New anti-malarial drug requires higher doses to treat infection
Introducing a drug that is too small to be effective for all patients who need it, according to a report published today in the journal eLife.
The new study found that treatment with 300 mg of tafenoquine per day might prevent relapses by 70% in up to 90% of patients. But upping that dose to 450 mg per day would mean that 84% of patients would be cured. Those who had the drug approved are at risk of contracting more malaria each year, so it is likely that people who take the drug at the higher dose will be cured more often than previously thought.
It is thought that tafenoquine, which is a new anti-malaria drug that has been used for 70 years, is more effective than current treatments.
It is normally prescribed that patients be treated with a single dose of tafenoquine for at least 10 years, which is useful because it avoids the need for multiple drugs. This is because different people have different body weights, which results in different doses of the drug being given. "The tafenoquine studies suggested that this single 300 mg dose was inferior to primaquine doses which are lower than those recommended by the WHO in Southeast Asia. This study has found that the dose of tafenoquine that is currently being prescribed for adults is not as effective as optimal primaquine treatment in reducing the likelihood that vivax malaria relapses in all endemic regions.
To better study tafenoquine's effectiveness and to determine if it is effective for all patients. In order to do that, they pooled data from individuals who participated in the clinical trials that led to its approval, and from healthy volunteers who took part in a previous pharmacokinetic study. They used computer modelling to find out how weight changes affected the risk of a relapse of malaria.
The researchers found an improvement in survival rates for patients who took any dose of tafenoquine that was up to 10 mg/kg in weight (based on the current dose) for a period of four months. By taking 4 mg/kg of tafenoquine in addition to the recommended dose, people who had previously failed malaria treatment were significantly reduced. This relationship between tafenoquine dosage and relapse rates was observed in people from Asia, Africa and the Americas.
They used data from the three efficacy trials to predict the effects of tafenoquine at doses of either 300 mg or 450 mg. A fixed tafenoquine dose of 300 mg would result in around 15% of the patients having a recurrence, whereas a dose of 450mg would reduce this proportion to 6%. Given that approximately half the patients given no anti-relapse treatment had a recurrence, this suggests that the lower 300 mg dose prevents 70% of recurrences whereas the 450 mg dose prevents 85% of recurrences.
To understand the mechanisms by which tafenoquine works, the team pooled the results of nearly 4,500 drug measurements taken from 718 people in the 3 efficacy trials to produce a pharmacokinetic model that looked at how drugs behave. They measured levels of methaemoglobin, a marker of how much oxygen is present in the blood. These two analyses revealed the drug's metabolism, reflected by its rate of elimination from the body, rather than exposure to the parent compound, determined its activity in preventing vivax malaria recurrences, and it suggests that the conversion of tafenoquine into oxidative metabolites was responsible for its antimalarial activity, just as for primaquine.