Chemical Stability of Artesunate Injection and Proposal for its Administration by Intravenous Infusion

Abstract

Artesunate, the only artemisinin analogue that can be given intravenously, 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 metabolite dihydroartemisinin relative to conventional dosing intervals. One method of extending the duration of action of artesunate could be to administer the drug by infusion rather than bolus injection, provided that it is chemically stable at ambient temperature. Artesunate was found to be stable in 0ṁ9% w/v sodium chloride at 9°C, 23°C and 36ṁ5°C for 130, 10ṁ6 and 1ṁ6 h, respectively. Interpolating from an Arrhenius plot, artesunate should be stable for approximately 4 h at 30°C, a temperature representative of ambient conditions in tropical countries. Exposure to light did not affect the degradation rate. Single compartment pharmacokinetic modelling was used to evaluate potential differences in artesunate and dihydroartemisinin plasma concentrations following administration of artesunate by intravenous bolus or infusion. A bolus injection of artesunate at a dose of 4 mg kg⁻¹ gives a peak concentration of 5ṁ3 mg L⁻¹, falling to 0ṁ005 mg L⁻¹ at 5 h. The same dose infused over 4h results in a peak concentration of 0ṁ92 mg L⁻¹ falling to 0ṁ005 mg L⁻¹ at 8h. Simultaneous modelling of dihydroartemisinin showed that while its peak plasma concentration was reduced by 27% and the peak delayed by 2.5 h following artesunate administration by infusion, substantially higher concentrations were maintained compared with those predicted after bolus artesunate. These data indicate that artesunate can be administered as a high-dose intravenous infusion, thus avoiding high plasma concentrations. This strategy also has the potential to prolong the duration of antimalarial effect and reduce toxicity, and consequently improve clinical outcome in seriously ill patients.