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 pharmacokineticpharmacodynamic (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.
Artemisinin, falciparum, endoperoxide, antimalarials, mechanism of action, pharmacokinetic, pharmacodynamic, drug-drug interaction, ACT
Director, Metabolism and Pharmacokinetics Department, Ranbaxy Research Laboratories, Gurgaon, India.