To this end, an extensive literature search was conducted utilizing the PubMed database and the bibliographies of identified articles in order to locate AS clinical pharm