Tafenoquine Therapy and Genotype

Tafenoquine is an antimalarial agent that was approved by the FDA in 2018 for (1) preventing malaria (brand name Arakoda, 100 mg tablets), and for (2) the radical cure of malaria (brand name Krintafel, 150 mg tablets) caused by Plasmodium vivax (P. vivax) (1, 2). Malaria is caused by the Plasmodium parasite, which infects mosquitos and is spread to humans when an infected mosquito bites a person. In 2018 the World Health Organization (WHO) estimated 228 million cases of malaria occurred worldwide (3). There are several clinical patterns of malaria that are caused by different species of the parasite. In P. vivax malaria, the parasite can lie dormant in the liver as hypnozoites, until it emerges weeks or months later, to cause a relapse of malaria. In combination with an antimalarial active against the blood stage parasites, tafenoquine provides a radical cure of P. vivax by targeting its dormant liver stage, thus preventing malaria relapse. Tafenoquine is the second drug of its kind (with hypnozoiticidal activity) to be approved by the FDA. The first was primaquine, approved in 1952. Because of its longer half-life, tafenoquine can be dosed less frequently than primaquine, which may improve compliance. For example, when used for the radical cure of P. vivax malaria, tafenoquine is taken as a single 300 mg dose (in uncomplicated cases, in persons aged 16 years and older). In contrast, primaquine radical cure is recommended to be given daily over 14 days (4), or higher doses over 7 days (5). Tafenoquine, like primaquine, should not be used in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In the case of tafenoquine, an individual with <70% of normal G6PD activity is considered deficient and should not take the drug (6).Worldwide, approximately 400 million people have a deficiency of the G6PD enzyme, but most are asymptomatic and do not know they are at risk (7). A lack of G6PD in red blood cells makes the cells susceptible to damage by oxidative stress. Usually, only low levels of oxidative stress occur naturally, and so the condition is undetected. However, certain drugs, which include tafenoquine and primaquine, are oxidizing agents. In people with G6PD deficiency, these drugs cause irreparable oxidative damage to the red blood cells, which are then rapidly destroyed (hemolysis). This can lead to a potentially life-threatening deficiency of mature red blood cells (hemolytic anemia). The FDA-approved drug label for tafenoquine states that testing for G6PD must be performed before starting tafenoquine therapy, and that all individuals should be monitored for signs of hemolysis (Table 1). In addition, because of the risk of tafenoquine causing fetal harm in a woman pregnant with a fetus with G6PD deficiency, pregnancy testing is highly recommended in women of reproductive age. Consequently, tafenoquine therapy is contraindicated in adults when the G6PD status is either unknown, intermediate or deficient, namely, enzyme activity lower than 70%, in pregnancy, and in breastfeeding mothers when the infant’s G6PD status is either unknown or deficient (1). To date, no safety studies have been reported in children.