Chemical formula: C₁₆H₂₆O₅ Molecular mass: 298.375 g/mol PubChem compound: 68911
The site of antiparasitic action of artemether is the food vacuole of the malarial parasite, where they are thought to interfere with the conversion of haem, a toxic intermediate produced during haemoglobin breakdown, to the nontoxic haemozoin, malaria pigment. Artemether generates reactive metabolites as a result of the interaction between its peroxide bridge and haem iron. Artemether has also a secondary action involving inhibition of nucleic acid and protein synthesis within the malarial parasite.
Artemether is absorbed fairly rapidly and dihydroartemisinin, the active metabolite of artemether, appears rapidly in the systemic circulation with peak plasma concentrations of both compounds reached about 2 hours after dosing.
Artemether is highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47-76%).
Biotransformation
Artemether is rapidly and extensively metabolised (substantial first-pass metabolism) both in vitro and in humans. Human liver microsomes metabolise artemether to the biologically active main metabolite dihydroartemisinin (demethylation), predominantly through the isoenzyme CYP3A4/5. This metabolite has also been detected in humans in vivo.
The pharmacokinetics of artemether in adults is time-dependent. During repeated administration of Riamet, plasma artemether levels decreased significantly, while levels of the active metabolite (dihydroartemisinin) increased, although not to a statistically significant degree. The ratio of day 3/day 1 AUC for artemether was between 0.19 and 0.44, and was between 1.06 and 2.50 for dihydroartemisinin. This suggests that there was induction of the enzyme responsible for the metabolism of artemether. Artemether was reported to have a mild inducing effect on CYP3A4 activity.
Artemether is rapidly cleared from plasma with a terminal half-life of about 2 hours. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of artemether.
No specific pharmacokinetic studies have been performed in elderly patients. However, there is no information suggesting that the dosage in patients over 65 years of age should be different than in younger adults.
In paediatric malaria patients, mean Cmax (CV%) of artemether (observed after first dose of Riamet) were 223 (139%), 198 (90%) and 174 ng/mL (83%) for body weight groups 5-<15, 15-<25 and 25-<35 kg, respectively, compared to 186 ng/mL (67%) in adult malaria patients. The associated mean Cmax of DHA were 54.7 (108%), 79.8 (101%) and 65.3 ng/mL (36%), respectively compared to 101 ng/mL (57%) in adult malaria patients. The elimination half-lives of artemether and lumefantrine in children are unknown.
No specific pharmacokinetic studies have been performed either in patients with hepatic or renal insufficiency or elderly patients. The primary clearance mechanism of artemether may be affected in patients with hepatic impairment. In patients with severe hepatic impairment, a clinically significant increase of exposure to artemether and/or their metabolites cannot be ruled out. Therefore caution should be exercised in dosing patients with severe hepatic impairment.
Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether and dihydroartemisinin, no dose adjustment for the use in patients with renal impairment is advised.
Studies in dogs and rats have shown that intramuscular injections of artemether resulted in brain lesions. Changes observed mainly in brainstem nuclei included chromatolysis, eosinophilic cytoplasmic granulation, spheroids, apoptosis and dark neurons. Lesions were observed in rats dosed for at least 7 days and dogs for at least 8 days, but lesions were not observed after shorter intramuscular treatment courses or after oral dosing. The estimated artemether 24 h AUC after 7 days of dosing at the no observed effect level is approximately 7-fold greater or more than the estimated artemether 24 h AUC in humans. The hearing threshold was affected at 20 dB by oral artemether administration to dogs at a dose of about 29 times the highest artemether clinical dose (160 mg/day) based on body surface area comparisons. Most nervous system disorder adverse events in the studies of the 6-dose regimen were mild in intensity and resolved by the end of the study.
Artemether and lumefantrine were not genotoxic/clastogenic based on in vitro and in vivo testing.
Carcinogenicity studies were not conducted.
Embryotoxicity was observed in rat and rabbit reproductive toxicity studies conducted with artemether, a derivative of artemisinin. Artemisinins are known to be embryotoxic.
Artemether caused increases in post-implantation loss and teratogenicity (characterised as a low incidence of cardiovascular and skeletal malformations) in rats and rabbits.
A study investigated the neurotoxicity of oral artemether in juvenile rats . Mortality, clinical signs and reductions in body weight parameters occurred most notably in younger rats. Despite the systemic toxicity noted, there were no effects of artemether on any of the functional tests performed and there was no evidence of a direct neurotoxic effect in juvenile rats.
Very young animals are more sensitive to the toxic effect of artemether than adult animals. There is no difference in sensitivity in slightly older animals compared to adult animals. Clinical studies have established the safety of artemether and lumefantrine administration in patients weighing 5 kg and above.
Based on the available non-clinical data, a potential for QTc prolongation in the human cannot be discounted.
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