Comparing malaria transmission blocking efficacy of Primaquine and Tafenoquine with in vivo pre-clinical models

Abstract

Background: The 8-aminoquinoline primaquine is used as a single low dose with antimalarial treatment to reduce malaria transmission. An alternative 8-aminoquinoline, tafenoquine has a substantially longer half-life and may therefore provide more sustained transmission-blocking activity, but direct comparisons with primaquine are limited. We compare the transmission-blocking activity and pharmacokinetics of these drugs in vivo. Methods: We assess primaquine dose response in Plasmodium berghei-infected mice and compare an equimolar dose of tafenoquine in a mouse-to-mosquito-to-mouse transmission model. We also assess both drugs against Plasmodium falciparum gametocytes in humanised immunodeficient mice using bioluminescence and microscopy, and measure plasma drug concentrations. Dose- response relationships are modelled using generalized linear and nonlinear regression, with appropriate statistical tests for transmission and parasite endpoints. Results: Here we show that primaquine produces stronger early transmission-blocking activity, reducing mosquito infection more effectively than tafenoquine 24 hours after treatment. In contrast, tafenoquine retains greater activity at later time points, coinciding with prolonged systemic exposure. Similar temporal differences are observed when the drugs are combined with the schizonticide sulphadiazine. In humanized mice, both drugs reduce gametocyte abundance in a 2 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 dose-dependent manner, while tafenoquine shows sustained exposure for several days compared with the more rapid decline of parent primaquine. Conclusions: Primaquine and tafenoquine have distinct temporal transmission-blocking profiles in vivo. Sustained activity of tafenoquine is consistent with prolonged exposure rather than greater intrinsic potency. These findings are observed across multiple models, both in the absence or presence of a partner schizonticide and thus demonstrate a potential advantage of the utilisation of tafenoquine when compared to primaquine.