Artemisinin-based combination therapy in Resistant Malaria

Rationale for use of artemisinin-based combination therapy

Artemisinin is the active antimalarial component isolated from the medicinal herb Artemisia annua, which has been used for centuries in China as a traditional treatment for fever and malaria. In recent years, artemisinin derivatives have become the focus of worldwide attention in the light of emerging resistance of Plasmodium falciparum to first line drugs; to date resistance to artemisinin has not been demonstrated in malaria parasites.

While artemisinin derivatives require at least seven days of treatment when administered alone, when combined with other first-line drugs, artemisinin-based combination therapies (ACTs) can eradicate parasites quickly and protect against the development of resistance to both drugs. Improved cure rates and decreased gametocyte carriage have been confirmed in field trials. Artemisinin derivatives are the only first-line malaria treatments to act on gametocytes (the stage of the malaria parasite’s life cycle responsible for ongoing malaria transmission) thereby potentially reducing malaria transmission and particularly the transmission of resistant strains of malaria.

Artemisinin-based Combination Therapy

With the possible exception of artemisinin derivatives, resistance of P falciparum to all available alternatives has been frequently documented. Artemisinin derivatives used alone are associated with high treatment failure rates unless administered for seven days, which is not often achieved as symptoms are generally relieved within two-three days. Thus, artemisinin derivatives should only be used in combination with a second effective antimalarial; poor efficacy of this component significantly compromises the efficacy of the combination.

Although there are some minor differences in oral absorption and bioavailability between the different artemisinin derivatives, there is no evidence that these differences are clinically significant in current formulations. It is the properties of the partner medicine that determine the effectiveness and choice of combination. ACTs with amodiaquine, atovaquone-proguanil, chloroquine, clindamycin, doxycycline, lumefantrine, mefloquine, piperaquine, pyronaridine, proguanil-dapsone, sulfadoxine–pyrimethamine and tetracycline have all been evaluated in trials carried out across the malaria-affected regions of the world. Some of these are studies for product development.

The following ACTs are currently recommended:

• artemether-lumefantrine,
• artesunate + amodiaquine,
• artesunate + mefloquine,
• artesunate + sulfadoxine–pyrimethamine.

Artemether-lumefantrine

Each coartemether tablet contains artemether (20 mg), a synthetic derivative of artemisinin, and lumefantrine (120 mg), a highly lipophilic aryl amino alcohol, structurally resembling halofantrine. Lumefantrine has a much longer elimination half-life (several days) than artemether, and is associated with a low recrudescence rate, but has a slower onset of action. However, when used together, the complementary properties of artemether with its fast onset of action and lumefantrine with its long duration of action and high cure rate result in a highly effective combination.

The hallmark of efficacy of an antimalarial is its ability to eliminate the malaria parasite from a patient’s blood and other tissues, thus bringing about the disappearance of symptoms, and a cure. Artemether-lumefantrine is the most viable artemisinin combination treatment available at the moment, because in addition to its efficacy, safety and tolerance profile, it is available as a fixed-dose formulation, increasing the likelihood of patient compliance with the drug regimen. A variety of studies have evaluated the efficacy of coartemether in terms of speed and degree of parasite elimination, and have shown the following:

• Fast parasite elimination
• Prompt reduction in fever
• Effective gametocyte clearance
• Cure rates as good as with current options
• Effectiveness in multi-drug resistant areas.

Recommended treatment schedule of Coartemether

Artemether-lumefantrine can be used for the treatment of uncomplicated infections with P.falciparum, including strains from multidrug-resistant areas. WHO recommends a standard treatment of six doses for children and adults in the treatment of uncomplicated malaria irrespective of the malaria transmission pattern or the immune status of the individual.

In areas with multidrug-resistant P. falciparum and in non-immune patients, an intensive six-dose course consisting of doses at 0 hour and 8 hours, and twice-daily doses on the next 2 days is recommended. Thus, the course for an adult would be four tablets at 0 hour and 8 hours and four tablets twice a day on the second and third days. The total course for adults is 24 tablets, which gives a total of 480 mg of artemether plus 2680 mg of lumefantrine.

There is no evidence of increased toxicity with the six-dose as compared to the four-dose regimen. For simplicity of implementation, it may be advantageous to use the six-dose regimen in all areas.

Pharmacokienetics of Coartemether

Under fasted conditions, artemether is rapidly absorbed, reaching peak plasma concentrations about 2 hours after dosing, whilst lumefantrine - a highly lipophilic molecule - is absorbed after a lag time of up to 2 hours, with peak plasma concentrations at 6 to 8 hours post-dose. Under fasted conditions, the oral bioavailability of both artemether and lumefantrine is variable and low. However, a high-fat meal increases the bioavailability of lumefantrine 16-fold and that of artemether more than two-fold.

Therefore it is recommended that the drug should be administered with fat containing food or drink (e.g. milk). Patients who remain averse to food during treatment should be closely monitored as they are at increased risk of treatment failure/recrudescence.

The elimination half-life is 88 hours in healthy subjects and about twice as long in malaria patients. The drug is excreted via the liver and faeces. There is no evidence of pharmacokinetic interaction between artemether and lumefantrine.

Drug Interactions with Artemether-lumefantrine

There is a possibility of interaction between coartemether and the following drugs when taken concomitantly: amiloride, amitriptyline, azithromycin, chloroquine,chlorpromazine,ciprofloxacin,clomipramine,erythromycin, fluconazole, fluphenazine, furosemide, grapefruit juice, hydrochlorothiazide, mefloquine, naldixic acid, ofloxacin, procainamide, pyrimethamine, quinidine, quinine, spironolactone, sulfadoxine + pyrimethamine

Contraindications with coartemether

Artemether-lumefantrine is contraindicated in pregnancy, lactating women, very young children (less than 10 kg body weight), history of arrhythmias, of clinically relevant bradycardia, and congestive heart failure accompanied by reduced left ventricular ejection fraction and those with known hypersensitivity to either of the components.

Coartemether safety and tolerability

• The most commonly reported adverse effects following coartemether therapy were gastrointestinal (abdominal pain, anorexia, nausea, vomiting, diarrhoea) and those of the central nervous system (headache, dizziness). Pruritus and rash were reported by less than 2% of patients.

• Compared to coartemether, there were significantly higher incidences of vomiting and pruritus with chloroquine, dizziness, nausea and vomiting with mefloquine + artesunate, vomiting and dizziness with quinine and somnolence with pyrimethamine + sulfadoxine.

• There are no serious or persistent neurological side effects related to coartemether administration.

• The frequency of QTc prolongation is similar to or lower than that observed with chloroquine, mefloquine, or artesunate + mefloquine; these changes occurred considerably less frequently than with quinine or halofantrine. All patients with QTc prolongation remained asymptomatic and no adverse clinical cardiac events were reported.

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