Artesunate

The antimalarial mechanism of action of artesunate is generally thought to depend upon activation involving iron-mediated cleavage of the endoperoxide bridge of DHA to generate an unstable organic free radical followed by alkylation, where the free radical binds to malarial proteins leading to destruction of parasite membranes.

In-vitro activity

Available in-vitro data indicate that artesunate 50% inhibitory concentrations (IC₅₀ values) are broadly comparable for P. falciparum and for the other Plasmodium species that cause malaria in humans (P. vivax, P. ovale, P. malariae, P. knowlesi).

Artemisinin resistance

Decreased susceptibility to artesunate and other artemisinins, manifesting clinically as slower rates of parasite clearance is associated with mutation in the K13 gene, which encodes the parasite’s Kelch propeller protein Kelch13.

Absorption

Following intravenous administration of artesunate as a bolus injection over 1-2 minutes, the pharmacokinetics of artesunate and dihydroartemisinin in plasma are shown in the following table.

Summary of pharmacokinetic parameters in patients with severe malaria:

Distribution

Artesunate and DHA distribute into the extracellular body fluid. DHA is approximately 93% protein-bound in patients with uncomplicated malaria infection. Erythrocytes infected with Plasmodia have been reported to contain very high DHA concentrations compared to plasma levels (e.g. 300-fold vs. mean plasma concentrations).

Biotransformation

Artesunate is converted to DHA by cytochrome 2A6 and blood esterases. In human liver microsomal incubations of DHA, DHA-glucuronide was the only metabolite found. In urine from patients, αDHA-β-glucuronide (α-DHA-G) and a variable amount of the tetrahydrofuran isomer of α-DHA-G was identified. DHA itself was present only in very small amounts.

Elimination

Artesunate is very rapidly eliminated from blood (within a few minutes) via conversion to DHA. DHA is eliminated from blood within a few hours after an intravenous dose, mainly via urinary excretion of glucuronides.

Special Populations

Elderly

There are no pharmacokinetic data available after intravenous artesunate dosing in patients aged 65 years or older with severe malaria.

Renal impairment

No pharmacokinetic data are available for patients with impaired renal function. Clinical trial data from patients with severe malaria and accompanying renal impairment at start of treatment indicate that no dose modifications are necessary.

Hepatic impairment

No pharmacokinetic data are available for patients with impaired hepatic function. Clinical trial data from patients with severe malaria and accompanying hepatic impairment at start of treatment indicate that no dose modifications are necessary.

Paediatric population

There are limited PK data on the use of IV artesunate in neonates and infants. Physiologically-based PK modelling and simulations predict that plasma exposures are likely to be higher in infants below 6 months of age compared to infants aged more than 6 months.

Artesunate was negative in an in vitro bacterial reverse mutation assay, an in vitro Chinese hamster ovary chromosome aberration assay, and an in vivo mouse bone marrow micronucleus assays. Carcinogenicity studies have not been conducted with artesunate.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Reproductive and developmental toxicity

Animal reproduction studies show a single IV administration of artesunate to rats early in gestation results in embryolethality. Oral administration of artesunate during organogenesis in rats, rabbits, and monkeys induces a dose-dependent increase in embryolethality and fetal malformations (including cardiovascular, brain, and/or skeletal) at 0.3 to 1.6-times the clinical dose based on body surface area (BSA) comparisons. Although animal reproduction studies in several species have demonstrated fetal harm from oral and IV administered artesunate and other artemisinin class drugs, the clinical relevance of the animal data is uncertain.

Studies in the literature indicate that artesunate oral administration in the male rat can cause a dose and duration dependent effect on the epididymis and testes with reversible decreases in the production of viable sperm at near clinical doses. No such effects were noted in rats or dogs in 28-day Good Laboratory Practice (GLP) studies conducted using IV dosing.