Randomized, Double-Blind Study of the Safety, Tolerability, and Efficacy of Tafenoquine versus Mefloquine for Malaria Prophylaxis in Nonimmune Subjects

Abstract

This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to be a highly efficacious drug for malaria prophylaxis.

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

“…The 8-aminoquinoline molecule tafenoquine, currently under late-stage clinical development, has a significantly longer elimination half-life than primaquine (12)(13)(14)(15)(16) and has single-dose radical curative activity in humans (3). Tafenoquine is also being developed as a chemoprophylactic agent and has demonstrated efficacy against Plasmodium vivax and Plasmodium falciparum (17)(18)(19)(20)(21). Despite the pharmacological advantages of tafenoquine over primaquine, both molecules seem to have the same pharmacogenomic liability of CYP 2D6-mediated activation for liver-stage antimalarial activity (7,10,22,23) and are not free of hemolytic liability in G6PD deficiency (24).…”

Malaria Chemoprophylaxis for the International Traveler, Current Options and Future Possibilities

“…In a subset of subjects (n=74) in the East Timor study who received tafenoquine, detailed safety assessments were conducted which detected vortex keratopathy. This finding had no effect on visual acuity and was fully resolved within one year following cessation of therapy (Nasveld et al, 2010). More extensive clinical ophthalmic evaluation of tafenoquine in a subsequent phase 1 safety trial further supports the vortex keratopathy seen with tafenoquine is not clinically significant (Leary et al, 2009).…”

“…Although treatment-emergent adverse events were similar between the two groups and tafenoquine was well-tolerated during the study, there were no cases of malaria in any group. Exposure to malaria could not be assessed and therefore efficacy was not established (Nasveld et al, 2010). In a subset of subjects (n=74) in the East Timor study who received tafenoquine, detailed safety assessments were conducted which detected vortex keratopathy.…”

Malaria prevention in travelling children

“…It appears to be safe and well tolerated, with few adverse effects. 19 Tafenoquine has been used as a prophylactic agent in adults, but has yet to be tested in children.…”