The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis
James A Watson, Robert J Commons, Joel Tarning, Julie A Simpson, Alejandro Llanos Cuentas, Marcus V G Lacerda, Justin A Green, Gavin C K W Koh, Cindy S Chu, François H Nosten, Richard N Price, Nicholas P J Day, Nicholas J White, James A Watson, Robert J Commons, Joel Tarning, Julie A Simpson, Alejandro Llanos Cuentas, Marcus V G Lacerda, Justin A Green, Gavin C K W Koh, Cindy S Chu, François H Nosten, Richard N Price, Nicholas P J Day, Nicholas J White
Abstract
Tafenoquine is a newly licensed antimalarial drug for the radical cure of Plasmodium vivax malaria. The mechanism of action and optimal dosing are uncertain. We pooled individual data from 1102 patients and 72 healthy volunteers studied in the pre-registration trials. We show that tafenoquine dose is the primary determinant of efficacy. Under an Emax model, we estimate the currently recommended 300 mg dose in a 60 kg adult (5 mg/kg) results in 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5 mg/kg (i.e. 450 mg) would result in 90% reduction in the risk of P. vivax recurrence. After adjustment for dose, the tafenoquine terminal elimination half-life, and day 7 methaemoglobin concentration, but not the parent compound exposure, were also associated with recurrence. These results suggest that the production of oxidative metabolites is central to tafenoquine's hypnozoiticidal efficacy. Clinical trials of higher tafenoquine doses are needed to characterise their efficacy, safety and tolerability.
Keywords: Plasmodium vivax; epidemiology; global health; haemolysis; infectious disease; microbiology; radical cure; tafenoquine.
Conflict of interest statement
JW, JS, AL, ML, CC, FN, RP, ND, NW No competing interests declared, RC has received an Emerging Leader Investigator Grant (1194702) from the Australian National Health & Medical Research Council. The author has no other competing interests to declare, JT Joel Tarning has participated on the Novartis Malaria Advisory Council (payments made to their institution) and acts as an ASCPT Infectious Diseases steering committee member. The author has no other competing interests to declare, JG, GK was formerly an employee of GlaxoSmithKline who funded the pre-registration studies of tafenoquine. The author holds stock in GlaxoSmithKline. The author has no other competing interests to declare
© 2022, Watson, Commons et al.
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