What is the mechanism of action (MOA) of artemether and lumefantrine (Antimalarials)?

From the Guidelines

Artemether and lumefantrine work together as antimalarial agents through complementary mechanisms of action, with artemether interfering with the parasite's ability to detoxify heme and lumefantrine disrupting the formation of β-hematin, leading to the elimination of residual parasites and prevention of recrudescence. The mechanism of action of artemether and lumefantrine can be broken down as follows:

• Artemether, a fast-acting artemisinin derivative, interferes with the parasite's ability to detoxify heme by inhibiting the parasite-specific calcium ATPase PfATP6, leading to the generation of free radicals that damage the parasite's membrane, causing rapid parasite clearance within 24-48 hours 1.
• Lumefantrine acts more slowly by disrupting the formation of β-hematin by complexing with hemin, interfering with the parasite's nucleic acid and protein synthesis, and inhibiting food vacuole function in the parasite 1. The combination of artemether and lumefantrine provides both rapid action (artemether) and prolonged activity (lumefantrine, with a half-life of 3-6 days) to eliminate residual parasites and prevent recrudescence, making artemether-lumefantrine (marketed as Coartem) effective against Plasmodium falciparum malaria, including drug-resistant strains 1. Some key points to consider when using artemether and lumefantrine include:
• The importance of taking the medication with a fatty meal or drink to enhance absorption 1.
• The potential for adverse reactions, such as headache, vertigo, and digestive disorders 1.
• The need to avoid using the medication in patients at risk of QTc prolongation and with comedication that prolongs QTc 1.
• The consideration of using alternative treatments, such as atovaquone-proguanil, in patients who are unable to take artemether-lumefantrine 1.

From the Research

Mechanism of Action of Artemether and Lumefantrine

• The exact mechanism of action of artemether and lumefantrine is not fully understood, but it is known that they have different modes of action that provide synergistic anti-malarial activity 2.
• Artemether is an artemisinin derivative, which has a short-lived action and should not be used as monotherapy 3.
• Lumefantrine is an antimalarial related to halofantrine, and its absorption is dependent on the presence of food in the stomach 3.
• The combination of artemether and lumefantrine has been shown to be effective in treating uncomplicated falciparum malaria, with 28-day PCR-corrected cure rates of >95% in many different patient populations around the world 2, 4.

Efficacy of Artemether and Lumefantrine

• The efficacy of artemether and lumefantrine has been confirmed in many clinical trials, with consistently high cure rates and significant gametocidal effect 2, 4.
• The combination has been shown to be effective in areas of widespread parasite resistance to other antimalarials 2, 3.
• A study comparing artemether-lumefantrine with dihydroartemisinin-piperaquine as rescue treatment for uncomplicated malaria in Ugandan children found that artemether-lumefantrine was less effective than dihydroartemisinin-piperaquine in preventing recurrent infections 5.

Safety and Tolerability

• Artemether and lumefantrine have been shown to be generally well tolerated, with mild adverse events such as gastrointestinal and neurological disorders 3, 6.
• Lumefantrine can prolong the QT interval, and its use requires ECG monitoring and blood potassium assays in certain patients 3.
• A study comparing artemether-lumefantrine with artemether-lumefantrine plus amodiaquine found that the combination with amodiaquine was associated with more adverse events, including vomiting and nausea 6.