Safety, tolerability and pharmacokinetic properties of intranasal artesunate in a first in human phase 1 trial

Abstract

Abstract Malaria is responsible for more than half a million deaths each year. Parenteral artesunate is the recommended first-line treatment for severe malaria, but prompt treatment is often delayed affecting patient outcomes. Rectal artesunate is recommended as a pre-referral treatment but shows variable absorption and can be problematic when treating children with gastrointestinal disturbances. Nasal drug administration offers a non-invasive and user-friendly alternative that enables rapid drug absorption. A Phase I, first in human trial was conducted to evaluate the safety, tolerability and pharmacokinetic properties of increasing doses of a novel intranasal formulation of artesunate powder. Three dosing regimens were assessed in adult volunteers. Plasma samples were collected for up to 24 h post-dose for drug measurements of artesunate and dihydroartemisinin. Intranasal artesunate was safe and well tolerated. Only mild adverse events were reported shortly after drug administration. No severe adverse events were observed. Pharmacokinetic analysis confirmed rapid systemic absorption of artesunate but with high inter-individual variability. Dose-normalized exposures to dihydroartemisinin suggested a non-linear dose-exposure relationship. Further evaluation of this novel formulation of artesunate is needed to establish safety and efficacy in patients with malaria. This, first in human, phase 1 provides justification for subsequent phase 2 clinical trials.