Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Amivas Ireland Ltd, 7 Durands Court, Parnell Street, Waterford, Ireland
Pharmacotherapeutic group: Antiprotozoals, artemisinin and derivatives
ATC code: P01BE03
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.
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).
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.
In SEAQUAMAT (South East Asian Quinine Artesunate Malaria Trial), an open-label, multicentre trial conducted in Bangladesh, India, Indonesia and Myanmar, 1461 patients (1259 adults and 202 children <15 years) with severe falciparum malaria were randomised to initial intravenous treatment with artesunate or quinine until oral medication could be tolerated. Artesunate was administered at 2.4 mg/kg IV at 0, 12 and 24 hours and then every 24 hours. Quinine was given IV at 20 mg/kg over 4 hours, followed by 10 mg/kg thrice daily over 2-8 hours. Mortality in the intention to treat population was 14.7% (107 of 730) in the artesunate group compared to 22.4% (164 of 731) in the quinine group, a reduction in the odds of death adjusted by study site of 40% (95% CI: 21%, 55%; p=0.0002). Mortality in patients with severe malaria in the artesunate group was 19.8% (101 of 509) compared to 28.1% (152 of 541), a reduction in the odds of death adjusted by study site of 35% (95% CI: 13%, 52%; p=0.003).
AQUAMAT (African Quinine Artesunate Malaria Trial) was an open-label multicentre trial in which African children aged <15 years (n=5425) with severe falciparum malaria were randomised to parenteral artesunate or parenteral quinine using the same dose as in SEAQUAMAT. Mortality in the intent to treat population was 8.5% (230 of 2712) in the artesunate group compared to 10.9% (297 of 2713) in the quinine group, a reduction in the odds of death adjusted by study site of 25% (95% CI: 10%, 37%; p=0.0022). Mortality in children with severe malaria in the artesunate group was 9.9% (226 of 2280) compared to 12.4% (291 of 2338) in the quinine group, a reduction in the odds of death adjusted by study site of 23% (95% CI: 7%, 36%; (p=0.0055).
Following intravenous administration of artesunate as a bolus injection over 1-2 minutes, the pharmacokinetics of artesunate and dihydroartemisinin in plasma are shown in Table 2.
Table 2. Summary of pharmacokinetic parameters in patients with severe malaria:
| Parameter | Artesunate | DHA |
|---|---|---|
| Cmax (ng/mL) | 1020-3260 | 2060-3140 |
| V (L/kg) | 1.3 | 0.75 (median value) |
| CL (L/kg/h) | 3.4 | 1.1 |
| t½ (min) | 15 | 80 |
| AUC (ng-h/mL) | 727-750 | 2017-3492 |
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).
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.
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.
There are no pharmacokinetic data available after intravenous artesunate dosing in patients aged 65 years or older with severe malaria (see sections 4.2 and 4.4).
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.
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.
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 (see section 4.4).
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:
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
