Abstract:
Uncomplicated malaria is effectively treated with oral artemisinin-based
combination therapy (ACT). Yet, there is an unmet clinical need for the
intravenous treatment of the more fatal severe malaria. There is no
combination intravenous therapy for uncomplicated due to the nonavailability
of a water-soluble partner drug for the artemisinin, artesunate. The currently
available treatment is a two-part regimen split into an intravenous artesunate
followed by the conventional oral ACT . In a novel application of polymer
therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to
a carrier polymer to create a new water-soluble chemical entity suitable for
intravenous administration in a clinically relevant formulation . The conjugate
is characterized by spectroscopic and analytical techniques, and the aqueous
solubility of lumefantrine is determined to have increased by three orders of
magnitude. Pharmacokinetic studies in mice indicate that there is a
significant plasma release of lumefantrine and production its metabolite
desbutyl-lumefantrine (area under the curve of metabolite is ≈10% that of the
parent). In a Plasmodium falciparum malaria mouse model, parasitemia
clearance is 50% higher than that of reference unconjugated lumefantrine.
The polymer-lumefantrine shows potential for entering the clinic to meet the
need for a one-course combination treatment for severe malaria.
