Characterizing the blood stage antimalarial activity of tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum

BackgroundThe long acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. MethodsHealthy G6PD-normal adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia, and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48{+/-}2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. ResultsTwelve participants were inoculated and administered 200 mg (n=3), 300 mg (n=4), 400 mg (n=2), or 600 mg (n=3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 h and 4.2 h respectively) was faster than with 200 mg or 300 mg (11.8 h and 9.6 h respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants), but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60 kg adult. ConclusionsAlthough a single dose or tafenoquine exhibits potent P. falciparum blood stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Main pointA single oral dose of tafenoquine is effective against blood stage Plasmodium falciparum infection. However, as the estimated dose to clear asexual parasitaemia is [≥]460 mg (in adults), prior screening for glucose 6-phosphate dehydrogenase deficiency will be required.