Tafenoquine

In prelicensure clinical trials, tafenoquine was linked to a low rate of transient and mild serum aminotransferase elevations during therapy, but not to serum enzyme elevations with jaundice or with clinically apparent acute liver injury. It has had limited widescale use but appears to have a low risk for hepatotoxicity, and its safety profile has been similar to that of primaquine. Tafenoquine can cause hemolysis in patients with G6PD deficiency, which can result in mild indirect hyperbilirubinemia and jaundice, but without significant accompanying evidence of liver injury.

In vitro studies have shown that tafenoquine presents an average 50% inhibitory concentration of 0.436 mcg against blood stages of seven strains of _P. falciparum_. In chloroquine-resistant _P. falciparum_ strains the IC50 of tafenoquine was greater when compared with primaquine and it ranged from 0.5 to 33.1 mcg. In studies evaluating the transmission-blocking activity of tafenoquine against the sporogonic stage of _P. vivax_, it was showed a reduced transmission at doses higher than 25 mg/kg. In clinical trials, it was reported a tafenoquine-induced relapse prevention of 91.9% in cases of vivax malaria when pretreated with chloroquine. In prophylactic studies, tafenoquine showed an efficacy range from 84 to 87% against falciparum malaria and 99.1% against vivax malaria.

The mechanism of action of tafenoquine is not well established but studies have reported a longer and more effective action when compared to primaquine. The active moiety of tafenoquine, 5,6 ortho quinone tafenoquine, seems to be redox cycled by _P. falciparum_ which are upregulated in gametocytes and liver stages. Once inside, the oxidated metabolite produces hydrogen peroxide and hydroxyl radicals. It is thought that these radicals produce leads to the parasite death. On the other hand, tafenoquine inhibits heme polymerase in blood stage of parasites which explains the activity against blood stages of parasites.

The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. This activation step produces the metabolite 5,6 ortho quinone tafenoquine. This metabolite is internalized by the parasite and reduced to radicals by ferredoxin-NADP+ reductase and diflavin reductase enzymes. In the human, tafenoquine is metabolized by several metabolic pathways including O-demethylation, N-dealkylation, N-oxidation and oxidative deamination as well as C-hydroxylation of the 8-aminoalkylamino side chain.