Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum

Abstract

Background: The 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.

Methods: Healthy adults with normal levels of G6PD 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.

Results: Twelve 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 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, 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.

Conclusions: Although a single dose of 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. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).

Keywords: Plasmodium falciparum; antimalarial; blood stage; tafenoquine.

Figure 1.

Trial profile. Eligible participants were enrolled in 1 of 3 cohorts. All participants in cohort 1 were allocated the same dose of tafenoquine (300 mg). Participants in cohorts 2 and 3 were randomized within each cohort to a dose group on the day of dosing with tafenoquine (8 days following challenge with blood-stage P. falciparum). All participants completed the study and were included in the analysis of study endpoints.

Figure 2.

Individual participant parasitemia-time profiles. Participants were inoculated intravenously with Plasmodium falciparum–infected erythrocytes on day 0 and were administered a single oral dose of 200 mg (A), 300 mg (B), 400 mg (C), or 600 mg (D) TQ on day 8 (indicated by the vertical dashed line). Definitive antimalarial treatment with a standard course of A/L was initiated in response to parasite regrowth or on day 48 ± 2 (indicated by the vertical dashed line). Parasitemia was measured using qPCR targeting the gene encoding P. falciparum 18S rRNA. The horizontal dotted line indicates the lower limit of quantitation of the assay (32 parasites/mL) [22]. Abbreviations: A/L, artemether-lumefantrine; qPCR, quantitative polymerase chain reaction; TQ, tafenoquine.