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

Duffey, M.; Zakutansky, S. E.; Gumpp, C.; Delves, M. J.; Sala, K. A.; Sherrard-Smith, E.; Baum, J.; Leroy, D. J.; Rottmann, M.; Blagborough, A. M.

doi:10.64898/2026.03.03.709295

bioRxiv · 10.64898/2026.03.03.709295

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

Duffey, M.·Zakutansky, S. E.·Gumpp, C.·Delves, M. J.·Sala, K. A.·Sherrard-Smith, E.·Baum, J.·Leroy, D. J.·Rottmann, M.·Blagborough, A. M.

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Abstract

The 8-aminoquinoline family are a well-established class of antimalarial drugs containing two clinically relevant analogues, primaquine and tafenoquine. These compounds have two therapeutically significant activities across the plasmodial lifecycle; elimination of Plasmodium vivax hypnozoites as part of a radical cure (relapse prevention), and as prophylactic transmission blocking compounds. Primaquine is currently recommended as a single low (0.25 mg/kg) dose administered with artemisinin-based combination therapy to reduce malarial transmission in areas at high risk of artemisinin partial resistance. Tafenoquine was approved in 2018 for radical cure when co-administered with chloroquine however, its transmission blocking efficacy in humans has not yet been fully evaluated, and direct head-to-head comparisons of transmission-blocking efficacy of primaquine and tafenoquine have not been performed. Given that primaquine and tafenoquine are presumed to have similar mechanisms of action, tafenoquine may have potential use as a transmission blocking intervention. Furthermore, tafenoquine has a substantially longer half-life than primaquine, which could provide a pharmacokinetic advantage if such efficacy is confirmed. However, assessment of 8-aminoquinoline efficacy against the sexual stages of Plasmodium is complicated by the requirement for metabolic activation to generate parasite-reactive species, limiting the utility of in vitro assays. Here, we directly compare the transmission blocking effects of primaquine and tafenoquine using two in vivo preclinical models. We titrate the transmission blocking efficacy of each compound, and evaluate the pharmacokinetics of each compound over time, linking drug exposure to efficacy. The evidence presented here suggests that beyond 24 hours, a single dose of tafenoquine is likely to have more clinically desirable pharmacokinetics, resulting in higher transmission blocking efficacy than primaquine. 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.

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Duffey, M., Zakutansky, S. E., Gumpp, C., Delves, M. J., Sala, K. A., Sherrard-Smith, E., Baum, J., Leroy, D. J., Rottmann, M., Blagborough, A. M.. 2026-03-03. Comparing the transmission blocking efficacy of Primaquine and Tafenoquine with in vivo pre-clinical models. https://doi.org/10.64898/2026.03.03.709295

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