Developing safe antimalaria drugs: Key lessons from mefloquine and halofantrine

Abstract

Mefloquine and halofantrine were discovered and developed by the US Army between 1963–1976, for use by travellers to regions with chloroquine-resistant malaria. The pre-licensing studies of both drugs were in prisoners and other non-travelling study populations. The US Food and Drug Administration granted marketing approval to mefloquine in 1989 and to halofantrine in 1992. Within months of licensing, major safety concerns emerged around both drugs. Halofantrine was found to cause dysrhythmias that were often fatal and from 1993 onwards was no longer in routine clinical use. Mefloquine was found to cause neurotoxicity and has been causally associated with 19 deaths in users, including 3 suicides; it is likely that this drug too will soon be abandoned. This represents a loss to medical science of two potentially valuable compounds, and a waste of US taxpayers' money. The pre-licensing studies carried out on halofantrine and mefloquine were inadequate and it is likely that more appropriate primary research would have resulted in safer products, with a longer commercial lifespan. The key lessons from these two compounds need to be applied in the development cycle of new and candidate antimalaria drugs, besides other novel agents targeted to highly specific patient groups.