Artesun Mechanism of Action

Pharmacotherapeutic group: Antimalarial. ATC code: P01BE03.
Pharmacology: Pharmacodynamics: Artesunate is a hemisuccinate derivative of dihydroartemisin, which itself formed by the reduction of artemisinin. Artemisinin is a sesquiterpene lactone endoperoxide extracted from qinghao (sweet wormwood, Artemisia annua L.), a plant which has been used for centuries in traditional Chinese medicine.
The mechanism of action of the artemisinin likely involves cleavage of the internal endoperoxide bridge through reaction with haeme within the infected erythrocyte, thereby generating free radicals which alkylate vital parasite proteins. However, artemisinins have also been reported to inhibit an essential parasite calcium adenosine triphosphatase.
The artemisinins are distinguished from other antimalarials by their ability to kill all erythrocytic stages of the malaria parasite, including the relatively inactive ring stage and late schizonts, as well as the gametocytes responsible for malaria transmission. Artesunate and the artemisinins are the most rapid acting of the antimalarials, and they have also been shown to enhance splenic clearance of infected erythrocytes by reducing cytoadherence.
In vitro, dyhydroartemisinin (DHA), the active metabolite of artesunate, exhibits similar potency against chloroquine-resistant and chloroquine-sensitive clones of P. falciparum. Artesunate and the other artemisinins are essentially inactive against extra-erythrocytic forms, sporozoites, liver schizontes or merozoites.
Clinical efficacy and safety: In the SEAQUAMAT (South East Asian Quinine Artesunate Malaria Trial), an international randomised, open-label, multicenter trial conducted in Bangladesh, India, Indonesia and Myanmar, 1461 patients with severe malaria (including 1259 adults) were treated intravenously with either artesunate or quinine. Artesunate was administered at 2.4 mg/kg IV at 0, 12 and 24 h and then every 24 h until the patient could tolerate oral medication. Quinine was given IV at 20 mg/kg over 4 hours, followed by 10 mg/kg over 2-8 hours, 3 times daily until oral therapy could be started. Mortality in the artesunate group was 15% versus 22% in the quinine group, for a reduction in risk of death of 34.7% (p=0.0002). Subgroup analysis suggested a greater benefit of artesunate versus quinine in patients with parasitemia >10%. The reduction in mortality observed in the 202 pediatric patients (<15 years of age) appeared consistent with the overall results, however the number of children was too small to demonstrate statistical significance. Post-treatment hypoglycaemia was more common in the quinine-treated group.
Paediatrics: The AQUAMAT (African Quinine Artesunate Malaria Trial) was an international, randomized open-label multicenter trial which sought to extend the results of the SEAQUAMAT study by comparing parenteral artesunate versus IV quinine for severe malaria in 5425 African children (<15 years) in 9 African countries (Mozambique, The Gambia, Ghana, Kenya, Tanzania, Nigeria, Uganda, Rwanda, and Democratic Republic of the Congo). Dosing was similar to SEAQUAMAT, except that both artesunate and quinine could be administered either intravenously or intramuscularly, using the same doses for IM and IV administered for each drug. Roughly one third of patients received study drug by intramuscular injection. Mortality in the artesunate group was 8.5% compared to the 10.9% in the quinine group, resulting in a relative risk reduction for death of 22.5% (p=0.0022); the risk reduction was similar for IV and IM administration. In addition, although the risk of neurological sequelae in survivors in both groups did not differ significantly by 28 days following treatment, in-hospital coma, convulsion, and deterioration of coma were all less frequent in the artesunate-treated patients. As in the SEAQUAMAT, post-treatment hypoglycaemia was more common in the quinine-treated group.
Pharmacokinetics: Intravenous: After intravenous injection artesunate is very rapidly biotransformed to its active metabolite, dihydroartemisinin (DHA). Consequently, artesunate half-life (t_½) is estimated to be less than following a single IV dose of 2.4 mg/kg, maximum artesunate plasma concentrations (C_max) were estimated to be 77 μmol/L in a study in Gabonese children with severe malaria, and 42 and 36 μmol/L in two studies in Vietnamese adults with uncomplicated malaria.
High concentrations of DHA are observed within 5 minutes of artesunate IV administration. In the previously mentioned studies (adult and paediatric), the ranges of values for the estimated to maximum concentration (t_max) and t_½ for DHA were 0.5-15 minutes and 21-64 minutes, respectively, while DHA C_max values ranged from 5.3-10.6 μmol/L.
Intramuscular: Artesunate is rapidly absorbed following intramuscular injection, and peak plasma levels are generally achieved within 30 minutes of administration. Thus, after IM injection of 2.4 mg/kg of artesunate, absorption was rapid in Gabonese children and Vietnamese adults, with T_max values of 8 and 12 minutes, respectively. The corresponding artesunate t_½ values were estimated to be 48 minutes in children and 41 minutes in adults, and C_max values were 1.7 and 2.3 μmol/L, for children and adults, respectively.
After IM injection artesunate C_max values were therefore lower by roughly 45-fold in children and 20-fold in adults when compared to IV injection. However, rates of artesunate elimination in children and adults were 32-fold and 13-fold slower, respectively, following IM injection, compared to IV administration.
Distribution: DHA has been shown to substantially accumulate in P. falciparum infected-erythrocytes. Plasma protein binding of dihydroartemisinin was determined to be 93% in patients and 88% in healthy volunteers.
Metabolism and elimination: Artesunate is extensively and rapidly hydrolysed by plasma esterases, with possible minimal contribution by CYP2A6. The main metabolite, dihydroartemisinin, accounts for most of the in vivo antimalarial activity of oral artesunate, however, following IV administration, artesunate may contribute more significantly. DHA is further metabolized in the liver via glucuronidation and is excreted in the urine; α-dihydroartemisinin-β-glucuronide has been identified as the major urinary product in patients with falciparum malaria.
Special population: No pharmacokinetic data are available for patients with impaired renal or hepatic function. However, based on the known mechanisms of metabolism and elimination of artesunate, combined with clinical data from patients with severe malaria and accompanying renal and/or hepatic compromise of various degrees, no dose modification are considered necessary in renal or hepatic impairment.
Toxicology: Preclinical safety data: General toxicity: Artesunate presents low acute toxicity. After repeated administration of 50 mg/kg/day in rats and 82.5 mg/kg/day in dogs, i.e. approximately 10 and 17 times the proposed maximal therapeutic dose in man, rare occurrences of moderate hepatotoxicity (4%) were reported, with regression in 100% of cases without sequelae. Hematopoietic toxicity on the red and white line is responsible for reticulocytopenia and leucopenia of central origin. The toxicity appears to be on the progenitors of the erythroid lineage. There is also a negative effect on the phagocytosis capacities of neutrophils and inhibition of lymphocyte proliferation (in vitro).
Genotoxicity: Artesunate did not show any mutagenic or clastogenic potential in in vitro or in vivo tests (Ames, mouse micronucleus).
Carcinogenesis: No studies of the carcinogenic potential of artesunate have been conducted.
Reproductive toxicology studies: Oral artesunate caused dose-dependent foetal toxicity in rats, rabbits and monkeys, resulting in foetal resorption and abortion, as well as low incidence of cardiac and skeletal defects. The no-observed-adverse-effect-level (NOAEL) was 12 mg/kg in pregnant monkeys (3 and 7 day exposures) and the no or low adverse effects level was 5-7 mg/kg in pregnant rats or rabbits (12 day exposures), both of which are above the therapeutic dose range (2.4-4.8 mg/kg) and expected duration of exposure for treatment of severe malaria in humans. In rats, the embryo-fetuses were most sensitive from gestational days 9-14; at other times embryotoxicity was significantly reduced.
Safety pharmacology studies: A slight sedative effect, decreased in body temperature, mild natriuretic effect and a decrease in creatinine clearance were observed with artesunate after single intravenous doses of 200 mg/kg (mice), 450 mg/kg (rats, rabbits and dogs) and following single oral doses of 180 mg/kg in male rats. Beagle dogs administered IV artesunate at 10, 20, 50, and 50 mg/kg for 14 days did not display significant clinical effects, including any signs of neurotoxicity, effects on body weight, ECG abnormalities (including QT interval changes), heart rate, blood pressure, or respiratory rate.