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Study to Evaluate Plasmodium vivax malaria pharmacometric Responses in blood and liver staGes to Eight AminoquinoliNe Treatments (SARGEANT)

Study to Evaluate Plasmodium vivax malaria pharmacometric Responses in blood and liver staGes to Eight AminoquinoliNe Treatments (SARGEANT)

Nicholas J White

Mahidol Oxford Tropical Medicine Research Unit

23 May 2022

Malaria is a mosquito-borne infectious disease that affects humans and other animals, with approximately 250 million cases diagnosed each year. Plasmodium vivax malaria one of the five human malaria parasites, found predominantly in South America, the Horn of Africa and across Asia. Vivax malaria is characterised by relapsing infections, which caused by dormant parasites (hypnozoites) in the liver. Relapsing vivax malaria is a major cause of illness and morbidity in endemic areas.Radical cure treatment is the combination of drugs that kill the asexual stages in the red blood cells (causing the illness) and the dormant liver stages, thus curing the current infection and preventing future relapsing infections. The main available drug that kills liver stage parasites is primaquine; however primaquine needs to be taken for 1-2 weeks resulting in poor adherence. In addition primaquine can causes the destruction of red blood cells in individuals with genetic polymorphisms causing glucose-6-phosphate dehydrogenase (G6PD) deficiency. Tafenoquine is a new antimalarial drug, recently approved, which solves the problem of adherence as it is taken as a single dose. However it is also contra-indicated in G6PD deficiency for the same reasons as primaquine.Single dose radical cure treatment using tafenoquine in combination with other antimalarials has the potential to accelerate the elimination of vivax malaria. However, the relationships between tafenoquine dose and its effect on the malaria parasites in the body has not been well characterised. This hinders determining the optimal dose. Both primaquine and tafenoquine are pro-drugs: their antimalarial activity against liver stage parasites relies on the conversion to bioactive oxidant metabolites. It is not currently possible to measure in vivo the concentration of these metabolites and thus assess pharmacokinetic-pharmacodynamic relationships. However, we have recently shown that in a cohort of over 600 patients with vivax malaria treated with primaquine on the Thailand-Myanmar border, methaemoglobin levels (produced as a consequence of the formation of oxidant metabolites) were predictive of recurrent illness. This suggests that methemoglobinemia could be used as a proxy for drug efficacy. Tafenoquine also results in increased methemoglobin levels and we want to test whether methemoglobin levels also predict outcomes in the tafenoquine clinical trials. In addition, in order to better distinguish relapsing infections from re-infections (due to new mosquito bites), we plan to use parasite genetic data. In previous work we showed how parasite genetic data in combination with the time-to-recurrence data, could be used to probabilistically determine whether a recurrence isrelapse in vivax malaria.The project will consist of fitting multiple structural statistical models that will incorporate (i) tafenoquine blood concentration data (plasma or whole blood drug measurements), (ii) serial methaemoglobin levels as a proxy measure of the drug exposure, (iii) parasite genotyping data (where available), and (iv) time-to-recurrence data in patients with observed recurrent vivax infections. The models will be fit sequentially in order to infer the concentration-effect relationships for both blood stage and liver stage activities of tafenoquine. The final model will be used to simulate clinical data to characterise optimal dosing in different epidemiological scenarios.

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Statistical Analysis Plan

Watson JA, Commons RJ, Tarning J, Simpson JA, Llanos Cuentas A, Lacerda MVG, Green JA, Koh GCKW, Chu CS, Nosten FH, Price RN, Day NPJ, White NJ. The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis. Elife. 2022 Dec 6;11:e83433.
DOI: 10.7554/eLife.83433