Dihydroartemisinin

Uses

For the treatment of uncomplicated Plasmodium falciparum infection in adults, children, and infants aged 6 months and up weighing over 5 kg . Used in combination with Piperaquine.

Dihydroartemisinin is also used to associated treatment for these conditions: Malaria caused by Plasmodium falciparum

How Dihydroartemisinin works

Artemisinins, including Dihydroartemisinin which is a major active metabolite of many artemisinins, are thought to act via a common mechanism . While the exact mechanism of action is not certain, theories exist as to how artemisinins produce their antimalarial effect.

Artemisinins are believed to bind to haem within the P. falciparum parasite . The source of this haem varies with the life stage of the parasite. When the parasite is in the early ring stage artemisinins are believed to bind haem produced by the parasite's haem biosynthesis pathway. In later stages artemisinins likely bind to haem released by haemoglobin digestion. Once bound to haem, artemisinins are thought to undergo activation involving ferrous iron via reductive scission which splits the endoperoxide bridge to produce a reactive oxygen . This reactive oxygen is thought to undergo a subsequent intramolecular hydrogen abstraction to produce a reactive carbon radical . The carbon radical is believed to be the source of the drugs potent activity against P. falciparum by alkylating a wide array of protein targets . The nature and magnitude of the effect on specific protein function as a result of this alkylation is unknown.

One target which has been the focus of research is the sarco/endoplasmic reticulum Ca2+ ATPase pump of P. falciparum . Artemisinins have been found to irreversably bind to and inhibit this protein at a binding site similar to that of Thapsigargin. The mechanism is likely the same as for other proteins, namely alkylation via the carbon radical intermediate.

Artemisinins appear to preferentially collect in infected erythrocytes, concentrating the drug by several hundred-fold compared to uninfected cells . This may play a role in why little alkylation is seen in uninfected erythrocytes .

Toxicity

In single dose studies in CD-1 male mice, Dihydroartemisinin did not show signs of toxicity up to 1200 mg/kg .

In repeated dose studies in CD-1 mice, the NOAEL for Dihydroartemisinin was determined to be 200 mg/kg/day . This value was determined to be 90 mg/kg/day in beagle dogs. The maximum tolerable dose in rats was observed to be 270 mg/kg/day. Doses of 540 mg/kg/day resulted in acute toxicity progressing to lethal effects. Toxicity was characterized by infiltration of macrophages and intracytoplasmic deposition of basophilic granular materials in macrophages consistent with phospholipidosis. Toxicity at high doses were accompanied by decreases in reticulocytes, and increases in AST and ALT.

Volume of Distribution

Dihydroartemisinin was observed to have a mean apparent volume of distribution of 0.801 L/kg in adult patients and 0.705 L/kg in pediatric patients wit P. falciparum malaria .

Elimination Route

The reported oral bioavailability of Dihydroartemisinin was reported to be 45% in healthy adults . The observed Tmax was 1-2 h This is known to increase in malaria infected patients which could be attributed to reduced metabolism by the liver or the drug's collection in infected erythrocytes. Dihydroartemisinin was obeserved to have flip-flop kinetics with an overall absorption half-life of 1.04 h. When administered with food the AUC for Dihydroartemisinin increases by 144%. Cmax was observed to increase by 129% but was not found to be statistically significant. Food was observed to delay Tmax by 1 h.

Half Life

Dihydroartemisinin was reported to have a half life of elimination of approximately 1 h .

Clearance

Dihydroartemisinin was observed to have a mean apparent clearance of 1.340 L/h/kg in adult patients and 1.450 L/h/kg in pediatric patients with P. falciparum malaria .

Elimination Route

Dihydroartemisinin is eliminated via metabolism to glucuronide conjugates . There is little data on elimination of Dihydroartemisinin but elimination of unchanged artemisinin compounds in feces and urine has been reported to be negligible.

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