Pharmacokinetic Interaction Between Coartem® and Either Nevirapine, Efavirenz or Rifampicin in HIV Positive Ugandan Patients

Coartem® is the combination of artemether and lumefantrine used for the treatment of uncomplicated falciparum malaria 1. This oral combination seems to be well-tolerated and is useful for treatment of multi-drug resistant Plasmodium falciparum. This unique anti-malarial agent combines the fast, but short-acting artemether with a less potent, but longer-acting lumefantrine. Original studies with the combination demonstrated safety and efficacy in adults and children with uncomplicated falciparum malaria. 2,3 Additional studies showed superiority with respect to parasite clearance time versus halofantrine,4 chloroquine5, and mefloquine6. Coartem® also demonstrated a faster reduction in parasite burden after 24-hours versus halofantrine4, chloroquine5 (in adults), chloroquine (in children) 7, and mefloquine6. Various other studies have shown artemether-lumefantrine to have a superior 28-day cure rate, as well as time to fever resolution compared to other antimalarial agents.1 Both components of Coartem® were discovered in China. Artemether was isolated from sweet wormwood, Atemisia annua, which has been used in traditional Chinese medicine for over 2000 years 1. Lumefantrine is a synthetic compound, which has structural and physiochemical characteristics; and a mode of action similar to other antimalarials, including quinine, mefloquine, and halofantrine 8. In vitro, the two antimalarial agents show synergistic activity against P.falciparum. Based on both in vitro and in vivo studies, a 1:6 ratio of artemether to lumefantrine has been described as optimal. Thus, the tablets are manufactured as 20mg artemether and 120mg lumefantrine. 8 Currently there are two recommended dosing regimen for adults and children above 35 kg; or 12 years of age or older. In partially immune patients, a 4-dose regimen is recommended. Four tablets as a single dose should be taken at time of diagnosis and then again at 8, 24, and 48 hours post-initial dose. A different regimen is recommended for either non-immune patients or patients in areas where multi-drug resistance to falciparum malaria is a problem. This is a 3-day regimen consisting of 4 tablets as a single dose given at the time of diagnosis, 8 hours later and then twice daily for the following two days. 1

Antimalarial Activity and Mechanism of Action: 1, 8 The antimalarial activity of artemether and that of its active metabolite, dihydroartemisinin (DHA) have been extensively studied in vitro. These are very potent antimalarial compounds. The IC50 of artemether ranges from 0.1 to 20 nmol/L and the IC50 for DHA ranges from 0.1 to 15 nmol/L. In vitro studies have shown artemether to be 2 to 3 times less active than its metabolite, DHA.

The exact mechanisms of action of artemether and lumefantrine are unknown, but both agents appear to act on the parasite's organelles. Artemether's action depends on its endoperoxide bridge, which interacts with heme iron to cause free radical damage to the malaria parasite. Lumefantrine most likely interferes with heme polymerization, which is a critical detoxifying pathway for the malaria parasite. Both agents may have secondary actions that include inhibition of parasite nucleic acid and protein synthesis; however, these actions have not been well-described.

The varied pharmacokinetic profiles of the two antimalarial agents appear to create a synergistic effect. Artemether works rapidly to decrease the parasite load and improve patients' clinical symptoms. Lumefantrine is long-acting and appears to prevent recrudescence (reappearance of the disease after inadequate or failed drug therapy). The different actions of the two agents may also reduce the emergence of resistance. Artemether and DHA have been shown to decrease parasite burden by about 104 per asexual life cycle in about 2 days. Thus, the 3-day course of the combination therapy can potentially decrease the parasite burden by about 108.

Drug Interactions Pharmacokinetic and electrocardiographic interactions between artemether-lumefantrine and the mefloquine were studied in 42 healthy volunteers. Like artemether-lumefantrine, mefloquine is a substrate for CYP 3A4; however, it is also a potential CYP 3A4 inhibitor. Pharmacokinetic parameters for artemether, DHA, and mefloquine were unchanged; however, lumefantrine concentrations decreased by 30-40% when given with mefloquine. The clinical significance of this interaction is not known. Co-administration of the antimalarial agents resulted in no increased adverse effects. 13