A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria.

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 this form of the disease mainly 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 monotherapy artesunate administered while the patient is admitted to a health centre and followed by the conventional oral ACT that is taken after the patient has been discharged. In a novel application of polymer therapeutics, we conjugated the aqueous insoluble but very important antimalarial lumefantrine to a carrier polymer to create a new water-soluble chemical entity (p-N-acryloylmorpholine-stat-p-acrylic acid-Lumefantrine) 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 about three orders of magnitude. Pharmacokinetic studies in mice indicates that there is significant release of lumefantrine in the plasma at relatively high concentrations and production of the liver metabolite desbutyl-lumefantrine (area under the curve of metabolite is about 10% that of the parent). In a Plasmodium falciparum severe malaria mouse model, parasitaemia clearance by PNAM-Lumefantrine is 50% higher than that of reference unconjugated lumefantrine. The polymer-lumefantrine shows potential for entering the clinic as a partner drug to artesunate to meet the need for a one-course treatment for severe malaria. This article is protected by copyright. All rights reserved.