Abstract
BackgroundLow-dose primaquine is a key candidate for use in malaria transmission reduction and elimination campaigns such as mass drug administration (MDA). Uncertainty about the therapeutic dose range (TDR) required for general and paediatric populations challenge the implementation of the World Health Organisation’s recommendation to add 0.25 mg/kg to current standard antimalarial treatment in such settings. Modelling work shows that for low-dose primaquine to have an impact, high efficacy and extensive population coverage are needed. In practice, age-based dose regimens, often used in MDA, could lead to safety concerns and a different effectiveness profile. We aimed to define TDRs for primaquine and to assess dosing accuracy of age-based dose regimens.MethodsOptimised regional age-based dosing regimens for low-dose primaquine were developed in steps. First, we identified potential TDR options based on suggested published efficacy and safety thresholds (i.e. 0.1–0.4, 0.125–0.375, 0.15–0.35 mg/kg). We then used our previously defined weight-for-age growth references and age-based dose optimisation tool to model predicted regimen accuracies for Africa, Asia and Latin America based on low-dose primaquine tablets (3.75 mg and 7.5 mg) currently under development by Sanofi while employing the identified dose range options and pre-specified regimen characteristics.ResultsDose regimens employing TDRs of 0.1–0.4 and 0.125–0.375 mg/kg had the highest average predicted dose accuracies in all regions with the widest dose range of 0.1–0.4 mg/kg resulting in ≥99% dose accuracy in all three regions. The narrower 0.15–0.35 mg/kg range was on average predicted to correctly dose 91.4% of the population in Africa, 93.2% in Asia and 92.6% in Latin America. This range would prescribe ≥20% of 3-year-olds doses below 0.15 mg/kg and ≥20% of 11-year-olds doses above 0.35 mg/kg. Widening the TDR from 0.15–0.35 to 0.1–0.4 mg/kg increased the dose accuracy by ≥20% in Africa, ≥15% in Asia and ≥10% in Latin America.ConclusionOptimised age-based dose regimens derived from wider TDRs are predicted to attain the dose accuracies required for effective MDA in malaria transmission reduction and elimination settings. We highlight the need for a clearly defined TDR and for safety and efficacy trials to focus on doses compatible with age-based dosing often employed in such settings.
Highlights
Low-dose primaquine is a key candidate for use in malaria transmission reduction and elimination campaigns such as mass drug administration (MDA)
Average dosing accuracies for the regional optimised regimens using a dose range of 0.15–0.35 mg/kg were: 91.4% for Africa, 93.2% for Asia and 92.6% for Latin America
In conclusion, our findings highlight the potential impact on the expected dose accuracy with shift in the agreed therapeutic dose range (TDR) and the need for clearly established minimum width of the TDR through safety and efficacy studies
Summary
Low-dose primaquine is a key candidate for use in malaria transmission reduction and elimination campaigns such as mass drug administration (MDA). Overdosing predisposes individuals to toxicity and adverse events that may outweigh the individual benefits of taking the drug This has the potential to have a significant impact on the success or failure of malaria control and elimination programs. Population-based antimalarial mass treatment campaigns often dose individuals by their age rather than weight to avoid the need for weighing scales. While this practice can pose a serious threat to the targeted impact of mass treatment campaigns, the optimization and evaluation of the performance of age-based dose regimens has so far received relatively little attention. One of few studies that have looked at age-based dose regimen of other antimalarials in Africa, reported a high prevalence of systematic dosing errors (only 23.5% received the target dose of SP in children less than five years old) [1]
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