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 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. 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 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. 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.

Putative Contribution of 8-Aminoquinolines to Preventing Recrudescence of Malaria

“…In vivo, TQ is by far superior to PQ as regards its inhibitory effect on asexual parasitaemia in various kinds of rodent malaria [ 72 ], while findings in P. vivax -infected Aotus monkeys revealed that TQ might be useful for treating chloroquine-resistant P. vivax malaria [ 73 ]. These diverse experimental situations aside, Barber et al [ 15 ] have demonstrated that TQ has potent antimalarial activity in human volunteers infected with the 3D7 strain of P. falciparum , but efficacy is dose-dependent.…”

“…This is the type of human malaria [ 6 ] that is the most widespread globally [ 7 ], and approximately 2.5 billion people are potentially at risk of contracting the disease. Unsurprisingly, a higher total dose of PQ [ 8 , 9 , 10 , 11 , 12 ], or a larger single dose of TQ [ 13 , 14 , 15 ], is more therapeutic than a lower dose, but how these drugs work in preventing recurrent P. vivax malaria is far from clear. The question of what effective 8-AQ dosages are safe to use is still being researched [ 14 , 16 , 17 , 18 , 19 ], as is how to distinguish between P. vivax malarial reinfections, recrudescences and relapses [ 20 ].…”

Longitudinal changes in iron homeostasis in human experimental and clinical malaria

“…Data were retrieved from the records of 55 participants enrolled in 7 induced blood stage malaria (IBSM) VIS conducted in Brisbane, Australia, between 2015 and 2021. [22][23][24][25][26] Study participants were malaria-naïve adults aged 18-55 years with no significant medical comorbidities or concurrent illness. Participants were inoculated with erythrocytes parasitized with either the P. falciparum 3D7 strain (n=45), or the artemisinin-resistant P. falciparum K13 strain (n=10).…”

“…A total of 55 participants were enrolled in the malaria VIS. The median age of participants was 26 years (IQR [22][23][24][25][26][27][28][29][30][31][32][33][34][35], and 19 (35%) were female (Table 1). Compared to males, at baseline females had lower ferritin (median 46 [IQR vs 101 [IQR 56-171] ng/mL, p=0.001), lower baseline sTfR (median 1.39 (IQR 1.12 -1.90) vs 2.01 (IQR 1.65 -2.43) 𝜇𝜇g/mL, p=0.002), and higher mean corpuscular volume (MCV; median 89 (IQR 85 -92) vs 86 (IQR 84 -88) 𝜇𝜇m 3 , p=0.011).…”

Characterizing the blood stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected withPlasmodium falciparum

“…Volunteer infection studies (VIS) using the induced blood stage malaria (IBSM) model have previously successfully characterized the PK/PD relationship of several experimental antimalarial compounds as well as antimalarial drugs currently in use [10][11][12][13]. The IBSM model involves intravenous inoculation of healthy malaria naïve adult participants with blood-stage parasites and subsequent administration of the test antimalarial.…”