Pharmacokinetics and Pharmacodynamics of Endoperoxide Antimalarials

Abstract

There are several clinically useful endoperoxides, mainly artemisinin derivatives available in market for the treatment of malaria. These are highly potent drugs, with fastest parasite reduction ratio, broadest parasite stage specificity and effectiveness against all species of plasmodium in human. Endoperoxides are crystalline compounds having poor aqueous solubility. Several theories have been proposed for their mechanism of action, but the understanding is still incomplete. The major limitation of this class of compounds is the short half-life, requiring frequent administration, leading to noncompliance and recrudescence. Therefore, WHO recommends their use in combination with long acting antimalarial drugs (Artemisinin based combination therapy, ACT) to manage drug resistance, recrudescence, and non compliance. Endoperoxide compounds bind selectively to malaria-infected red blood cells and moderately to human plasma proteins. Artemisinin derivatives are converted primarily to the bioactive metabolite dihydroartemisinin after parenteral, oral or rectal administration. The rate of conversion is lowest for artelinic acid and highest for the water-soluble artesunate. Such conversion occurs largely in the liver by CYP enzymes. Oral bioavailability in animals ranges between 19 to 35%. Based on their liphophilicity, they tend to cross the blood-brain barrier, causing neurotoxicity in animal models. Efforts have been made to understand and develop pharmacokinetic-pharmacodynamic (PK-PD) correlation and identify PK-PD indices of endoperoxides. In the absence of the above, the selection of doses in ACTs has been empirical. There are several reports on clinical pharmacokinetic interactions of endoperoxides and their long acting partner drugs but as on date no clinically significant interaction has been reported. This review is an update on physicochemical, pharmacokinetic and pharmacodynamic properties of the endoperoxide antimalarials.

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

“…However, the widespread and excessive use of these agents has resulted in drug resistance (Wernsdorfer, 1991;Price and Nosten, 2001;Le Bras and Durand, 2003). In several studies, artemisinins, unique sesquiterpene lactone endoperoxides, have been used in areas with multidrug-resistant Plasmodium falciparum malaria (Woodrow et al, 2005;Gautam et al, 2009;World Health Organization, 2010).…”

The Impact of Pharmacokinetic Mismatched Antimalarial Drug Combinations on the Emergence and Spread of Drug Resistant Parasites

“…These compounds exhibit variable PK profiles and lack established PK/PD relationships to support defining rational dosage regimens for malaria treatment. Future efforts should focus on understanding all of the parameters required to conduct a valid PK/PD match between an artemisinin compound and an appropriate partner drug [67].…”

Pharmacokinetics of Artesunate Alone and in Combination with Sulfadoxine/Pyrimethamine in Healthy Sudanese Volunteers

“…[35][36][37] The lack of effect of SP on the pharmacokinetic parameters of AS and DHA could be caused by the difference in metabolic pathways of AS and SP. In this regard, AS is known to be completely hydrolyzed in the blood by tissue cholinesterases to yield its active metabolite, DHA, 38 and DHA is further conjugated by the UDP-glucuronosyltransferase system. 39 In addition, AS has been reported to be metabolized by CYP450.…”