CHEMICAL-STABILITY OF ARTESUNATE INJECTION AND PROPOSAL FOR ITS ADMINISTRATION BY INTRAVENOUS-INFUSION

Artesunate, the only artemisinin analogue that can be given intravenou sly, produces rapid parasite and fever clearance in falciparum malaria . A significant therapeutic problem is a high, late recrudescence rate , probably due to short half-lives of both artesunate and its active m etabolite dihydroartemisinin relative to conventional dosing intervals . One method of extending the duration of action of artesunate could b e to administer the drug by infusion rather than bolus injection, prov ided that it is chemically stable at ambient temperature. Artesunate w as found to be stable in 0.9% w/v sodium chloride at 9 degrees C, 23 d egrees C and 36.5 degrees C for 130, 10.6 and 1.6 h, respectively. Int erpolating from an Arrhenius plot, artesunate should be stable for app roximately 4 h at 30 degrees C, a temperature representative of ambien t conditions in tropical countries. Exposure to light did not affect t he degradation rate. Single compartment pharmacokinetic modelling was used to evaluate potential differences in artesunate and dihydroartemi sinin plasma concentrations following administration of artesunate by intravenous bolus or infusion. A bolus injection of artesunate at a do se of 4 mg kg(-1) gives a peak concentration of 5.3 mg L(-1), falling to 0.005 mg L(-1) at 5 h. The same dose infused over 4 h results in a peak concentration of 0.92 mg L(-1), falling to 0.005 mg L(-1) at 8 h. Simultaneous modelling of dihydroartemisinin showed that while its pe ak plasma concentration was reduced by 27% and the peak delayed by 2.5 h following artesunate administration by infusion, substantially high er concentrations were maintained compared with those predicted after bolus artesunate. These data indicate that artesunate can be administe red as a high-dose intravenous infusion, thus avoiding high plasma con centrations. This strategy also has the potential to prolong the durat ion of antimalarial effect and reduce toxicity, and consequently impro ve clinical outcome in seriously ill patients.