Malaria study: New antimalarial drug, tafenoquine, requires higher doses to achieve cure reliably

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A new antimalarial drug has been offered at a dose that is too low to be effective for all patients who need it, according to a report published in the journal eLife.

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The study reports that the current dose of 300 mg of tafenocaine for adults reduces recurrent active malaria by 70%, while increasing it to 450 mg would reduce recurrent infection by 85%. This means that for every 11 people treated with the higher dose, an additional person will be treated.

Tafenocaine is the first newly approved anti-relapse drug in 70 years, and its main advantage is that it can be taken as a single dose, unlike primaquine (the current treatment) which must be taken daily for 7-14 days.

The same single dose of tafenoquin is recommended for all adults and this has important practical advantages. However, due to the difference in body weight, this dose leads to a large variance in exposure to the drugs,” explains lead author James Watson, MD, researcher at Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. Studies of tafenoquine have suggested that these The single dose of 300 mg was inferior to the lower WHO-recommended doses of primaquine in Southeast Asia.In general, it appears that the currently recommended adult dose of tafenocaine is not as good as the optimal treatment of primaquine in preventing relapses of active malaria in all contaminated areas.”

To understand more about tafenoquine’s mechanism of action and optimal dosing, the team conducted a meta-analysis in which they combined data from individual malaria patients who participated in the three clinical trials that led to the drug’s approval, and healthy volunteers who participated in an earlier trial. Pharmacokinetic study. They then used statistical models to characterize the relationship between the weight-adjusted dose of tafenoquine or primaquine and the likelihood of malaria recurrence.

They found that each additional mg/kg of tafenoquin significantly reduced the chance of developing recurrent active malaria infections within four months. For example, increasing the dose from 3 mg/kg to 4 mg/kg reduces the proportion of patients with recurrent infections from 30% to 20%. This association between tafenoquine dose and relapse rate has been observed in patients from Asia, Africa, and the Americas.

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They then used patients’ weight data from the three efficacy trials to calculate the average potential efficacy of tafenoquine at either the 300 mg or 450 mg dose. A fixed tafenoquin dose of 300 mg will cause a recurrence in about 15% of patients, while a 450 mg dose will reduce this to 6%. Given that approximately half of the patients who did not receive anti-relapse treatment experienced a recurrence, this indicates that the lower 300 mg dose prevents 70% of recurrences while the 450 mg dose prevents 85% of recurrences.

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To study tafenoquine’s mechanism of action, the team combined pharmacokinetic data from healthy volunteers in the initial study with patients from efficacy trials — nearly 4,500 pharmacokinetic measurements from 718 individuals. They also measured methemoglobin levels, which is a measure of oxidative activity in the body. These two analyzes revealed the metabolism of the drug, reflected by its rate of removal from the body, rather than exposure to the parent compound, which determined its activity in preventing recurrence of active malaria, and suggested that conversion of tafenocaine to oxidized metabolites was responsible for its effect. Antimalarial activity, like primaquine.

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“Our analysis provides strong evidence that the currently recommended adult dose of tafenoquine is insufficient for radical therapy in all adults,” concludes senior author Nicholas White, MD, Professor of Tropical Medicine at the College of Tropical Medicine, Mahidol University, Thailand and Center for Tropical Medicine and Health. Global, University of Oxford. “In endemic areas, it relapses Plasmodium active Malaria causes significant morbidity and contributes to mortality, especially in young children. Tafenocaine can prevent relapses of malaria with a single therapeutic dose and, therefore, is potentially a major advance in antimalarial therapies. Getting the correct dose is crucial. The efficacy, tolerability, and safety of increased doses should now be evaluated in future studies.”

The malaria vaccine, Mosquirix, has been granted pre-qualification by the World Health Organization



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