Artemether

Other Names

(+)-(3α,5aβ,6β,8aβ,9α,12β,12aR)-decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine(1R,4S,5R,8S,9R,10S,12R,13R)-10-methoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0^{4,13}.0^{8,13}]hexadecane(3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-methoxy-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromene(3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-methoxy-3,6,9-trimethyldecahydro-3,12-epoxypyrano[4,3-j][1,2]benzodioxepine3,12-Epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin, decahydro-10-methoxy-3,6,9-trimethyl-, (3R,5aS,6R,8aS,9R,10S,12R,12aR)-ArtemeteroArtemetheriArtemetherumDihydroartemisinin methyl etherDihydroqinghaosu methyl etherFalcidolSM-224SM224β-Artemetherβ-Dihydroartemisinin methyl ether

Synopsis

Artemether: A Comprehensive Reference

1. Identity: Chemical Names, Sources, and Preparations

1.1 Chemical Identity

Artemether is a semisynthetic derivative of artemisinin, the bioactive sesquiterpene lactone endoperoxide isolated from the plant Artemisia annua L. (sweet wormwood). Artemether is a methyl ether derivative of artemisinin, which is a peroxide-containing lactone isolated from the antimalarial plant Artemisia annua. Its CAS Registry Number is 71963-77-4.

Chemical derivatives of artemisinin include dihydroartemisinin, artemether, arteether, and artesunate. The essential endoperoxide pharmacophore common to artemisinin and all its derivatives is the defining structural feature; the C-10 position substituent unique to each individual derivative determines its water and lipid solubility and therefore some of its pharmacokinetic properties. In artemether specifically, the C-10 position bears a methoxy (–OCH₃) group, rendering it lipophilic and oil-soluble.

Artemisinin itself is a sesquiterpene lactone endoperoxide derived from the glandular secretory trichomes of Artemisia annua, with a molecular weight of 282 Da, molecular formula C₁₅H₂₂O₅, and a melting point of 156–157 °C. Its systematic IUPAC name is (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclohexadecan-10-one. Chemically it is a sesquiterpene lactone containing a pharmacologically significant 1,2,4-trioxane structure with a peroxide bridge actively responsible for its mechanism of action.

The drugs currently used as components of artemisinin-based combination therapy (ACT) are no longer "natural" artemisinins, as extraction from the plant is followed by a semisynthetic process to transform the molecule first into dihydroartemisinin, then into artemether or artesunate.

1.2 Botanical Source

Artemisia annua L. (Qinghao) is the only known natural source of the sesquiterpene artemisinin, which is used in the treatment of malaria. Biosynthesis of artemisinin occurs in specialized 10-celled biseriate glandular trichomes present on the leaves, stems, and inflorescences of Artemisia annua. Concentrations of artemisinin can range from 0.01 to 1.4% of leaf dry weight.

Artemisinin is biosynthesized in the plant by a series of enzymatic reactions leading to the formation of artemisinic aldehyde and, subsequently, to dihydroartemisinic acid. Dihydroartemisinic acid undergoes spontaneous photooxidation to produce artemisinin.

1.3 Preparations and Dosage Forms

Because artemisinin does not dissolve in oil or water, it is used as a parent compound for semisynthetic derivatives modified at the C-10 position by chemical changes to produce dihydroartemisinin, artemether, arteether, artesunate, and others. Artemether, being lipophilic, is formulated for oral administration (tablets), intramuscular (oil-based) injection, and in some markets as rectal preparations. Its best-known commercial form is the fixed-dose combination tablet Coartem (artemether/lumefantrine), developed originally by Novartis. Its combination co-formulation with lumefantrine has first been marketed by Novartis under the brand names Riamet and Coartem. Today, this combination therapy is available as generic from several manufacturers.

Coartem is indicated for the treatment of infants, children, and adults with acute, uncomplicated infection due to Plasmodium falciparum or mixed infections including P. falciparum. A formulation with improved palatability has been developed especially for children (Coartem Dispersible), which rapidly disperses in a small amount of water for ease of administration.

2. Traditional and Historical Use

2.1 Ancient Chinese Medicine

Recorded evidence in traditional Chinese literature describing the use of Qinghao in alleviating malaria-like symptoms led to the discovery of artemisinin. The first and most famous record was written by Ge Hong during the East Jin Dynasty in A Handbook of Prescriptions for Emergencies. One compound was particularly effective — sweet wormwood (Artemisia annua), which was used for "intermittent fevers," a hallmark of malaria. Its preparation was described in a recipe from a 1,600-year-old traditional Chinese herbal medicine text titled Emergency Prescriptions Kept Up One's Sleeve.

Tu Youyou discovered that a low-temperature extraction process could be used to isolate an effective antimalarial substance from the plant, influenced by the source written in 340 CE by Ge Hong, which states that the herb should be steeped in cold water. The book instructed the reader to immerse a handful of qinghao in water, wring out the juice, and drink it all.

After reading the ancient Chinese medical description, "take one bunch of Qinghao, soak in two sheng (~0.4 liters) of water, wring it out to obtain the juice and ingest it in its entirety" in The Handbook of Prescriptions for Emergency Treatments by Ge Hong (283–343 CE) during the Jin Dynasty, Professor Tu realized the significance of a cold-water preparation.

Nobel Prize laureate Youyou Tu explained in her book that in Traditional Chinese Medicine, "Qing Hao" is the generic name of a category of medicinal herbs containing six varieties, each with different chemical components and different degrees of efficacy in treating malaria. Although there are different varieties of Qing Hao, only Artemisia annua L. has proven strong antimalarial activity.

2.2 Modern Discovery: Project 523 and the Isolation of Artemisinin

Educated in pharmaceutical sciences, Tu Youyou was recruited to Chinese military research Program 523, with the aim of finding new drugs for the treatment of malaria. A malaria epidemic during the Vietnam War had led Ho Chí Minh to request medical help from China. In response, Chairman Mao approved Project 523, which involved over 500 scientists, military personnel, and medical practitioners, and ran from 1967 to 1980.

Tu Youyou and colleagues investigated more than 2,000 recipes of Chinese traditional herbs, compiling 640 recipes that might have some antimalarial activity. They tested more than 200 recipes with Chinese traditional herbs and 380 extracts from those herbs in a rodent malaria model. Among the promising results, extracts from Artemisia annua L. (Qinghao), a type of wormwood native to Asia, were shown to inhibit parasite growth by 68%.

In 1972, Tu's team obtained the pure active substance from this extract and determined its chemical structure, naming it qinghaosu, or artemisinin. A series of chemical derivatives of artemisinin were subsequently developed by Project 523, including dihydroartemisinin, artemether, and artesunate. For her discoveries, Tu received the 2015 Nobel Prize for Physiology or Medicine.

After their first human experiments, Tu and her team went to Hainan to verify the efficacy of the extract clinically, and carried out antimalarial trials with patients infected with both P. vivax and P. falciparum. These clinical trials produced encouraging feedback, achieving a rapid disappearance of fever and parasites from the blood as compared with the control group using chloroquine.

3. Key Constituents and Active Compounds

3.1 The Endoperoxide Bridge: Core Pharmacophore

Artemisinin is a highly oxygenated sesquiterpene containing a unique 1,2,4-trioxane ring structure, which is responsible for the antimalarial activity of this natural product. Unlike previously used antimalarial medicines such as chloroquine and quinolines, artemisinin is a sesquiterpene lactone containing an unusual peroxy group, which is essential for its antimalarial activity. The peroxy group is cleaved inside infected erythrocytes, yielding free radicals to alkylate susceptible parasitic proteins or to generate reactive oxygen species that kill the parasite.

The presence of the endoperoxide bridge and production of reactive oxygen species (ROS) is suggested as an important feature not only in antimalarial action but also in anticancer activity.

3.2 Dihydroartemisinin: The Active Metabolite

Artemether is metabolized in the human body to the active metabolite dihydroartemisinin, primarily by hepatic enzymes CYP3A4/5. Artemether is absorbed quickly; peak concentrations of artemether and its main active metabolite, dihydroartemisinin (DHA), occur at approximately two hours post-dose, leading to a rapid reduction in asexual parasite mass and a prompt resolution of symptoms. Both artemether and DHA are very active antimalarial agents that produce a reduction in asexual parasite mass of approximately 10,000-fold per reproductive cycle, accompanied by a prompt resolution of symptoms such as fever.

4. Mechanisms of Action

4.1 Antimalarial Mechanisms

The specific mechanism of action of artemisinin is not fully understood, and there is ongoing research directed at elucidating it. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin and liberates free heme, an iron-porphyrin complex. When artemether enters the Plasmodium-infected red blood cells, it interacts with the heme component released during hemoglobin digestion by the malaria parasite. The interaction between artemether and heme leads to the cleavage of the endoperoxide bridge in the artemether molecule. This cleavage results in the production of free radicals, highly reactive molecules that can damage cellular components.

A possible mechanism of action is that artemisinin drugs exert their cidal action by inhibiting PfATP6. Since PfATP6 is an enzyme regulating cellular calcium concentration, its malfunctioning will lead to intracellular calcium accumulation, which in turn causes cell death. Artemisinins have also been shown to inhibit PfATP6, a SERCA-type enzyme (calcium transporter), and artemisinin has been shown to compete with thapsigargin for SERCA binding, though artemisinin is much less toxic to mammalian cells.

The antimalarial properties of artemether stem from interference with parasite transport proteins, disruption of parasite mitochondrial function, inhibition of angiogenesis, and modulation of host immune function. Both artemether and lumefantrine inhibit nucleic acid and protein synthesis.

4.2 Anticancer Mechanisms (Preclinical)

Studies have mainly reported the anticancer effects of artemisinin and its derivatives on breast cancer, lung cancer, liver cancer, and colon cancer, including inhibiting cell proliferation and metastasis, suppressing angiogenesis, promoting cell cycle arrest, inducing cell death, inhibiting glycolysis, targeting the STAT3 pathway and cancer stem cells, and regulating immunity.

Data indicated that artemether exhibited anticancer activity by inhibiting the expression of cell cycle genes and c-Myc, and promoting Caspase-3 and PARP1 cleavage.

4.3 Anti-inflammatory and Immunomodulatory Mechanisms

The anti-inflammatory and neuroprotective effects of artemether are mediated by Nrf2-dependent mechanisms. Specifically, artemether suppresses pro-inflammatory mediators including prostaglandin E₂. The antimalarial drug artemether inhibits neuroinflammation in BV2 microglia through Nrf2-dependent mechanisms.

Artemisinin-based antimalarial drugs such as artesunate, dihydroartemisinin, and artemether not only possess excellent antimalarial properties but also exhibit antitumor, antifungal, and immunomodulatory effects. These compounds induce immunosuppression by inhibiting the activation of pathogenic T cells, suppressing B cell activation and antibody production, and enhancing the differentiation of regulatory T cells.

As small molecules, artemether could enhance gephyrin-mediated GABA-A signaling by increasing gephyrin enzymatic activity in alpha cells. This gephyrin-mediated pathway has been investigated in the context of type 1 diabetes and pancreatic beta-cell biology, as described below.

4.4 Antiparasitic Mechanism in Schistosomiasis

Artemether exhibits antiparasitic activity and inhibits parasite growth in a dose-dependent manner. The inhibition occurs primarily in intracellular proliferation, achieved by reducing the mitochondrial membrane integrity of the parasite and stimulating reactive oxygen species (ROS) production.

5. Scientific Evidence by Area of Use

5.1 Malaria (Plasmodium falciparum and Mixed Infections)

This is the area of use with by far the strongest, highest-quality clinical evidence for artemether. Artemether and its companion derivatives have become part of the artemisinin combination therapies (ACTs), currently the World Health Organisation (WHO)-recommended first-line drugs to combat malaria. Artemether-lumefantrine is an artemisinin-derived combination antimalarial approved by the Food and Drug Administration in 2009 for the treatment of P. falciparum malaria.

The efficacy of the six-dose regimen of artemether/lumefantrine has been confirmed in many different patient populations around the world, consistently achieving 28-day PCR-corrected cure rates of >95% in the evaluable population, rapidly clearing parasitaemia. A 6-dose regimen over 3 days is reported to cure more than 95% of acute uncomplicated multidrug-resistant falciparum malaria.

Current WHO guidelines for the treatment of uncomplicated falciparum malaria recommend the use of artemisinin-based combination therapy. Artemether/lumefantrine is an ACT prequalified by the WHO for efficacy, safety, and quality, approved by Swissmedic in December 2008 and subsequently by the US FDA.

Artemether-lumefantrine is the first fixed-dose ACT prequalified by WHO and it has been subsequently adopted by many countries as first-line treatment for uncomplicated P. falciparum malaria or mixed infections (P. falciparum and Plasmodium vivax). In clinical studies, AL has consistently demonstrated good efficacy (cure rate) and safety profiles.

The dual mechanisms of action of artemether-lumefantrine provide rapid and sustained parasite clearance. Because of its rapid onset of action, co-artemether may prevent progression to cerebral malaria.

The safety and effectiveness of Coartem Tablets have been established in pediatric patients aged 2 months and older with a body weight of 5 kg and above for the treatment of acute, uncomplicated malaria. The safety and effectiveness have not been established in pediatric patients younger than 2 months old or who weigh less than 5 kg.

Evidence strength: Very strong. Multiple large randomized controlled trials, WHO prequalification, and FDA approval. Consistent cure rates exceeding 95% across geographically and demographically diverse populations establish artemether/lumefantrine as among the best-evidenced antimalarial treatments available.

5.2 Schistosomiasis Prevention and Treatment

Derivatives of artemisinin, already effectively used in the treatment of malaria, also exhibit antischistosomal properties. Significant advances have been made with artemether, the methyl ether derivative of artemisinin. Artemether kills immature schistosomes of Schistosoma japonicum and reduces the incidence of infection in field trials. Laboratory studies have also showed activity against S. mansoni.

A randomised double-blind placebo-controlled clinical trial of artemether to prevent S. mansoni infection was done in an area of western Côte d'Ivoire endemic for S. mansoni. A total of 354 schoolchildren were enrolled. Findings revealed that administration of oral artemether showed no adverse reaction, with an observation of a relatively lower incidence of S. mansoni infection (31/128 vs. 68/140; relative risk, 0.50; 95% confidence interval, 0.35–0.71; p < 0.05).

Randomized controlled clinical trials confirmed that artemether, orally administered at a dose of 6 mg/kg once every 2–3 weeks, results in no drug-related adverse effects, and significantly reduces the incidence and intensity of schistosome infections. Combined treatment with artemether and praziquantel, given to animals harbouring juvenile and adult schistosome worms, resulted in significantly higher worm burden reductions than each drug administered singly.

In view of concern about the development of tolerance and/or resistance to praziquantel, there is a need for research and development of novel drugs for the prevention and cure of schistosomiasis. Artemether — integrated with other control strategies — has considerable potential for reducing the current burden of schistosomiasis in different epidemiological settings.

Evidence strength: Moderate. Multiple randomized controlled trials support the prophylactic and antischistosomal activity of artemether at 6 mg/kg doses; however, it is not yet an approved first-line therapy for schistosomiasis, and praziquantel remains the standard treatment.

5.3 Oncology (Anticancer Activity)

Preclinical investigation and clinical experience have provided evidence on the potential anticancer effect of artemisinin and its derivatives (ARTs) in the recent two decades. Artemether and arteether have been shown to have antitumor activities in some malignant cells, such as gastric cancer, glioma, and breast cancer.

In breast cancer, Phase I/II clinical trials, including NCT00764036, have evaluated oral artemether at doses of 100, 150, or 200 mg daily, showing preliminary anticancer efficacy with good safety and tolerability, although no Phase III trials have been initiated.

Artemether demonstrates potent anticancer activity in various cancer cells. A study demonstrated that artemether significantly inhibited proliferation of diffuse large B cell lymphoma (DLBCL) in vivo and in vitro, and led to G0/G1 phase arrest.

Clinical trials have demonstrated the efficacy and safety of artemisinin and artesunate in cancer therapy. Because of the pharmacokinetic limitations of artemisinin, more studies have focused on dihydroartemisinin, artesunate, and artemether.

Evidence strength: Preliminary and largely preclinical. The vast majority of anticancer data for artemether specifically derives from in vitro cell-line studies and animal tumor models. Phase I/II clinical data exist for breast cancer, but no Phase III trials have been completed as of current reporting. Anticancer use of artemether is not approved in any jurisdiction and remains investigational.

5.4 Polycystic Ovary Syndrome (PCOS)

Researchers at Fudan University (Shanghai) described a potential new use for artemether: they discovered that the compound could be the first effective treatment for polycystic ovary syndrome (PCOS), a widespread endocrine disorder that affects approximately 10% of reproductive-age women. In a pilot clinical study of 19 women with PCOS, most of the subjects exhibited fewer symptoms of the syndrome and had more regular menstrual cycles.

Evidence strength: Very preliminary. This finding is based on a small pilot study (n = 19) and requires replication in larger, properly controlled trials before any conclusions can be drawn.

5.5 Type 2 Diabetes (Preclinical)

Previous studies have demonstrated that artemether has anti-diabetes and anti-inflammation activities, though its mechanism has not been fully elucidated. Research examined the impact of artemether on glucolipid metabolism in a type 2 diabetes mellitus model using db/db mice, treating them with 80 and 160 mg/kg of artemether for 8 weeks, with metformin as a positive control. Artemether treatment (160 mg/kg) observably ameliorated insulin resistance, hyperglycemia, hyperlipemia, and pathological injury in the liver and pancreas. In addition, artemether significantly decreased the expression of TNF-α, IL-1β, IL-6, NF-κB, and IL-17A, and significantly increased the level of IL-10 in diabetic mice.

In addition to its antimalarial property, artemisinin is believed to have potential preclinical activities in the treatment of tumors, diabetes, and Alzheimer's disease.

Evidence strength: Preclinical only. Evidence is confined to animal models; no clinical trials in humans for the treatment of diabetes have been reported for artemether specifically.

5.6 Autoimmune and Inflammatory Conditions (Preclinical)

Recent preclinical studies will help lay the groundwork for clinical trials using ARTs to treat various immune-based disorders, especially autoimmune diseases. Cumulative research indicates that artemisinin and its derivatives possess immunoregulatory effects in addition to their antimalarial, anticancer, and anti-inflammatory activities.

Early studies found that artemether could effectively limit T cell proliferation and reduce IL-2 levels, thereby restricting Treg function. Work in arthritis animal models has suggested potential benefits in rheumatoid arthritis, though these remain at a preclinical stage.

Evidence strength: Preclinical only. No human clinical trial data on artemether specifically for autoimmune diseases have been published at scale. Most immunomodulatory evidence comes from other artemisinin derivatives (artesunate, dihydroartemisinin) and animal models.

5.7 Toxoplasmosis (Toxoplasma gondii)

Artemether is an important drug for malaria, and several studies have indicated that it also exhibits anti-T. gondii activity; however, its specific effect and mechanisms are still not clear. The CC₅₀ value of artemether was found to be 866.4 μM and IC₅₀ was 9.035 μM. It exhibited anti-T. gondii activity and inhibited the growth of T. gondii in a dose-dependent manner. Inhibition occurred primarily in intracellular proliferation, achieved by reducing the mitochondrial membrane integrity of T. gondii and stimulating ROS production.

Evidence strength: In vitro only. Activity against T. gondii has been demonstrated in cell culture and mechanistic studies, but no clinical human data exist.

6. Body Systems and Health Areas of Association

Hematological/Parasitological system: Primary and best-evidenced use — elimination of asexual blood-stage Plasmodium parasites in malaria.
Immune system: Demonstrated immunomodulatory effects in preclinical studies, including modulation of T-cell subsets, cytokine profiles, and inflammatory signaling pathways.
Hepatic system: Artemether is extensively metabolized in the liver (CYP3A4/5); preclinical evidence also suggests hepatoprotective effects in diabetic liver injury models.
Oncological: Preclinical antiproliferative, pro-apoptotic, and anti-angiogenic effects observed across multiple cancer cell types; early-phase clinical investigation underway.
Endocrine/Reproductive system: Early-stage clinical pilot work in PCOS; preclinical GABA-A signaling effects in pancreatic alpha-cells relevant to beta-cell biology.
Neurological system: Anti-neuroinflammatory effects observed in microglial cell models via Nrf2-dependent mechanisms; studied in the context of cerebral malaria neuroprotection.
Parasitological (beyond malaria): Antischistosomal (clinical RCT data) and anti-Toxoplasma (in vitro) activity documented.

7. Dosage Forms and Dosages Reported in Studies

7.1 Malaria Treatment (Artemether/Lumefantrine — Coartem)

Each tablet of Coartem contains 20 mg of artemether and 120 mg of lumefantrine, and the standard regimen consists of twice-daily administration for three days (six doses in total), covering at least two asexual parasite life cycles with artemether and optimising exposure to lumefantrine to prevent recrudescence.

Artemether-lumefantrine (Coartem) is given as an oral six-dose regimen, administered twice daily over three days, with one to four tablets (20/120 mg) per dose, depending on patient body weight.

Twice-daily dosing maintains artemether and DHA concentrations at supratherapeutic levels, and a standard six-dose, three-day regimen of AL is estimated to reduce the parasite biomass by a factor of 10⁸.

7.2 Schistosomiasis Prevention

Randomized controlled clinical trials confirmed that artemether, orally administered at a dose of 6 mg/kg once every 2–3 weeks, results in no drug-related adverse effects, and significantly reduces the incidence and intensity of schistosome infections. The single oral dose of artemether (6 mg/kg) needed to prevent schistosomiasis is higher than the initial dose of 4 mg/kg given on the first day of the normal 7-day treatment course of malaria. Daily administration of the drug is not required for the prevention of schistosomiasis, but repeated administration with 2–4-week intervals is recommended.

7.3 Anticancer Clinical Trials

Phase I/II clinical trials in breast cancer evaluated oral artemether at doses of 100, 150, or 200 mg daily, showing preliminary anticancer efficacy with good safety and tolerability.

7.4 Pharmacokinetic Parameters

Absorption of artemether is improved 2- to 3-fold with food. It is highly bound to protein (95.4%). Peak concentrations of artemether are seen 2 hours after administration. Both the parent drug and active metabolite are eliminated with a half-life of about 2 hours.

Food intake significantly enhances the bioavailability of both artemether and lumefantrine, an effect which is more apparent for the highly lipophilic lumefantrine. However, a meal with only a small amount of fat (1.6 g) is considered sufficient to achieve adequate exposure to lumefantrine.

The time to peak plasma concentration of artemether and DHA is similar in healthy volunteers and malaria patients, but the peak level may be higher in individuals with malaria compared with healthy volunteers. Artemether and DHA exhibit considerable variation in plasma concentration profiles both between individuals and from dose to dose, largely accounted for by their low and variable bioavailability and the influence of food on absorption.

8. Safety Considerations and Drug Interactions

8.1 General Tolerability

The wealth of safety data on artemether/lumefantrine has not identified any neurological, cardiac, or haematological safety concerns. In addition, repeated administration is not associated with an increased risk of adverse drug reactions including neurological adverse events. The six-dose regimen of artemether/lumefantrine is therefore well tolerated in a wide range of patient populations.

The most commonly reported adverse effects are nausea, vomiting, and diarrhea. Pruritus and rash occur in less than 2% of patients. Other reported adverse effects include headache and dizziness.

8.2 Neurotoxicity

Neurotoxicity has been observed following high-dose parenteral administration of lipophilic artemisinin derivatives such as artemether. However, this toxicity is not apparent following oral administration and does not appear to be enhanced by the co-administration of lumefantrine. Audiometric studies in healthy volunteers and patients administered co-artemether did not show any evidence of brainstem toxicity.

There was no indication of neurotoxicity following repeated high doses of artemether given fortnightly for up to 5 months in schistosomiasis prophylaxis studies.

8.3 Cardiac Effects

The most important concern with artemether/lumefantrine is prolongation of the QT interval on electrocardiograms. Coartemether is contraindicated for patients with a family history of sudden heart death or prolongation of the QTc interval. However, although lumefantrine possesses a similar chemical structure to halofantrine, which is known to cause cardiac arrhythmia and sudden death, safety studies have not shown lumefantrine to be cardiotoxic or to prolong the QTc interval at therapeutic doses.

8.4 Drug Interactions: CYP3A4

Both artemether and lumefantrine are metabolized primarily by CYP3A4; therefore the malarial treatment must be used with caution in individuals taking CYP3A4 inducers or inhibitors simultaneously. Artemether metabolism through CYP3A4 produces the active metabolite dihydroartemisinin (DHA), which contributes substantially to its antimalarial activity. Artemether is also a CYP3A4 inducer, while lumefantrine inhibits CYP2D6.

Oral administration of rifampin (600 mg daily), a strong CYP3A4 inducer, with Coartem Tablets (6-dose regimen over 3 days) in six HIV-1 and tuberculosis co-infected adults resulted in significant decreases in exposure, in terms of AUC, to artemether, DHA, and lumefantrine by 89%, 85%, and 68%, respectively, when compared to exposure values after Coartem Tablets alone.

Co-administration with strong CYP3A4 inducers can result in decreased serum concentrations and loss of antimalarial efficacy. Phenytoin can decrease the level or effect of artemether/lumefantrine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Other strong CYP3A4 inducers documented to interact include carbamazepine, primidone, and rifabutin. Artemether/lumefantrine should not be used with drugs that inhibit CYP3A4. Hormonal contraceptives may not be as efficacious when used with artemether/lumefantrine.

Absorption of artemether from the intramuscular route in patients with malaria is very poor and highly variable, may take many hours to reach maximal concentrations, and has been shown to be associated with impaired parasite clearance. Artemether is metabolized by several hepatic and intestinal CYP enzymes, including CYP3A4, 2C11, and 2B6. It is likely to be a substrate of intestinal CYP3A4, suggested by a rise in artemether bioavailability when administered with grapefruit juice.

8.5 Interactions with Antiretroviral Therapy

Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions. Despite substantially higher lumefantrine exposure, intensive monitoring in a relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed.

8.6 Pregnancy

Data are available to show that there were no clinically relevant differences in pregnancy outcomes in women exposed to artemether/lumefantrine compared with sulphadoxine-pyrimethamine during pregnancy. No randomized study has compared the pharmacokinetics of either agent in pregnant versus non-pregnant women.

8.7 Resistance Concerns

Resistance to artemisinin is conferred by a single mutation in the calcium transporter PfATP6. This mutation has been studied in the laboratory, and a study from French Guiana in field isolates of malaria parasites identified a different mutation in the calcium transporter associated with resistance to artemether, lending support to the idea that PfATP6 is the target for artemisinins. The risk that artemether treatment regimens might select for resistance, particularly for resistant plasmodia, appears to be low.

References

Health Conditions

Health conditions that Artemether may help support.

Viral Immune ResponseScientific
Artemether is a lipid-soluble artemisinin derivative with WHO-approved antimalarial use and documented antiviral activity against multiple viruses including SARS-CoV-2, CMV, EBV, HBV, HSV, and influenza. Its endoperoxide mechanism generates ROS that damage viral proteins, and it has been incorporated in Chinese COVID-19 treatment protocols.

Body Systems

Body systems that Artemether may help support.

No body systems available.