artesunate

Artesunate

Artesunate is the firstline treatment for severe malaria according to WHO recomendation. Its administration is followed by other antimalarials like quinine tablets or artemether Lumefantrine 

Moa

Artesunate is a hemisuccinate  derivative of dihydroartemisinin, which is itself formed by the reduction of artemisinin .artemisinin is a sesquiterpene lactone endoperoxide extracted from qinghao (sweet wormwood, Artemisia annua) , a plant which has been used for centauries in traditional Chinese medicine. The mechanism of action of artemisinins likely involves cleavage of the internal endoperoxide bride through reaction with the heme 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 triphosphate.

The artemisinins are distinguished by their ability to kill erythrocytic stages of the malaria parasite, including the relatively inactive ring stage and late schizonts, as well as gametocytes responsible for malaria transmission. Artesunate and artemisisnins are the most rapid acting of the antimalarials, and they have also been shown to enhance splenic clearance of infected erythrocytes by reducing cytoadhearance.

Invitro dihydroartemisinin(DHA), the active ingredient of artesunate ,exhibits similar potency against chloroquine-resistant and chloroquine sensitive clones of P. falciparum.

Artesunate and other artemisinins  are essentially inactive against extra erythrocyte forms, sporozoites, liver schizonts or merozoites.

Pharmacokinetics

Intravenous

After intravenous infusion, artesunate is rapidly biotransformes to its active metabolite , dihydroartemisinin (DHA) , consequently artesunates half life (t1/2) is estimated to be less than 5 minutes. Following a single dose of 2.4/kg, the maximum artesunate plasma concentration  (Cmax)  were estimated to be 77µmol/l in a study in Gabonese children with severe malaria , and 42 and 367µmol/l in two studies in Vietnamese adults with uncomplicated malaria. High concentration of DHA are observed within 5 minutes of artesunate administration. In the above studies , (adult and pediatric), the ranges of value for the estimated time to maximum concentration (tmax) and t1/2 for DHA were 0.5-15 minutes and 21-6 minutes , respectively ,while DHA Cmax 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  intramuscular injection, 2.4 mg/kg of artesunate , absorption was rapid in Gabonese children and Vietnamese adults, with Tmax values of 8-12 minutes, respectively. The corresponding t1/2 values were estimated to be 48 minutes in children and 41 minutes in adults, and the Cmax values were 1.7 and 2.3 µmol/l for children and adults respectively

Distribution

DHA  has been shown to substantially accumulate in P.falciparum infected erythrocytes . Plasma protein binding was estimated to be 93% in patients and 88% in healthy volunteers.

Metabolism and elimination

Artesunate is extensively and rapidly hydrolyzed by plasma esterases, with possible minimal contribution by CYP2A6. The main metabolite, dihydroartemisinin accounts for most of the in-vivo anti-malarial 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 urine ; α-dihydroartemisinin-β-glucuronide  has been identified as the major urinary product in patients with falciparum malaria

Special populations

No pharmacokinetic data are available for patients with impaired renal or hepatic functions. However, based on the known mechanism 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 modifications are considered necessary in renal or hepatic impairment

Preclinical safety data

General toxicity

Artesunate poses low acute toxicity . After repeated administration of 50mg/kg/day in rats, and 82.5mg/kg/day in dogs, i.e approximately 10 and 17 times the proposed maximal therapeutic dose in man, no evidence of toxicity were observed in the hematopoietic  organs, the immune system and  response , the liver and kidneys.

Genotoxicity

Artesunate did not show any mutagenic or clastrogenic potential in invitro and in invivo tests (Ames, mouse, micronucleus)

Carcinogenesis

No studies of carcinogen