Artenimol + piperaquine. Very slow piperaquine elimination: cardiovascular risks and interactions

For the treatment of uncomplicated Plasmodium falciparum malaria, drug combinations based on artemisinin derivatives (such as artemether + lumefantrine in France) are an alternative to atovaquone + proguanil, especially when there is a high risk of resistance to drugs commonly used for malaria prevention. A second fixed-dose combination containing an artemisinin derivative was recently marketed in the EU. It consists of artenimol (aka dihydroartemisinin) and piperaquine, a compound chemically related to chloroquine. Artenimol is the main active metabolite of artemether and artesunate. In clinical trials involving thousands of adults and children living in areas of chloroquine resistance, the artenimol + piperaquine combination showed similar clinical and parasitological efficacy to that of other combinations based on artemisinin derivatives, including artemether + lumefantrine and artesunate + mefloquine. We found no randomised controlled trials versus atovaquone + proguanil or versus quinine. The artenimol + piperaquine combination prolongs the QT interval more than artemether + lumefantrine and artesunate + mefloquine. In clinical trials, this resulted in a larger number of cardiac adverse events (11.3% versus 9.2%). The potential for drug interactions with the artenimol + piperaquine combination is higher and longer-lasting than with artemether + lumefantrine. Piperaquine can act variably as a cytochrome P450 inducer or inhibitor. The dosing schedule is simpler with the artenimol + piperaquine combination than with artemether + lumefantrine. However, the long half-life of piperaquine (about 3 weeks) complicates treatment management, as the risk of interactions persists long after the end of treatment. It is therefore recommended that the artenimol + piperaquine combination be administered no more than twice a year. In practice, this fixed-dose combination based on an artemisinin derivative does not represent an advance in the treatment of uncomplicated P. falciparum malaria. When treatment with an artemisinin derivative is warranted, it is best to choose artemether + lumefantrine, a combination (available in France) that appears to carry a lower risk of serious cardiac rhythm disorders and drug-drug interactions.