Coartem® for Malaria in the United States
By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
On April 8, 2009, the fda approved the use of Coartem® tablets in the treatment of acute, uncomplicated malaria in adults and in children weighing at least 5 kg. Coartem® tablets contain 20 mg artemether and 120 mg lumefantrine, each of which is a blood schizonticide but with dissimilar modes of action.1 Current evidence indicates that the activity of the artemisinins (of which artemether is one) may result from free radical injury, while that of lumefantrine is undefined, but has been suggested to result from complexation with hemin.
The peak plasma concentrations of artemether and its active metabolite, dihydroartemisinin, are reached approximately two hours after ingestion of Coartem® in tablet form, while that of lumefantrine is not achieved until 6-8 hours. In healthy volunteers, when compared to fasted conditions, ingestion after a high-fat meal increased the absorption and bioavailability of artemether more than two-fold, while that of lumefantrine increased 16-fold. In malaria patients, however, lumefantrine exposure was only increased approximately two-fold when taken after a meal.
Both drugs are primarily metabolized to their active metabolites, dihydroartemisinin and desbutyl-lumefantrine, by hepatic CYP3A4. Artemether does not appear to be a significant inhibitor of CYP45 enzymes at clinically relevant concentration, while lumefantrine may inhibit CYP2D6 and, as a consequence, Coartem® should not be administered with drugs such as some neuroleptics and tricyclic antidepressants, which are metabolized by this isoenzyme. While coadministration of potent inhibitors of CYP3A4, such as ketoconazole, results in increased exposure to the antimalarial, the increase is insufficient to warrant a dose adjustment. Artemether is removed from plasma with a half-life of 2-3 hours, while the T1/2 of lumefantrine is 3-6 days. Although not studied in humans, renal excretion was not detected in animal models.
Studies in a number of geographic venues indicate that Coartem® therapy produces high rates of success in the treatment of infection due to Plasmodium falciparum. While less data are available, it is also active in the treatment of P. vivax infection (although, as with other therapies, administration of primaquine is required to prevent relapse). In the United States, the only other fixed-dose combination oral therapeutic for P. falciparum infection is Malarone®, which is comprised of atovaquone and proguanil. In a randomized trial involving 97 patients with falciparum malaria in southwestern Ethiopia, there were no treatment failures in Coartem® recipients at 28 days, but PCR-confirmed recrudescence rates were 9% in Malarone® and 6% in those treated with quinine.2 A single recrudescence occurred in a quinine recipient at day 40 and in a Coartem® recipient at day 70. Thus, it seems likely that Coartem® is superior to both Malarone® and quinine.
The recommended Coartem® treatment course consists of a total of six doses over three days. In patients 16 years of age or greater, weighing at least 35 kg, a total of 24 tablets are given: four tablets should be given initially, followed by another four tablets in eight hours later, followed by four tablets twice daily for the following two days.
- Gurkov R, et al. Ototoxicity of artemether/lumefantrine in the treatment of falciparum malaria: A randomized trial. Malar J. 2008;7:179-190.